Startseite Naturwissenschaften Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment
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Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment

  • Kirti Sharma , Atul Sharma , Mohit Sanduja , Vikas Jogpal , Asim Kumar Mishra EMAIL logo , Girish Kumar , Tarun Virmani EMAIL logo , Omar M. Noman und Abdulsalam Alhalmi
Veröffentlicht/Copyright: 2. Oktober 2024
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Open Chemistry
Aus der Zeitschrift Open Chemistry Band 22 Heft 1

Abstract

The rising instances of drug resistance in Mycobacterium tuberculosis strains pose a significant global health challenge. Conventional tuberculosis (TB) treatments, which typically involve multiple antibiotics, face hurdles like drug resistance, reduced effectiveness, and heightened toxicity. Consequently, there is a pressing need for innovative anti-TB agents with new modes of action. Decaprenyl-phosphoryl-β-d-ribose 2′-epimerase 1(DprE1), a crucial enzyme in Mycobacterium tuberculosis, plays a vital role in cell wall biosynthesis – a critical aspect for the bacterium’s survival. Building on the success of diarylquinolines like bedaquiline, targeting DprE1 presents a promising avenue for developing anti-TB drugs, especially against drug-resistant strains. Our research focused on discovering novel DprE1 inhibitors using a ligand-based drug design strategy, starting with the established non-covalent inhibitor Ty38c. We assembled a library of 16 molecules, modifying them based on factors like drug-like properties, chemical accessibility, and synthetic feasibility. Molecular docking analyses of this library identified three molecules with binding affinities comparable to Ty38c. Among these, KS_QD_05 and KS_QD_04 are promising candidates, which were further validated through molecular dynamics simulation studies where root-mean-square deviation (RMSD) values of all three complexes reached a plateau, measuring around 0.3 nm, indicating that the apoprotein and all complexes stabilized during the simulation. The ligands KS_QD_04 and KS_QD_05 displayed significantly stable deviation. KS_QD_05 reached about 0.1 nm equilibrium value. However, the ligand KS_QD_04 reached an RMSD value of 0.17 nm and showed distress at 70 nm. KS_QD_04 and KS_QD_05 showed an average value of 1-3 H-bond interaction and regarding the RMSF values, both the compounds showed fluctuations less than 0.5 nm in the case of Mtb. DprE1 enzyme. This indicates the potential of both compounds to become lead compounds in the pursuit of DprE1 inhibitors for TB treatment.

Keywords: DprE1; Ty38c; root mean square deviation; root mean square fluctuation; quinoxalines; hydrophobic interactions

1 Introduction

Tuberculosis (TB), a highly infectious disease caused by Mycobacterium tuberculosis, primarily affects the lungs but can also target other body parts. Despite being one of the oldest known human diseases, TB remains a significant global health issue, especially in developing countries [1]. According to the World Tuberculosis Report 2022, there were approximately 10.6 million TB cases globally in 2021, a 4.5% increase from the previous year. Tragically, 1.6 million people succumbed to this disease during the same period [2]. TB spreads through the air when an infected person coughs or sneezes, making it highly contagious. The bacteria can remain dormant in the body for years, known as latent TB, and can become active if the immune system weakens.

The standard TB treatment involves a combination of antibiotics over an extended period to ensure complete eradication of the bacteria. However, the emergence of drug-resistant strains, such as multidrug-resistant TB and extensively drug-resistant TB (XDR-TB), poses a significant challenge to global TB control efforts [3]. This situation underscores the urgent need for novel antitubercular agents with new mechanisms of action.

One promising target in TB drug research is decaprenyl-phosphoryl-β-d-ribose 2′-epimerase 1 (DprE1), an enzyme involved in the biosynthesis of the Mycobacterium TB cell wall. Inhibiting DprE1 disrupts cell wall formation, weakening the bacterium and making it more susceptible to the immune system and other drugs [4]. Identifying and developing DprE1 inhibitors have shown considerable promise in antitubercular activity [5].

Our study aimed to design novel DprE1 inhibitors through a ligand-based drug design approach or in silico approach [6], leveraging the well-established non-covalent inhibitor Ty38c as a starting point. We curated a library of 16 molecules with chemical modifications guided by drug-like properties, chemical accessibility, and synthetic feasibility. Molecular docking analyses identified three molecules with notable binding affinities similar to Ty38c. Among these, KS_QD_05 and KS_QD_04 emerged as promising candidates, validated through molecular dynamics (MD) simulation studies [7,8], which also provides a potential platform for evaluating the natural products [9,10] reinforcing their potential as lead compounds in developing DprE1 inhibitors for TB treatment.

This research holds the potential to contribute significantly to the development of new drugs with improved efficacy and safety profiles, enhancing the arsenal against TB and potentially overcoming drug-resistant strains.

Quinoxalines are fused ring systems of pyrazine and benzopyrazine moieties (Figure 1) with the molecular formula C8H6N2 [11]. It is a low-melting solid, with a melting point ranging from 29 to 30°C and possesses the ability to dissolve in water and is classified as a weak base, as indicated by its pK a value of 0.56 [12]. Quinoxalines are N-heterocyclic compounds that have garnered significant attention in the scientific community due to the distinctive arrangement of the two nitrogen atoms within one of its rings. This structural feature is commonly found in numerous naturally occurring and synthetic compounds, making it a focal point of extensive research efforts [13]. Moreover, the ease of synthesizing quinoxaline derivatives has been a key factor in their broad applications as potential medicinal agents.

Figure 1 Basic skeleton of quinoxaline.
Figure 1

Basic skeleton of quinoxaline.

Over time, researchers have developed a unique assortment of novel quinoxaline frameworks through the synthesis and evaluation of derivatives featuring various substitutions. These derivatives serve diverse biological functions. By virtue of its distinct electrostatic potential, the quinoxaline molecule exhibits specific hydrophobic and hydrophilic interactions with other molecules, thereby influencing the physicochemical properties observed within the quinoxaline system. Extensive research has been conducted over the past 20 years on the synthesis of quinoxaline, resulting in a comprehensive understanding of these chemical synthetic pathways [11]. A simple yet effective technique for producing quinoxaline is through the condensation reaction of ortho-phenylenediamine with dicarbonyl compounds, which gives a significant yield. To carry out this method effectively, it is imperative to employ a high temperature, a robust acid catalyst, and extensive heating durations [14]. Recently, there has been a remarkable increase in the application of green methodologies for the synthesis of quinoxalines, including the use of recyclable catalysts [15], one-pot synthesis techniques [16], microwave-assisted synthesis procedures [17,18], and reactions carried out in aqueous solutions [19]. Nowadays, there is a variety of methods available to synthesize quinoxaline derivatives that involve condensation of 1,2-diamines with a-diketones [20], 1,4-addition of 1,2-diamines to diazenylbutenes [21], cyclizatione oxidation of phenacyl bromides [22], and oxidative coupling of epoxides with ene-1,2-diamines [23].

By making slight modifications to the structure of quinoxalines, different molecules are produced that are found to exert remarkable pharmacological efficacy in combating a range of diseases with minimal occurrence of side effects. In regard to this, in the last two decades, several quinoxaline derivatives have been tested for different biological profiles (Figure 2) [24,25]. The most promising activity exhibited by quinoxaline are anti-cancer [26,27], anti-hyperglycemic as PPAR-γ and sulphonyl urea agonists [28], anti-microbial agents [29], anti-convulsant agents [30], anti-fungal agents [31], anti-tubercular agents [32], anti-malarial [33], anti-leishmanial [34], anti-amoebic, anti-HCV [35], anti-inflammatory [36], and anti-viral [37] agents. Most of the authorized medicines contain quinoxaline, demonstrating the scaffolds’ adaptability.

Figure 2 Drugs having quinoxaline as the lead moiety.
Figure 2

Drugs having quinoxaline as the lead moiety.

In a similar context, the present computational research highlights the potential of substituted 2,3-diaryl quinoxalines and 2-phenyl quinoxalines against DprE1 inhibitors, which can be proven as a potential lead in the discovery of anti-tubercular agents.

2 Materials and methods

2.1 Molecular docking technique

2.1.1 Protein preparation

PDB ID 4P8K was selected based on its interaction with the enzyme DprE1 [38,39], which allowed the three-dimensional (3D) retrieval of the protein DprE1. The protein was prepared using Glide, a software suite from Schrödinger.

The protein was then subjected to a number of preprocessing procedures, such as bond order assignment, hydrogen removal, and addition, zero-order bond formation to metals, disulphide bond formation, conversion of seleno-methionines to methionines, side chain and loop aided by primers, extraction of water molecules larger than 5 Å from hetero groups, and creation of a HET state with the aid of Epik at pH 7.0 ± 2.0. After that, the protein was refined using PROPKA at pH 7.0, sampling water orientations to assign H-bonds, and fine-tuning its structure. The protein was further subjected to restrained minimization utilizing the OPLS3 force field, as described in previous studies.

2.1.2 Receptor grid generation

A 20 Å receptor grid was constructed once the protein was prepared. The co-crystallized ligand Ty38c served as the reference point for this grid, which was centred at the active site.

2.1.3 Ligand preparation

The ligands were prepared using Glide, a software suite from Schrödinger.

All of the molecules were built, transformed into 3D structures, and then Maestro’s Ligprep and Confgen functions were used to minimize energy. Next, maegz formatting was used to hold the created library.

2.1.4 Molecular docking

After that, molecular docking was carried out to evaluate the interactions between proteins and ligands and ascertain their binding affinities. This was done using the Glide programme and the standard precision (SP) method. The solutions to improve the planarity of the conjugated pi group functions and to incorporate Epik state penalties in the docking scores were selected. The co-crystallized ligand was positioned inside the grid during a re-docking technique to confirm molecular docking; the resultant root-mean-square deviation (RMSD) of 0.197 was considered appropriate for validation.

2.2 Molecular dynamic simulation

Using GROMACS 2022.2, an MD simulation was performed. The subsequent procedures were employed.

2.2.1 (a) Preparation of the enzyme

The 3D models of the ligand–protein complexes were exported to the .pdb format using Pymol. Simulations were performed to evaluate the dynamic behaviour of the complexes using the GROMACS package software (version 2022.2) [40,41,42]. pdb2gmx and the CHARMM27 force field were used to build the protein topology. The ligand topology was produced using the SwissParam server [43].

2.2.2 (b) System set-up for the simulation

The force field was applied before the complexes were added to the system. With periodic boundary conditions, they were solvated using the TIP3P water model in a cubic box, which was 1 nm further from the protein border. The Na+ ions were used to neutralize the system, followed by a 50,000-step phase of energy minimization using the steepest descent approach. Next, 100 ps of a constant-temperature and constant-volume (NVT) simulation at 300 K and 100 ps of NPT simulation were used to bring the system to equilibrium. The components, such as proteins, ligands, water molecules, and ions, were linked independently by the constant-temperature, constant-pressure (NPT) ensemble using the leapfrog approach. The Berendsen temperature and pressure coupling constants were set to 1 and 2, respectively, to maintain the system operative in a stable environment (300 K temperature and 1 bar pressure) [44]. Finally, an MD simulation was run at 300 K for 100 ns in an ensemble under isothermal and isobaric conditions. The bond lengths were restricted using the LINCS approach [45], and the pressure coupling with a time constant was set at 1 ps in order to maintain the pressure at 1 bar. The PME approach [46], which was a part of GROMACS, was used to decrease the error originating from the van der Waals and Coulomb interaction termination at 1.2 nm. To gain insight into the binding free energy, we used the Prime MM-GBSA (molecular mechanics-generalized Born surface area), a method provided by Schrödinger for predicting the free energy of binding of ligands to their target proteins. It combines molecular mechanics energies with continuum solvation models to give a detailed picture of molecular interactions. Prime MM-GBSA is a post-processing method used to calculate the binding free energies based on MD or Monte Carlo simulations. It is often employed in drug discovery for ranking ligands based on their predicted binding affinities to target proteins [47].

The binding free energy (ΔG bind) is calculated using the equation

Δ G bind = Δ E MM + Δ G solv + Δ G SA ,

where ΔE MM is the difference in the molecular mechanic's energy between the complex and sum of the energies of the protein and ligand in their unbound states, ΔG solv is the solvation-free energy change upon binding, and ΔG SA is the change in the surface area-related non-polar solvation energy upon binding.

2.2.3 (c) Simulation analysis and visualization

Using VMD, trajectory files were shown (Visual MD 1.9.2.) [48] and examined using the locally created HeroMD Analysis programme [49,50] and Xmgrace 5.1.25 [51].

3 Results and discussion

3.1 Drug design

A commonly employed method in pharmaceutical research involves “ligand-based drug design,” where the objective is to develop new compounds by mimicking the structural and functional features of the established active substances, known as “ligands.” In the pursuit of developing novel substituted 2,3-diaryl-quinoxaline derivatives for inhibiting DprE1, the strategy employed entails initiating the drug discovery process with a well-known ligand, specifically Tyr38c, which is itself a quinoxaline derivative. Tyr38c serves as the foundational compound for the design of these newer substituted derivatives (Figure 3). The improvement of binding affinity, drug-like qualities, chemical availability, and synthesis ease were the main criteria for chemical alterations.

Figure 3 Ligand-based strategy for drug design to design newer substituted 2,3-diaryl-quinoxaline derivatives for inhibiting the DprE1 enzyme.
Figure 3

Ligand-based strategy for drug design to design newer substituted 2,3-diaryl-quinoxaline derivatives for inhibiting the DprE1 enzyme.

3.2 Creating a library of derivatives of 2,3-diaryl-quinoxaline

Based on modifications at different R1 positions at the 2,3-diaryl-quinoxaline and some of the 2-phenyl quinoxaline nucleus based on drug-like properties, availability of chemicals, and their ease of synthesis, a library of 16 molecules was created. The creation of this library of 16 molecules of 2,3-diaryl-quinoxaline derivatives was done carefully based on the principles of medicinal chemistry. The primary objective was to design and synthesize a diverse set of compounds with the potential to inhibit the target enzyme, DprE1, while considering critical factors, such as drug-like properties, chemical availability, and synthetic feasibility. The results are shown in Figure 4.

Figure 4 The library of newly designed inhibitors for DprE1, designed around the structure of 2,3-diaryl-quinoxaline derivatives.
Figure 4

The library of newly designed inhibitors for DprE1, designed around the structure of 2,3-diaryl-quinoxaline derivatives.

3.3 Molecular docking

The evaluation of molecule binding within the active site of the DprE1 enzyme was conducted using SP docking. A library of 16 molecules, selected based on their synthetic feasibility and drug-like properties, was employed for this analysis. The precision of the approach was first demonstrated via successfully docking the coupled crystal ligand, Ty38c, which replicated the binding posture and orientation seen in the crystal structure. The RMSD value for this validation was 0.197. Subsequently, the same docking protocol was applied to the library of 16 molecules against DprE1. Consequently, three substances have demonstrated high interactions with the catalytic residues found in the DprE1 enzyme’s active site. These interactions primarily involved hydrogen bonding and hydrophobic interactions. Among these hits, KS_QD_04 and KS_QD_05 demonstrated notable binding interactions and were selected for further investigation through MD studies with DprE1 (PDB ID: 4P8K) (Figure 5, Table 1).

Figure 5 Studies of docking indicate orientations at which molecules bind (a) KS_QD_05, (b) KS_QD_04, and (c) Ty38c in the active site of the DprE1 enzyme. The ligand molecules are depicted as a bold stick representation, with the carbon atoms in green, while the interacting residues within a 4.0 Å radius are shown using stick and wire representations, with the carbon atoms in grey. Hydrogen-bonding interactions are indicated by blue dotted lines, along with the corresponding distances in Å.
Figure 5

Studies of docking indicate orientations at which molecules bind (a) KS_QD_05, (b) KS_QD_04, and (c) Ty38c in the active site of the DprE1 enzyme. The ligand molecules are depicted as a bold stick representation, with the carbon atoms in green, while the interacting residues within a 4.0 Å radius are shown using stick and wire representations, with the carbon atoms in grey. Hydrogen-bonding interactions are indicated by blue dotted lines, along with the corresponding distances in Å.

Table 1

Studies using molecular docking of different compounds inside the DprE1 active site

S.no Molecules Docking score Model score Interactions
1. KS_QD_05 −7.635 −67.223 H-bond interaction with GLY55 and ASN178
2. KS_QD_04 −7.519 −60.17 H-bond interaction with ARG58 and ASN63; ionic contact with 2X ARG58
3. KS_QD_03 −7.459 −54.699 H-bond interaction with SER228; pi-stacking interaction with LYS134
4. KS_QD_06 −6.914 −53.557 Hydrophobic interaction with TYR314, PRO316, LEU317, LEU363, and VAL365
5. KS_QD_10 −6.613 −47.321 Hydrophobic interaction with PRO316 and LEU317
6. KS_QD_12 −6.57 −48.996 Hydrophobic interaction with TYR314, PRO316, LEU317, and VAL365
7. KS_QD_11 −6.549 −46.818 Hydrophobic interaction with TYR314, PRO316, LEU317, and VAL365
8. KS_QD_01 −6.521 −49.794 Hydrophobic interaction with PHE313, PRO316, LEU317, and VAL365
9. KS_QD_02 −6.467 −60.917 H-bond interaction with SER228; pi-stacking interaction with LYS134
10. KS_QD_07 −6.386 −42.785 Hydrophobic interaction with TYR314, LEU315, PRO316, LEU317, and VAL365
11. KS_QD_09 −6.321 −49.961 Hydrophobic interaction with TYR314, PRO316, LEU317, VAL365, and CYS387
12. KS_QD_08 −6.307 −45.633 Hydrophobic interaction with TYR314, PRO316, LEU317, and VAL365
13. KS_QD_16 −6.24 −47.127 Hydrophobic interaction with PRO316, LEU317, and VAL365
14. KS_QD_14 −5.941 −44.492 Hydrophobic interaction with VAL365, PHE369, and CYS387
15. KS_QD_13 −5.927 −45.758 Hydrophobic interaction with TYR314, PRO316, VAL365, and CYS387
16. KS_QD_15 −5.471 −44.513 Hydrophobic interaction with TYR314, PRO316, and VAL365
17. Ty38c (standard) −8.210 −80.970 H-bond interaction with TYR60 and LYS418

3.4 DprE1 combined with ligands and as an apoprotein using molecular dynamic simulations, KS_QD_04, and KS_QD_05

To comprehend conformational changes and assess the molecular binding of KS_QD_04 and KS_QD_05 against DprE1, we performed 100 ns of MD simulation on the three models, apoprotein, KS_QD_04-Mtb. DprE1, and KS_QD_05-Mtb. DprE1 (Figure 6). Several statistical measures, such as hydrogen bond interactions, their % age occupancy, RMSD, and root-mean-square-fluctuation (RMSF), were used to assess their simulations.

Figure 6 Visual depiction of protein–ligand combinations: (a) KS_QD_04-Mtb. DprE1 and (b) KS_QD_05-Mtb. DprE1, when the ligand is depicted as a translucent surface in a bond representation and the protein is displayed as a cartoon.
Figure 6

Visual depiction of protein–ligand combinations: (a) KS_QD_04-Mtb. DprE1 and (b) KS_QD_05-Mtb. DprE1, when the ligand is depicted as a translucent surface in a bond representation and the protein is displayed as a cartoon.

3.4.1 RMSD analysis

Analysing the protein-RMSD can help understand any structural alterations to the protein that occur throughout the simulation procedure. Figure 7 shows a temporal multiplot of the protein Cα during three simulations. RMSD values of all three complexes reached a plateau, measuring around 0.3 nm, indicating that the apoprotein and all complexes stabilized during the simulation [52].

Figure 7 Visual depiction showing protein Cα RMSD (nm) against time (100 nm) for apoprotein (green in colour), KS_QD_04-Mtb DprE1 (red in colour), and KS_QD_05-Mtb DprE1 (blue in colour) complexes.
Figure 7

Visual depiction showing protein Cα RMSD (nm) against time (100 nm) for apoprotein (green in colour), KS_QD_04-Mtb DprE1 (red in colour), and KS_QD_05-Mtb DprE1 (blue in colour) complexes.

By examining the ligand-RMSD, one can ascertain the stability of the ligand in relation to the protein and binding pocket. The ligand RMSD (nm) against time multiplot for the three simulations is shown in Figure 8. The ligands, KS_QD_04, and KS_QD_05 have displayed significantly stable deviation. KS_QD_05 reached an equilibrium value of about 0.1 nm. However, the ligand KS_QD_04 reached an RMSD value of 0.17 nm and showed distress at 70 nm. The RMSD values of the ligand, as observed in the cases, have indicated that all the ligands were capable of binding their respective proteins. RMSD is used to evaluate the stability of the protein–ligand complexes during the MD simulations. In this study, the RMSD analysis of the Cα atoms of the apoprotein and its complexes with the ligands KS_QD_04 and KS_QD_05 indicates that the structures were stable throughout the simulation period. This stability suggests that the binding of the ligands did not induce significant conformational changes in the protein structure, maintaining the overall structural integrity of the DprE1 enzyme.

Figure 8 An illustration of the graphs displaying RMSD (nm) against time (100 ns) for apoprotein (green colour), KS_QD_04-Mtb DprE1 (red in colour), and KS_QD_05-Mtb DprE1 (blue in colour) complexes.
Figure 8

An illustration of the graphs displaying RMSD (nm) against time (100 ns) for apoprotein (green colour), KS_QD_04-Mtb DprE1 (red in colour), and KS_QD_05-Mtb DprE1 (blue in colour) complexes.

3.4.2 RMSF analysis

Protein-RMSF may be used to characterize the changes at specific locations throughout the protein chain. The multiplot of protein-RMSF (nm) vs the residue number index is shown in Figure 9(a). The plot shows fluctuations less than 0.5 nm in the case of the Mtb. DprE1 enzyme when in an apoprotein form and also in complex with KS_QD_04 and KS_QD_05. It can be concluded that ligand binding brings stability to the conformation of the protein. The RMSF measures the flexibility of individual residues within the protein structure. RMSF analysis reveals the fluctuation values for the Mtb DprE1 enzyme, both in its apoprotein form and in complex with KS_QD_04 and KS_QD_05. This indicates that the binding of these ligands contributes to the stabilization of the protein structure, reducing the flexibility of the residues and thus possibly enhancing the binding efficacy and specificity of the inhibitors.

Figure 9 (a) Plots displaying RMSF (nm) of the protein against its residue index number are graphically shown for apoprotein (green colour), KS_QD_04-Mtb DprE1 (red in colour), and KS_QD_05-Mtb DprE1 (blue colour) complexes. (b) The region of the protein that has the greatest RMSF fluctuation (shown in blue).
Figure 9

(a) Plots displaying RMSF (nm) of the protein against its residue index number are graphically shown for apoprotein (green colour), KS_QD_04-Mtb DprE1 (red in colour), and KS_QD_05-Mtb DprE1 (blue colour) complexes. (b) The region of the protein that has the greatest RMSF fluctuation (shown in blue).

3.4.3 H-bond interaction

Molecular interactions, especially those involving hydrogen bonds, are dependent on both distance and angle, and they can break down in dynamic environments. In this section, we have investigated the ligand–protein interactions for each complex. Figure 10 shows the plot of hydrogen number against time. During the course of simulations, KS_QD_04 and KS_QD_05 showed an average value of 1–3 H-bond interaction. To determine which residues are involved in this type of interaction and their respective stabilities, the percentage of occupancies compared to the residues was also calculated.

Figure 10 Visual depiction of the quantity of H-bond connections: (a) KS_QD_04 (red colour) and (b) KS_QD_05 with Mtb. DprE1.
Figure 10

Visual depiction of the quantity of H-bond connections: (a) KS_QD_04 (red colour) and (b) KS_QD_05 with Mtb. DprE1.

The % occupancies of the H-bond connections formed by the two ligands are displayed as a histogram in Figure 11. Figure 11a illustrates the ability of the ligand KS_QD_04 to establish stable interactions with DprE1 residues THR118 and ASN63, with occupancies of 6.83 and 6.54%, respectively. On the other hand, the ligand KS_QD_05 displayed significant hydrogen-bond interactions with residues ARG58, GLY57, and ASN178, which remained stable for 12.78, 8.55, and 5.39% of the simulation duration, respectively (Figure 11b). In summary, both ligands exhibit the potential to bind to Mtb DprE1, but KS_QD_05 appears to be the most efficient ligand. Hydrogen-bond interactions play a crucial role in the stability and specificity of protein–ligand binding. The occupancy of these hydrogen bonds over the simulation period was also assessed, revealing that the ligand KS_QD_04 formed stable interactions with residues THR118 and ASN63 with occupancies of 6.83 and 6.54%, respectively. On the other hand, KS_QD_05 exhibited more significant hydrogen-bond interactions with residues ARG58, GLY57, and ASN178, with occupancies of 12.78, 8.55, and 5.39%, respectively. These data indicate that KS_QD_05 has a higher potential for stable binding with the DprE1 enzyme, making it a more effective ligand compared to KS_QD_04.

Figure 11 A histogram showing the percentage of H-bond protein–ligand interactions that are occupied for (a) KS_QD_04 and (b) KS_QD_05 in complex with Mtb. DprE1.
Figure 11

A histogram showing the percentage of H-bond protein–ligand interactions that are occupied for (a) KS_QD_04 and (b) KS_QD_05 in complex with Mtb. DprE1.

The fluctuations observed in the residues ASP268 to GLY301 and ASN309 to GLY331 in the Mtb enzyme DprE1 can be attributed to the inherent flexibility of these regions. Specifically, ASP268 to GLY301 corresponds to a loop region, which naturally exhibits higher mobility, resulting in fluctuations up to 0.5 nm. Similarly, the region from ASN309 to GLY331 contains both a small helix and a loop, contributing to fluctuations up to 0.45 nm. It is important to note that these fluctuating regions do not participate in direct interactions with the ligand. Our structural analysis, using the high-resolution crystal structure of M. TB DprE1 in complex with the non-covalent inhibitor Ty38c (PDB ID 4P8K, resolution: 2.49 Å) confirms that the binding site is distinct and remains stable despite the mobility in these adjacent regions. Therefore, the observed fluctuations in the loop and small helix regions do not adversely affect the overall stability of the ligand–protein complex, ensuring the integrity and reliability of our binding analysis.

3.4.4 In silico ADMET studies

Swiss ADME software was used to perform the in silico ADMET studies [53,54]. All molecules in the KS_QD series have low gastrointestinal (GI) absorption. This indicates that these compounds may not be effectively absorbed through the GI tract when administered orally. None of the molecules are able to permeate the blood–brain barrier (BBB). This is significant for drug design, as it suggests that these compounds are unlikely to affect the central nervous system (CNS), which can be beneficial if the side effects of CNS are to be avoided. All of the molecules are substrates for P-glycoprotein. Pgp is a transporter protein that pumps foreign substances out of the cells. Being a Pgp substrate may affect the distribution and excretion of these molecules, potentially leading to drug resistance or reduced efficacy. All of the molecules inhibit CYP1A2, CYP2C19, CYP2D6, and CYP3A4. These enzymes are crucial for drug metabolism:

  • CYP1A2: Inhibition can affect the metabolism of drugs like caffeine and theophylline.

  • CYP2C19: Inhibition can impact the metabolism of drugs such as omeprazole and clopidogrel.

  • CYP2D6: Inhibition can interfere with the metabolism of drugs like codeine and beta-blockers.

  • CYP3A4: Inhibition can affect the metabolism of a wide range of drugs, including statins and some antiretrovirals.

The KS_QD series of molecules demonstrate low oral bioavailability due to poor GI absorption and are not suitable for CNS-targeted therapies due to their inability to cross the BBB. They are substrates for P-glycoprotein, which may influence their distribution and elimination. The broad inhibition of CYP enzymes indicates a high potential for drug–drug interactions, which is important for their therapeutic use. Low skin permeability further restricts their administration routes. These factors should be carefully considered in the development and clinical application of these compounds (Table 2).

Table 2

In silico ADMET studies of the proposed drug molecules

Molecule GI absorption BBB permeant Pgp substrate CYP1 2 inhibitor CYP2C19 inhibitor CYP2C9 inhibitor CYP2D6 inhibitor CYP3A4 inhibitor log Kp (cm/s)
KS_QD_01 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_02 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_03 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_04 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_05 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_06 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_07 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_08 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_09 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_10 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_11 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_12 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_13 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_14 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_15 Low No Yes Yes Yes No Yes Yes −4.38
KS_QD_16 Low No Yes Yes Yes No Yes Yes −4.38

Drug-likeness results were obtained using Swiss ADME software. All 16 compounds have the same pattern of violations across the different rules (Lipinski, Ghose, Egan, and Muegge) and share the same bioavailability score. The single violations in Lipinski, Ghose, Egan, and Muegge's rules suggest that while these compounds might have certain properties that deviate from the optimal ranges, they still retain a moderate probability of bioavailability (0.55). The absence of violations in the Veber rule indicates favourable properties for oral bioavailability in terms of rotatable bonds and polar surface area.

These findings suggest that while the compounds might need some optimization to fully align with all drug-likeness criteria, they possess a reasonable probability of being bioavailable, warranting further investigation and development (Table 3).

Table 3

Drug-likeness results for the proposed drug molecules

Molecule Lipinski #violations Ghose #violations Veber #violations Egan #violations Muegge #violations Bioavailability score
KS_QD_01 1 1 0 1 1 0.55
KS_QD_02 1 1 0 1 1 0.55
KS_QD_03 1 1 0 1 1 0.55
KS_QD_04 1 1 0 1 1 0.55
KS_QD_05 1 1 0 1 1 0.55
KS_QD_06 1 1 0 1 1 0.55
KS_QD_07 1 1 0 1 1 0.55
KS_QD_08 1 1 0 1 1 0.55
KS_QD_09 1 1 0 1 1 0.55
KS_QD_10 1 1 0 1 1 0.55
KS_QD_11 1 1 0 1 1 0.55
KS_QD_12 1 1 0 1 1 0.55
KS_QD_13 1 1 0 1 1 0.55
KS_QD_14 1 1 0 1 1 0.55
KS_QD_15 1 1 0 1 1 0.55
KS_QD_16 1 1 0 1 1 0.55

PAINS (pan-assay interference compounds) alerts indicate the presence of substructures that are likely to interfere with various biological assays, leading to false positives. All of the molecules listed (KS_QD_01 to KS_QD_16) have a PAINS alert value of 0. This indicates that none of the molecules have substructures that are likely to cause assay interference, which is a positive indicator of their potential as drug candidates. Brenk alerts identify substructures that are problematic in drug development due to toxicity, reactivity, or poor pharmacokinetics. All the molecules listed have a Brenk #alert value of 0. This indicates that none of the molecules contain substructures that are flagged as problematic by this criterion, further supporting their potential suitability as drug candidates. Leadlikeness refers to the properties that make a molecule suitable as a lead compound in drug discovery. The criteria typically include molecular weight, log P (octanol–water partition coefficient), and the number of hydrogen-bond donors and acceptors. All of the molecules have two violations of leadlikeness criteria. While the specific criteria violated are not provided, this suggests that the molecules may have properties slightly outside the ideal range for lead compounds. However, having only two violations is relatively minor and does not necessarily preclude these molecules from being good starting points for drug development. This metric, typically on a scale from 1 (very easy to synthesize) to 10 (very difficult to synthesize), indicates how challenging it is to chemically synthesize the molecules. All the molecules have a synthetic accessibility score of 2.97. This score suggests that the molecules are relatively easy to synthesize, which is advantageous in drug development as it allows for easier production and modification of the compounds (Table 4).

Table 4

Synthetic accessibility of the proposed drug molecules

Molecule PAINS #alerts Brenk #alerts Leadlikeness #violations Synthetic accessibility
KS_QD_01 0 0 2 2.97
KS_QD_02 0 0 2 2.97
KS_QD_03 0 0 2 2.97
KS_QD_04 0 0 2 2.97
KS_QD_05 0 0 2 2.97
KS_QD_06 0 0 2 2.97
KS_QD_07 0 0 2 2.97
KS_QD_08 0 0 2 2.97
KS_QD_09 0 0 2 2.97
KS_QD_10 0 0 2 2.97
KS_QD_11 0 0 2 2.97
KS_QD_12 0 0 2 2.97
KS_QD_13 0 0 2 2.97
KS_QD_14 0 0 2 2.97
KS_QD_15 0 0 2 2.97
KS_QD_16 0 0 2 2.97

Molecules KS_QD_01 to KS_QD_16 show promising characteristics as potential drug candidates. These molecules do not have substructures that would typically cause false positives in assays or pose significant risks in terms of toxicity or reactivity. While there are two violations for each molecule, this is not a major issue and can be addressed through further optimization. The ease of synthesis for these molecules makes them attractive candidates for further development and testing. In conclusion, these molecules present a strong foundation for further investigation and optimization in the context of drug discovery, particularly for their intended application as DprE1 inhibitors for antitubercular activity.

3.4.5 Structure–activity relationship

Molecular docking studies identified KS_QD_04 and KS_QD_05 as the most promising compounds with high binding affinities to the DprE1 enzyme. Notably, KS_QD_05 demonstrated significant hydrogen-bond interactions with ARG58, GLY57, and ASN178, with occupancies of 12.78, 8.55, and 5.39%, respectively. The SAR analysis is detailed as follows:

  1. Hydrophobic and hydrogen bonding interactions: The binding affinity of the inhibitors is strongly influenced by the presence of hydrophobic interactions and hydrogen bonds. KS_QD_05 exhibited notably strong and stable hydrogen bonds, which are critical for effective inhibition. This suggests that enhancing these interactions can lead to more potent inhibitors.

  2. Structural features: The binding affinity is significantly affected by the substituents at specific positions of the 2,3-diaryl-quinoxaline nucleus. For example, the presence of hydrophobic groups and hydrogen bond donors/acceptors at positions interacting with GLY55 and ASN178 (for KS_QD_05), and ARG58 and ASN63 (for KS_QD_04) contributes to improved binding.

  3. Stability in the binding pocket: KS_QD_05 demonstrated superior stability within the binding pocket, as indicated by lower RMSD values, suggesting it is a more promising lead compound. The stability highlights the importance of hydrophobic interactions and hydrogen bonding in the inhibitory activity of substituted 2,3-diaryl-quinoxalines against DprE1.

The SAR analysis, supported by molecular docking and MD simulations, underscores the crucial role of hydrophobic interactions and hydrogen bonding in the inhibitory activity of substituted 2,3-diaryl-quinoxalines against DprE1. KS_QD_05, with its strong and stable interactions, emerges as the most promising candidate for further development as a DprE1 inhibitor. Future research should aim at optimizing these interactions to enhance both potency and selectivity.

4 Conclusions

The study focused on identifying novel DprE1 inhibitors as potential anti-TB agents using a ligand-based drug design approach. A library of 16 substituted 2,3-diaryl-quinoxaline derivatives was designed and evaluated through molecular docking and MD simulations. Protein stability is evaluated by the RMSD analysis, which showed that both the apoprotein and protein–ligand complexes reached a stable plateau around 0.3 nm, indicating structural stability during the 100 ns simulation. The ligand RMSD plots demonstrated that both KS_QD_04 and KS_QD_05 maintained relatively stable interactions with DprE1. KS_QD_05 achieved an equilibrium RMSD of about 0.1 nm, while KS_QD_04 showed some disturbance around 70 ns but stabilized at 0.17 nm. RMSF analysis revealed fluctuations less than 0.5 nm for both the apoprotein and ligand-bound complexes, suggesting that ligand binding contributed to protein conformational stability, which established the protein stability. Both ligands formed an average of 1–3 hydrogen bonds throughout the simulation. KS_QD_04 formed stable interactions with THR118 (6.83% occupancy) and ASN63 (6.54% occupancy). KS_QD_05 showed more significant hydrogen bonding with ARG58 (12.78% occupancy), GLY57 (8.55% occupancy), and ASN178 (5.39% occupancy). In conclusion, the MD simulations support the potential of both KS_QD_04 and KS_QD_05 as DprE1 inhibitors. However, KS_QD_05 demonstrated more stable and extensive hydrogen bonding interactions, suggesting it may be a more promising candidate for further development as an anti-TB agent. These findings provide a solid foundation for future experimental validation and optimization of these compounds in the ongoing search for effective treatments against drug-resistant tuberculosis.

Acknowledgments

The authors extend their appreciation to Researchers Supporting Project number (RSPD2024R1087), King Saud University, Riyadh, Saudi Arabia, for funding this work.

  1. Funding information: This research was funded by Researchers Supporting Project number (RSPD2024R1087), King Saud University, Riyadh, Saudi Arabia.

  2. Author contributions: Conceptualization, K.S. and A.S.; methodology, K.S.; software, M.S.; validation, V.J., A.K.M. and A.A.; formal analysis, G.K. and A.A; investigation, T.V.; resources, G.K.; data curation, O.M.N.; writing – original draft preparation, K.S.; writing – review and editing, A.S., M.S., V.J., G.K., T.V., O.M.N., and A.A.; visualization, T.V.; supervision, A.K.M.; project administration and funding acquisition, O.M.N. All authors have read and agreed to the published version of the manuscript.

  3. Conflict of interest: The authors declare no conflicts of interest.

  4. Data availability statement: Data of this research are available upon request from the corresponding authors.

References

[1] Lawn SD, Zumla AI. Tuberculosis. Lancet. 2011 Jul;378(9785):57–72.10.1016/S0140-6736(10)62173-3Suche in Google Scholar PubMed

[2] Kumar M, Virmani T, Kumar G, Deshmukh R, Sharma A, Duarte S, et al. Nanocarriers in tuberculosis treatment: challenges and delivery strategies. Pharmaceuticals. 2023;16(10):1360.10.3390/ph16101360Suche in Google Scholar PubMed PubMed Central

[3] WHO. Global Tuberculosis Report 2022 [Internet]. [cited 2024 Mar 28]. Available from https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022.Suche in Google Scholar

[4] Dean AS, Auguet OT, Glaziou P, Zignol M, Ismail N, Kasaeva T, et al. 25 years of surveillance of drug-resistant tuberculosis: achievements, challenges, and way forward. Lancet Infect Dis. 2022;22(7):e191–6.10.1016/S1473-3099(21)00808-2Suche in Google Scholar PubMed PubMed Central

[5] Ahalwat S, Bhatt DC, Rohilla S, Jogpal V, Sharma K, Virmani T, et al. Mannose-functionalized isoniazid-loaded nanostructured lipid carriers for pulmonary delivery: in vitro prospects and in vivo therapeutic efficacy assessment. Pharmaceuticals. 2023;16(8):1108.10.3390/ph16081108Suche in Google Scholar PubMed PubMed Central

[6] Neto RD, Santos CB, Henriques SV, Machado LD, Cruz JN, da Silva CH, et al. Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations. J Biomol Struct Dyn. 2022;40(5):2204–16.10.1080/07391102.2020.1839562Suche in Google Scholar PubMed

[7] Silva LB, Ferreira EFB, Maryam, Espejo-Román JM, Costa GV, Cruz JV, et al. Galantamine based novel acetylcholinesterase enzyme inhibitors: a molecular modeling design approach. Molecules. 2023;28:1035. 10.3390/molecules28031035.Suche in Google Scholar PubMed PubMed Central

[8] de Almeida RBM, Barbosa DB, do Bomfim MR, Amparo JAO, Andrade BS, Costa SL, et al. Identification of a novel dual inhibitor of acetylcholinesterase and butyrylcholinesterase: in vitro and in silico studies. Pharmaceuticals. 2023;16:95. 10.3390/ph16010095.Suche in Google Scholar PubMed PubMed Central

[9] Mesquita KD, Feitosa BD, Cruz JN, Ferreira OO, Franco CD, Cascaes MM, et al. Chemical composition and preliminary toxicity evaluation of the essential oil from peperomia circinnata link var. circinnata. (piperaceae) in artemia salina leach. Molecules. 2021;26:7359. 10.3390/molecules26237359.Suche in Google Scholar PubMed PubMed Central

[10] Alves FS, Rodrigues Do Rego JA, Da Costa ML, Lobato Da Silva LF, Da Costa RA, Cruz JN. Spectroscopic methods and in silico analyses using density functional theory to characterize and identify piperine alkaloid crystals isolated from pepper (Piper Nigrum L.). J Biomol Struct Dyn. 2019;38(9):2792–9. 10.1080/07391102.2019.1639547.Suche in Google Scholar PubMed

[11] Vitaku E, Smith DT, Njardarson JT. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals: miniperspective. J Med Chem. 2014;57(24):10257–74.10.1021/jm501100bSuche in Google Scholar PubMed

[12] Khatoon H, Abdulmalek E. Novel synthetic routes to prepare biologically active quinoxalines and their derivatives: A synthetic review for the last two decades. Molecules. 2021;26(4):1055.10.3390/molecules26041055Suche in Google Scholar PubMed PubMed Central

[13] Abulkhair HS, Elmeligie S, Ghiaty A, El‐Morsy A, Bayoumi AH, Ahmed HEA, et al. In vivo‐and in silico‐driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors. Arch Pharm (Weinh). 2021;354(5):2000449.10.1002/ardp.202000449Suche in Google Scholar PubMed

[14] Zayed MF. Medicinal chemistry of quinazolines as anticancer agents targeting tyrosine kinases. Sci Pharm. 2023;91(2):18.10.3390/scipharm91020018Suche in Google Scholar

[15] Niknam K, Saberi D, Mohagheghnejad M. Silica bonded S-sulfonic acid: a recyclable catalyst for the synthesis of quinoxalines at room temperature. Molecules. 2009;14(5):1915–26.10.3390/molecules14051915Suche in Google Scholar PubMed PubMed Central

[16] Thakuria H, Das G. One-pot efficient green synthesis of 1, 4-dihydro-quinoxaline-2, 3-dione derivatives. J Chem Sci. 2006;118:425–8.10.1007/BF02711453Suche in Google Scholar

[17] da Costa CF, Nora de Souza MV, Brandao Gomes CR, Facchinetti V. Microwave-assisted synthesis of quinoxalines-A review. Curr Microw Chem. 2017;4(4):277–86.10.2174/2213335604666171010153416Suche in Google Scholar

[18] Rostamizadeh S, Jafari S. The synthesis of quinoxalines under microwave irradiation. Indian J Heterocycl Chem. 2001;10(4):303–4.Suche in Google Scholar

[19] Arde SM, Patil AD, Mane AH, Salokhe PR, Salunkhe RS. Synthesis of quinoxaline, benzimidazole and pyrazole derivatives under the catalytic influence of biosurfactant-stabilized iron nanoparticles in water. Res Chem Intermed. 2020;46:5069–86.10.1007/s11164-020-04240-6Suche in Google Scholar

[20] Brown DJ. The Chemistry of Heterocyclic Compounds-The Naphthyridines. Hoboken, New Jersey: John Wiley & Sons, Inc; 2022.Suche in Google Scholar

[21] Aparicio D, Attanasi OA, Filippone P, Ignacio R, Lillini S, Mantellini F, et al. Straightforward access to pyrazines, piperazinones, and quinoxalines by reactions of 1, 2-diaza-1, 3-butadienes with 1, 2-diamines under solution, solvent-free, or solid-phase conditions. J Org Chem. 2006;71(16):5897–905.10.1021/jo060450vSuche in Google Scholar PubMed

[22] Shi D, Dou G, Ni S, Shi J, Li X. An efficient synthesis of quinoxaline derivatives mediated by stannous chloride. ChemInform. 2009;40(15):1797–801.10.1002/chin.200915171Suche in Google Scholar

[23] Antoniotti S, Duñach E. Direct and catalytic synthesis of quinoxaline derivatives from epoxides and ene-1, 2-diamines. Tetrahedron Lett. 2002;43(22):3971–3.10.1016/S0040-4039(02)00715-3Suche in Google Scholar

[24] Sharma A, Deep A, Marwaha MG, Marwaha RK. Quinoxaline: A chemical moiety with spectrum of interesting biological activities. Mini Rev Med Chem. 2022;22(6):927–48.10.2174/1389557521666210927123831Suche in Google Scholar PubMed

[25] Tariq S, Somakala K, Amir M. Quinoxaline: An insight into the recent pharmacological advances. Eur J Med Chem. 2018;143:542–57.10.1016/j.ejmech.2017.11.064Suche in Google Scholar PubMed

[26] Ingle R, Marathe R, Magar D, Patel HM, Surana SJ. Sulphonamido-quinoxalines: Search for anticancer agent. Eur J Med Chem. 2013;65:168–86.10.1016/j.ejmech.2013.04.028Suche in Google Scholar PubMed

[27] El Newahie AMS, Ismail NSM, Abou El Ella DA, Abouzid KAM. Quinoxaline‐based scaffolds targeting tyrosine kinases and their potential anticancer activity. Arch Pharm (Weinh). 2016;349(5):309–26.10.1002/ardp.201500468Suche in Google Scholar PubMed

[28] Ibrahim MK, Eissa IH, Abdallah AE, Metwaly AM, Radwan MM, ElSohly MA. Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of novel quinoxaline derivatives as potential PPARγ and SUR agonists. Bioorg Med Chem. 2017;25(4):1496–513.10.1016/j.bmc.2017.01.015Suche in Google Scholar PubMed

[29] Shintre SA, Ramjugernath D, Islam MS, Mopuri R, Mocktar C, Koorbanally NA. Synthesis, in vitro antimicrobial, antioxidant, and antidiabetic activities of thiazolidine–quinoxaline derivatives with amino acid side chains. Med Chem Res. 2017;26:2141–51.10.1007/s00044-017-1922-xSuche in Google Scholar

[30] El-Helby A-GA, Ayyad RRA, El-Adl K, Elwan A. Quinoxalin-2 (1 H)-one derived AMPA-receptor antagonists: Design, synthesis, molecular docking and anticonvulsant activity. Med Chem Res. 2017;26:2967–84.10.1007/s00044-017-1996-5Suche in Google Scholar

[31] Guillon J, Nim S, Moreau S, Ronga L, Savrimoutou S, Thivet E, et al. Synthesis of new piperazinyl-pyrrolo [1, 2-a] quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction. RSC Adv. 2020;10(5):2915–31.10.1039/C9RA09348FSuche in Google Scholar PubMed PubMed Central

[32] Shekhar AC, Rao PS, Narsaiah B, Allanki AD, Sijwali PS. Emergence of pyrido quinoxalines as new family of antimalarial agents. Eur J Med Chem. 2014;77:280–7.10.1016/j.ejmech.2014.03.010Suche in Google Scholar PubMed

[33] Cogo J, Kaplum V, Sangi DP, Ueda-Nakamura T, Correa AG, Nakamura CV. Synthesis and biological evaluation of novel 2, 3-disubstituted quinoxaline derivatives as antileishmanial and antitrypanosomal agents. Eur J Med Chem. 2015;90:107–23.10.1016/j.ejmech.2014.11.018Suche in Google Scholar PubMed

[34] Soto-Sánchez J, Caro-Gómez LA, Paz-González AD, Marchat LA, Rivera G, Moo-Puc R, et al. Biological activity of esters of quinoxaline-7-carboxylate 1, 4-di-N-oxide against E. histolytica and their analysis as potential thioredoxin reductase inhibitors. Parasitol Res. 2020;119:695–711.10.1007/s00436-019-06580-8Suche in Google Scholar PubMed

[35] Chakraborty J, Kanungo A, Mahata T, Kumar K, Sharma G, Pal R, et al. Quinoxaline derivatives disrupt the base stacking of hepatitis C virus-internal ribosome entry site RNA: reduce translation and replication. Chem Commun. 2019;55(93):14027–30.10.1039/C9CC06531HSuche in Google Scholar

[36] Shen Q-K, Gong G-H, Li G, Jin M, Cao L-H, Quan Z-S. Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4, 5-dihydro-[1, 2, 4] triazolo [4, 3-a] quinoxaline-1-carbox-amide derivatives as anti-inflammatory agents. J Enzyme Inhib Med Chem. 2020;35(1):85–95.10.1080/14756366.2019.1680658Suche in Google Scholar PubMed PubMed Central

[37] Montana M, Montero V, Khoumeri O, Vanelle P. Quinoxaline derivatives as antiviral agents: a systematic review. Molecules. 2020;25(12):2784.10.3390/molecules25122784Suche in Google Scholar PubMed PubMed Central

[38] Neres J, Hartkoorn RC, Chiarelli LR, Gadupudi R, Pasca MR, Mori G, et al. 2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1. ACS Chem Biol. 2015;10:705–14.10.1021/cb5007163Suche in Google Scholar PubMed

[39] Hu XP, Yang L, Chai X, Lei YX, Alam MS, Liu L, et al. Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening. Acta Pharmacol Sin. 2022 Jun;43(6):1605–15. 10.1038/s41401-021-00779-1, Epub 2021 Oct 19 PMID: 34667293; PMCID: PMC9160271.Suche in Google Scholar PubMed PubMed Central

[40] Bekker H, Berendsen HJC, Dijkstra EJ, Achterop S, Vondrumen R, Vanderspoel D, et al. Gromacs-a parallel computer for molecular-dynamics simulations. 4th International Conference on Computational Physics (PC 92). World Scientific Publishing; 1993. p. 252–6.Suche in Google Scholar

[41] Ganesan A, Coote ML, Barakat K. Molecular dynamics-driven drug discovery: leaping forward with confidence. Drug Discov Today. 2017;22(2):249–69.10.1016/j.drudis.2016.11.001Suche in Google Scholar PubMed

[42] Thalla M, Kant K, Dalchand, Rawat R, Banerjee S. Merged experimental guided computational strategy toward tuberculosis treatment mediated by alveolar macrophages mannose receptor. J Biomol Struct Dyn. 2020;38(17):5195–203.10.1080/07391102.2019.1697369Suche in Google Scholar PubMed

[43] Schmid N, Eichenberger AP, Choutko A, Riniker S, Winger M, Mark AE, et al. Definition and testing of the GROMOS force-field versions 54A7 and 54B7. Eur Biophys J. 2011;40:843–56.10.1007/s00249-011-0700-9Suche in Google Scholar PubMed

[44] Van Aalten DMF, Bywater R, Findlay JBC, Hendlich M, Hooft RWW, Vriend G. PRODRG, a program for generating molecular topologies and unique molecular descriptors from coordinates of small molecules. J Comput Aided Mol Des. 1996;10:255–62.10.1007/BF00355047Suche in Google Scholar PubMed

[45] Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput Phys Commun. 1995;91(1–3):43–56.10.1016/0010-4655(95)00042-ESuche in Google Scholar

[46] Di Pierro M, Elber R, Leimkuhler B. A stochastic algorithm for the isobaric–isothermal ensemble with Ewald summations for all long range forces. J Chem Theory Comput. 2015;11(12):5624–37.10.1021/acs.jctc.5b00648Suche in Google Scholar PubMed PubMed Central

[47] Li J, Abel R, Zhu K, Cao Y, Zhao S, Friesner RA. The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling. Proteins. 2011;79:2794–812.10.1002/prot.23106Suche in Google Scholar PubMed PubMed Central

[48] Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–8.10.1016/0263-7855(96)00018-5Suche in Google Scholar PubMed

[49] Rawat R, Kant K, Kumar A, Bhati K, Verma SM. HeroMDAnalysis: an automagical tool for GROMACS-based molecular dynamics simulation analysis. Future Med Chem. 2021;13(5):447–56.10.4155/fmc-2020-0191Suche in Google Scholar PubMed

[50] Devi S, Rangra NK, Rawat R, Alrobaian MM, Alam A, Singh R, et al. Anti-atherogenic effect of Nepitrin-7-O-glucoside: A flavonoid isolated from Nepeta hindostana via acting on PPAR–α receptor. Steroids. 2021;165:108770.10.1016/j.steroids.2020.108770Suche in Google Scholar PubMed

[51] Vaught A. Graphing with Gnuplot and Xmgr: two graphing packages available under linux. Linux J. 1996;1996(28es):7-es.Suche in Google Scholar

[52] Adnan C. In silico studies on stilbenolignan analogues as SARS-CoV-2 Mpro inhibitors. Chem Phys Lett. May 2021;771:138563.10.1016/j.cplett.2021.138563Suche in Google Scholar PubMed PubMed Central

[53] Cetin A. Some flavolignans as potent SARS-CoV-2 inhibitors via molecular docking, molecular dynamic simulations and ADME analysis. Curr Comput Aided Drug Des. 2022;18:337–46.10.2174/1573409918666220816113516Suche in Google Scholar PubMed

[54] Seyma Sevincli Z, Bildirici N, Cetin A, Bildirici I. GABA–AT inhibitors: design, synthesis, pharmacological characterization, molecular docking and ADMET studies. ChemistrySelect. 2023;8:1–12. 10.1002/slct.202302683.Suche in Google Scholar
Received: 2024-04-18
Revised: 2024-07-21
Accepted: 2024-08-10
Published Online: 2024-10-02

© 2024 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  52. Processing of alcohol pomelo beverage (Citrus grandis (L.) Osbeck) using saccharomyces yeast: Optimization, physicochemical quality, and sensory characteristics
  53. Specialized compounds of four Cameroonian spices: Isolation, characterization, and in silico evaluation as prospective SARS-CoV-2 inhibitors
  54. Identification of a novel drug target in Porphyromonas gingivalis by a computational genome analysis approach
  55. Physico-chemical properties and durability of a fly-ash-based geopolymer
  56. FMS-like tyrosine kinase 3 inhibitory potentials of some phytochemicals from anti-leukemic plants using computational chemical methodologies
  57. Wild Thymus zygis L. ssp. gracilis and Eucalyptus camaldulensis Dehnh.: Chemical composition, antioxidant and antibacterial activities of essential oils
  58. 3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer
  59. Deciphering the influenza neuraminidase inhibitory potential of naturally occurring biflavonoids: An in silico approach
  60. Determination of heavy elements in agricultural regions, Saudi Arabia
  61. Synthesis and characterization of antioxidant-enriched Moringa oil-based edible oleogel
  62. Ameliorative effects of thistle and thyme honeys on cyclophosphamide-induced toxicity in mice
  63. Study of phytochemical compound and antipyretic activity of Chenopodium ambrosioides L. fractions
  64. Investigating the adsorption mechanism of zinc chloride-modified porous carbon for sulfadiazine removal from water
  65. Performance repair of building materials using alumina and silica composite nanomaterials with electrodynamic properties
  66. Effects of nanoparticles on the activity and resistance genes of anaerobic digestion enzymes in livestock and poultry manure containing the antibiotic tetracycline
  67. Effect of copper nanoparticles green-synthesized using Ocimum basilicum against Pseudomonas aeruginosa in mice lung infection model
  68. Cardioprotective effects of nanoparticles green formulated by Spinacia oleracea extract on isoproterenol-induced myocardial infarction in mice by the determination of PPAR-γ/NF-κB pathway
  69. Anti-OTC antibody-conjugated fluorescent magnetic/silica and fluorescent hybrid silica nanoparticles for oxytetracycline detection
  70. Curcumin conjugated zinc nanoparticles for the treatment of myocardial infarction
  71. Identification and in silico screening of natural phloroglucinols as potential PI3Kα inhibitors: A computational approach for drug discovery
  72. Exploring the phytochemical profile and antioxidant evaluation: Molecular docking and ADMET analysis of main compounds from three Solanum species in Saudi Arabia
  73. Unveiling the molecular composition and biological properties of essential oil derived from the leaves of wild Mentha aquatica L.: A comprehensive in vitro and in silico exploration
  74. Analysis of bioactive compounds present in Boerhavia elegans seeds by GC-MS
  75. Homology modeling and molecular docking study of corticotrophin-releasing hormone: An approach to treat stress-related diseases
  76. LncRNA MIR17HG alleviates heart failure via targeting MIR17HG/miR-153-3p/SIRT1 axis in in vitro model
  77. Development and validation of a stability indicating UPLC-DAD method coupled with MS-TQD for ramipril and thymoquinone in bioactive SNEDDS with in silico toxicity analysis of ramipril degradation products
  78. Biosynthesis of Ag/Cu nanocomposite mediated by Curcuma longa: Evaluation of its antibacterial properties against oral pathogens
  79. Development of AMBER-compliant transferable force field parameters for polytetrafluoroethylene
  80. Treatment of gestational diabetes by Acroptilon repens leaf aqueous extract green-formulated iron nanoparticles in rats
  81. Development and characterization of new ecological adsorbents based on cardoon wastes: Application to brilliant green adsorption
  82. A fast, sensitive, greener, and stability-indicating HPLC method for the standardization and quantitative determination of chlorhexidine acetate in commercial products
  83. Assessment of Se, As, Cd, Cr, Hg, and Pb content status in Ankang tea plantations of China
  84. Effect of transition metal chloride (ZnCl2) on low-temperature pyrolysis of high ash bituminous coal
  85. Evaluating polyphenol and ascorbic acid contents, tannin removal ability, and physical properties during hydrolysis and convective hot-air drying of cashew apple powder
  86. Development and characterization of functional low-fat frozen dairy dessert enhanced with dried lemongrass powder
  87. Scrutinizing the effect of additive and synergistic antibiotics against carbapenem-resistant Pseudomonas aeruginosa
  88. Preparation, characterization, and determination of the therapeutic effects of copper nanoparticles green-formulated by Pistacia atlantica in diabetes-induced cardiac dysfunction in rat
  89. Antioxidant and antidiabetic potentials of methoxy-substituted Schiff bases using in vitro, in vivo, and molecular simulation approaches
  90. Anti-melanoma cancer activity and chemical profile of the essential oil of Seseli yunnanense Franch
  91. Molecular docking analysis of subtilisin-like alkaline serine protease (SLASP) and laccase with natural biopolymers
  92. Overcoming methicillin resistance by methicillin-resistant Staphylococcus aureus: Computational evaluation of napthyridine and oxadiazoles compounds for potential dual inhibition of PBP-2a and FemA proteins
  93. Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment
  94. Drimia maritima flowers as a source of biologically potent components: Optimization of bioactive compound extractions, isolation, UPLC–ESI–MS/MS, and pharmacological properties
  95. Estimating molecular properties, drug-likeness, cardiotoxic risk, liability profile, and molecular docking study to characterize binding process of key phyto-compounds against serotonin 5-HT2A receptor
  96. Fabrication of β-cyclodextrin-based microgels for enhancing solubility of Terbinafine: An in-vitro and in-vivo toxicological evaluation
  97. Phyto-mediated synthesis of ZnO nanoparticles and their sunlight-driven photocatalytic degradation of cationic and anionic dyes
  98. Monosodium glutamate induces hypothalamic–pituitary–adrenal axis hyperactivation, glucocorticoid receptors down-regulation, and systemic inflammatory response in young male rats: Impact on miR-155 and miR-218
  99. Quality control analyses of selected honey samples from Serbia based on their mineral and flavonoid profiles, and the invertase activity
  100. Eco-friendly synthesis of silver nanoparticles using Phyllanthus niruri leaf extract: Assessment of antimicrobial activity, effectiveness on tropical neglected mosquito vector control, and biocompatibility using a fibroblast cell line model
  101. Green synthesis of silver nanoparticles containing Cichorium intybus to treat the sepsis-induced DNA damage in the liver of Wistar albino rats
  102. Quality changes of durian pulp (Durio ziberhinus Murr.) in cold storage
  103. Study on recrystallization process of nitroguanidine by directly adding cold water to control temperature
  104. Determination of heavy metals and health risk assessment in drinking water in Bukayriyah City, Saudi Arabia
  105. Larvicidal properties of essential oils of three Artemisia species against the chemically insecticide-resistant Nile fever vector Culex pipiens (L.) (Diptera: Culicidae): In vitro and in silico studies
  106. Design, synthesis, characterization, and theoretical calculations, along with in silico and in vitro antimicrobial proprieties of new isoxazole-amide conjugates
  107. The impact of drying and extraction methods on total lipid, fatty acid profile, and cytotoxicity of Tenebrio molitor larvae
  108. A zinc oxide–tin oxide–nerolidol hybrid nanomaterial: Efficacy against esophageal squamous cell carcinoma
  109. Research on technological process for production of muskmelon juice (Cucumis melo L.)
  110. Physicochemical components, antioxidant activity, and predictive models for quality of soursop tea (Annona muricata L.) during heat pump drying
  111. Characterization and application of Fe1−xCoxFe2O4 nanoparticles in Direct Red 79 adsorption
  112. Torilis arvensis ethanolic extract: Phytochemical analysis, antifungal efficacy, and cytotoxicity properties
  113. Magnetite–poly-1H pyrrole dendritic nanocomposite seeded on poly-1H pyrrole: A promising photocathode for green hydrogen generation from sanitation water without using external sacrificing agent
  114. HPLC and GC–MS analyses of phytochemical compounds in Haloxylon salicornicum extract: Antibacterial and antifungal activity assessment of phytopathogens
  115. Efficient and stable to coking catalysts of ethanol steam reforming comprised of Ni + Ru loaded on MgAl2O4 + LnFe0.7Ni0.3O3 (Ln = La, Pr) nanocomposites prepared via cost-effective procedure with Pluronic P123 copolymer
  116. Nitrogen and boron co-doped carbon dots probe for selectively detecting Hg2+ in water samples and the detection mechanism
  117. Heavy metals in road dust from typical old industrial areas of Wuhan: Seasonal distribution and bioaccessibility-based health risk assessment
  118. Phytochemical profiling and bioactivity evaluation of CBD- and THC-enriched Cannabis sativa extracts: In vitro and in silico investigation of antioxidant and anti-inflammatory effects
  119. Investigating dye adsorption: The role of surface-modified montmorillonite nanoclay in kinetics, isotherms, and thermodynamics
  120. Antimicrobial activity, induction of ROS generation in HepG2 liver cancer cells, and chemical composition of Pterospermum heterophyllum
  121. Study on the performance of nanoparticle-modified PVDF membrane in delaying membrane aging
  122. Impact of cholesterol in encapsulated vitamin E acetate within cocoliposomes
  123. Review Articles
  124. Structural aspects of Pt(η3-X1N1X2)(PL) (X1,2 = O, C, or Se) and Pt(η3-N1N2X1)(PL) (X1 = C, S, or Se) derivatives
  125. Biosurfactants in biocorrosion and corrosion mitigation of metals: An overview
  126. Stimulus-responsive MOF–hydrogel composites: Classification, preparation, characterization, and their advancement in medical treatments
  127. Electrochemical dissolution of titanium under alternating current polarization to obtain its dioxide
  128. Special Issue on Recent Trends in Green Chemistry
  129. Phytochemical screening and antioxidant activity of Vitex agnus-castus L.
  130. Phytochemical study, antioxidant activity, and dermoprotective activity of Chenopodium ambrosioides (L.)
  131. Exploitation of mangliculous marine fungi, Amarenographium solium, for the green synthesis of silver nanoparticles and their activity against multiple drug-resistant bacteria
  132. Study of the phytotoxicity of margines on Pistia stratiotes L.
  133. Special Issue on Advanced Nanomaterials for Energy, Environmental and Biological Applications - Part III
  134. Impact of biogenic zinc oxide nanoparticles on growth, development, and antioxidant system of high protein content crop (Lablab purpureus L.) sweet
  135. Green synthesis, characterization, and application of iron and molybdenum nanoparticles and their composites for enhancing the growth of Solanum lycopersicum
  136. Green synthesis of silver nanoparticles from Olea europaea L. extracted polysaccharides, characterization, and its assessment as an antimicrobial agent against multiple pathogenic microbes
  137. Photocatalytic treatment of organic dyes using metal oxides and nanocomposites: A quantitative study
  138. Antifungal, antioxidant, and photocatalytic activities of greenly synthesized iron oxide nanoparticles
  139. Special Issue on Phytochemical and Pharmacological Scrutinization of Medicinal Plants
  140. Hepatoprotective effects of safranal on acetaminophen-induced hepatotoxicity in rats
  141. Chemical composition and biological properties of Thymus capitatus plants from Algerian high plains: A comparative and analytical study
  142. Chemical composition and bioactivities of the methanol root extracts of Saussurea costus
  143. In vivo protective effects of vitamin C against cyto-genotoxicity induced by Dysphania ambrosioides aqueous extract
  144. Insights about the deleterious impact of a carbamate pesticide on some metabolic immune and antioxidant functions and a focus on the protective ability of a Saharan shrub and its anti-edematous property
  145. A comprehensive review uncovering the anticancerous potential of genkwanin (plant-derived compound) in several human carcinomas
  146. A study to investigate the anticancer potential of carvacrol via targeting Notch signaling in breast cancer
  147. Assessment of anti-diabetic properties of Ziziphus oenopolia (L.) wild edible fruit extract: In vitro and in silico investigations through molecular docking analysis
  148. Optimization of polyphenol extraction, phenolic profile by LC-ESI-MS/MS, antioxidant, anti-enzymatic, and cytotoxic activities of Physalis acutifolia
  149. Phytochemical screening, antioxidant properties, and photo-protective activities of Salvia balansae de Noé ex Coss
  150. Antihyperglycemic, antiglycation, anti-hypercholesteremic, and toxicity evaluation with gas chromatography mass spectrometry profiling for Aloe armatissima leaves
  151. Phyto-fabrication and characterization of gold nanoparticles by using Timur (Zanthoxylum armatum DC) and their effect on wound healing
  152. Does Erodium trifolium (Cav.) Guitt exhibit medicinal properties? Response elements from phytochemical profiling, enzyme-inhibiting, and antioxidant and antimicrobial activities
  153. Integrative in silico evaluation of the antiviral potential of terpenoids and its metal complexes derived from Homalomena aromatica based on main protease of SARS-CoV-2
  154. 6-Methoxyflavone improves anxiety, depression, and memory by increasing monoamines in mice brain: HPLC analysis and in silico studies
  155. Simultaneous extraction and quantification of hydrophilic and lipophilic antioxidants in Solanum lycopersicum L. varieties marketed in Saudi Arabia
  156. Biological evaluation of CH3OH and C2H5OH of Berberis vulgaris for in vivo antileishmanial potential against Leishmania tropica in murine models
https://doi.org/10.1515/chem-2024-0086
Schlagwörter für diesen Artikel
DprE1; Ty38c; root mean square deviation; root mean square fluctuation; quinoxalines; hydrophobic interactions
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Regular Articles
  2. Porous silicon nanostructures: Synthesis, characterization, and their antifungal activity
  3. Biochar from de-oiled Chlorella vulgaris and its adsorption on antibiotics
  4. Phytochemicals profiling, in vitro and in vivo antidiabetic activity, and in silico studies on Ajuga iva (L.) Schreb.: A comprehensive approach
  5. Synthesis, characterization, in silico and in vitro studies of novel glycoconjugates as potential antibacterial, antifungal, and antileishmanial agents
  6. Sonochemical synthesis of gold nanoparticles mediated by potato starch: Its performance in the treatment of esophageal cancer
  7. Computational study of ADME-Tox prediction of selected phytochemicals from Punica granatum peels
  8. Phytochemical analysis, in vitro antioxidant and antifungal activities of extracts and essential oil derived from Artemisia herba-alba Asso
  9. Two triazole-based coordination polymers: Synthesis and crystal structure characterization
  10. Phytochemical and physicochemical studies of different apple varieties grown in Morocco
  11. Synthesis of multi-template molecularly imprinted polymers (MT-MIPs) for isolating ethyl para-methoxycinnamate and ethyl cinnamate from Kaempferia galanga L., extract with methacrylic acid as functional monomer
  12. Nutraceutical potential of Mesembryanthemum forsskaolii Hochst. ex Bioss.: Insights into its nutritional composition, phytochemical contents, and antioxidant activity
  13. Evaluation of influence of Butea monosperma floral extract on inflammatory biomarkers
  14. Cannabis sativa L. essential oil: Chemical composition, anti-oxidant, anti-microbial properties, and acute toxicity: In vitro, in vivo, and in silico study
  15. The effect of gamma radiation on 5-hydroxymethylfurfural conversion in water and dimethyl sulfoxide
  16. Hollow mushroom nanomaterials for potentiometric sensing of Pb2+ ions in water via the intercalation of iodide ions into the polypyrrole matrix
  17. Determination of essential oil and chemical composition of St. John’s Wort
  18. Computational design and in vitro assay of lantadene-based novel inhibitors of NS3 protease of dengue virus
  19. Anti-parasitic activity and computational studies on a novel labdane diterpene from the roots of Vachellia nilotica
  20. Microbial dynamics and dehydrogenase activity in tomato (Lycopersicon esculentum Mill.) rhizospheres: Impacts on growth and soil health across different soil types
  21. Correlation between in vitro anti-urease activity and in silico molecular modeling approach of novel imidazopyridine–oxadiazole hybrids derivatives
  22. Spatial mapping of indoor air quality in a light metro system using the geographic information system method
  23. Iron indices and hemogram in renal anemia and the improvement with Tribulus terrestris green-formulated silver nanoparticles applied on rat model
  24. Integrated track of nano-informatics coupling with the enrichment concept in developing a novel nanoparticle targeting ERK protein in Naegleria fowleri
  25. Cytotoxic and phytochemical screening of Solanum lycopersicum–Daucus carota hydro-ethanolic extract and in silico evaluation of its lycopene content as anticancer agent
  26. Protective activities of silver nanoparticles containing Panax japonicus on apoptotic, inflammatory, and oxidative alterations in isoproterenol-induced cardiotoxicity
  27. pH-based colorimetric detection of monofunctional aldehydes in liquid and gas phases
  28. Investigating the effect of resveratrol on apoptosis and regulation of gene expression of Caco-2 cells: Unravelling potential implications for colorectal cancer treatment
  29. Metformin inhibits knee osteoarthritis induced by type 2 diabetes mellitus in rats: S100A8/9 and S100A12 as players and therapeutic targets
  30. Effect of silver nanoparticles formulated by Silybum marianum on menopausal urinary incontinence in ovariectomized rats
  31. Synthesis of new analogs of N-substituted(benzoylamino)-1,2,3,6-tetrahydropyridines
  32. Response of yield and quality of Japonica rice to different gradients of moisture deficit at grain-filling stage in cold regions
  33. Preparation of an inclusion complex of nickel-based β-cyclodextrin: Characterization and accelerating the osteoarthritis articular cartilage repair
  34. Empagliflozin-loaded nanomicelles responsive to reactive oxygen species for renal ischemia/reperfusion injury protection
  35. Preparation and pharmacodynamic evaluation of sodium aescinate solid lipid nanoparticles
  36. Assessment of potentially toxic elements and health risks of agricultural soil in Southwest Riyadh, Saudi Arabia
  37. Theoretical investigation of hydrogen-rich fuel production through ammonia decomposition
  38. Biosynthesis and screening of cobalt nanoparticles using citrus species for antimicrobial activity
  39. Investigating the interplay of genetic variations, MCP-1 polymorphism, and docking with phytochemical inhibitors for combatting dengue virus pathogenicity through in silico analysis
  40. Ultrasound induced biosynthesis of silver nanoparticles embedded into chitosan polymers: Investigation of its anti-cutaneous squamous cell carcinoma effects
  41. Copper oxide nanoparticles-mediated Heliotropium bacciferum leaf extract: Antifungal activity and molecular docking assays against strawberry pathogens
  42. Sprouted wheat flour for improving physical, chemical, rheological, microbial load, and quality properties of fino bread
  43. Comparative toxicity assessment of fisetin-aided artificial intelligence-assisted drug design targeting epibulbar dermoid through phytochemicals
  44. Acute toxicity and anti-inflammatory activity of bis-thiourea derivatives
  45. Anti-diabetic activity-guided isolation of α-amylase and α-glucosidase inhibitory terpenes from Capsella bursa-pastoris Linn.
  46. GC–MS analysis of Lactobacillus plantarum YW11 metabolites and its computational analysis on familial pulmonary fibrosis hub genes
  47. Green formulation of copper nanoparticles by Pistacia khinjuk leaf aqueous extract: Introducing a novel chemotherapeutic drug for the treatment of prostate cancer
  48. Improved photocatalytic properties of WO3 nanoparticles for Malachite green dye degradation under visible light irradiation: An effect of La doping
  49. One-pot synthesis of a network of Mn2O3–MnO2–poly(m-methylaniline) composite nanorods on a polypyrrole film presents a promising and efficient optoelectronic and solar cell device
  50. Groundwater quality and health risk assessment of nitrate and fluoride in Al Qaseem area, Saudi Arabia
  51. A comparative study of the antifungal efficacy and phytochemical composition of date palm leaflet extracts
  52. Processing of alcohol pomelo beverage (Citrus grandis (L.) Osbeck) using saccharomyces yeast: Optimization, physicochemical quality, and sensory characteristics
  53. Specialized compounds of four Cameroonian spices: Isolation, characterization, and in silico evaluation as prospective SARS-CoV-2 inhibitors
  54. Identification of a novel drug target in Porphyromonas gingivalis by a computational genome analysis approach
  55. Physico-chemical properties and durability of a fly-ash-based geopolymer
  56. FMS-like tyrosine kinase 3 inhibitory potentials of some phytochemicals from anti-leukemic plants using computational chemical methodologies
  57. Wild Thymus zygis L. ssp. gracilis and Eucalyptus camaldulensis Dehnh.: Chemical composition, antioxidant and antibacterial activities of essential oils
  58. 3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer
  59. Deciphering the influenza neuraminidase inhibitory potential of naturally occurring biflavonoids: An in silico approach
  60. Determination of heavy elements in agricultural regions, Saudi Arabia
  61. Synthesis and characterization of antioxidant-enriched Moringa oil-based edible oleogel
  62. Ameliorative effects of thistle and thyme honeys on cyclophosphamide-induced toxicity in mice
  63. Study of phytochemical compound and antipyretic activity of Chenopodium ambrosioides L. fractions
  64. Investigating the adsorption mechanism of zinc chloride-modified porous carbon for sulfadiazine removal from water
  65. Performance repair of building materials using alumina and silica composite nanomaterials with electrodynamic properties
  66. Effects of nanoparticles on the activity and resistance genes of anaerobic digestion enzymes in livestock and poultry manure containing the antibiotic tetracycline
  67. Effect of copper nanoparticles green-synthesized using Ocimum basilicum against Pseudomonas aeruginosa in mice lung infection model
  68. Cardioprotective effects of nanoparticles green formulated by Spinacia oleracea extract on isoproterenol-induced myocardial infarction in mice by the determination of PPAR-γ/NF-κB pathway
  69. Anti-OTC antibody-conjugated fluorescent magnetic/silica and fluorescent hybrid silica nanoparticles for oxytetracycline detection
  70. Curcumin conjugated zinc nanoparticles for the treatment of myocardial infarction
  71. Identification and in silico screening of natural phloroglucinols as potential PI3Kα inhibitors: A computational approach for drug discovery
  72. Exploring the phytochemical profile and antioxidant evaluation: Molecular docking and ADMET analysis of main compounds from three Solanum species in Saudi Arabia
  73. Unveiling the molecular composition and biological properties of essential oil derived from the leaves of wild Mentha aquatica L.: A comprehensive in vitro and in silico exploration
  74. Analysis of bioactive compounds present in Boerhavia elegans seeds by GC-MS
  75. Homology modeling and molecular docking study of corticotrophin-releasing hormone: An approach to treat stress-related diseases
  76. LncRNA MIR17HG alleviates heart failure via targeting MIR17HG/miR-153-3p/SIRT1 axis in in vitro model
  77. Development and validation of a stability indicating UPLC-DAD method coupled with MS-TQD for ramipril and thymoquinone in bioactive SNEDDS with in silico toxicity analysis of ramipril degradation products
  78. Biosynthesis of Ag/Cu nanocomposite mediated by Curcuma longa: Evaluation of its antibacterial properties against oral pathogens
  79. Development of AMBER-compliant transferable force field parameters for polytetrafluoroethylene
  80. Treatment of gestational diabetes by Acroptilon repens leaf aqueous extract green-formulated iron nanoparticles in rats
  81. Development and characterization of new ecological adsorbents based on cardoon wastes: Application to brilliant green adsorption
  82. A fast, sensitive, greener, and stability-indicating HPLC method for the standardization and quantitative determination of chlorhexidine acetate in commercial products
  83. Assessment of Se, As, Cd, Cr, Hg, and Pb content status in Ankang tea plantations of China
  84. Effect of transition metal chloride (ZnCl2) on low-temperature pyrolysis of high ash bituminous coal
  85. Evaluating polyphenol and ascorbic acid contents, tannin removal ability, and physical properties during hydrolysis and convective hot-air drying of cashew apple powder
  86. Development and characterization of functional low-fat frozen dairy dessert enhanced with dried lemongrass powder
  87. Scrutinizing the effect of additive and synergistic antibiotics against carbapenem-resistant Pseudomonas aeruginosa
  88. Preparation, characterization, and determination of the therapeutic effects of copper nanoparticles green-formulated by Pistacia atlantica in diabetes-induced cardiac dysfunction in rat
  89. Antioxidant and antidiabetic potentials of methoxy-substituted Schiff bases using in vitro, in vivo, and molecular simulation approaches
  90. Anti-melanoma cancer activity and chemical profile of the essential oil of Seseli yunnanense Franch
  91. Molecular docking analysis of subtilisin-like alkaline serine protease (SLASP) and laccase with natural biopolymers
  92. Overcoming methicillin resistance by methicillin-resistant Staphylococcus aureus: Computational evaluation of napthyridine and oxadiazoles compounds for potential dual inhibition of PBP-2a and FemA proteins
  93. Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment
  94. Drimia maritima flowers as a source of biologically potent components: Optimization of bioactive compound extractions, isolation, UPLC–ESI–MS/MS, and pharmacological properties
  95. Estimating molecular properties, drug-likeness, cardiotoxic risk, liability profile, and molecular docking study to characterize binding process of key phyto-compounds against serotonin 5-HT2A receptor
  96. Fabrication of β-cyclodextrin-based microgels for enhancing solubility of Terbinafine: An in-vitro and in-vivo toxicological evaluation
  97. Phyto-mediated synthesis of ZnO nanoparticles and their sunlight-driven photocatalytic degradation of cationic and anionic dyes
  98. Monosodium glutamate induces hypothalamic–pituitary–adrenal axis hyperactivation, glucocorticoid receptors down-regulation, and systemic inflammatory response in young male rats: Impact on miR-155 and miR-218
  99. Quality control analyses of selected honey samples from Serbia based on their mineral and flavonoid profiles, and the invertase activity
  100. Eco-friendly synthesis of silver nanoparticles using Phyllanthus niruri leaf extract: Assessment of antimicrobial activity, effectiveness on tropical neglected mosquito vector control, and biocompatibility using a fibroblast cell line model
  101. Green synthesis of silver nanoparticles containing Cichorium intybus to treat the sepsis-induced DNA damage in the liver of Wistar albino rats
  102. Quality changes of durian pulp (Durio ziberhinus Murr.) in cold storage
  103. Study on recrystallization process of nitroguanidine by directly adding cold water to control temperature
  104. Determination of heavy metals and health risk assessment in drinking water in Bukayriyah City, Saudi Arabia
  105. Larvicidal properties of essential oils of three Artemisia species against the chemically insecticide-resistant Nile fever vector Culex pipiens (L.) (Diptera: Culicidae): In vitro and in silico studies
  106. Design, synthesis, characterization, and theoretical calculations, along with in silico and in vitro antimicrobial proprieties of new isoxazole-amide conjugates
  107. The impact of drying and extraction methods on total lipid, fatty acid profile, and cytotoxicity of Tenebrio molitor larvae
  108. A zinc oxide–tin oxide–nerolidol hybrid nanomaterial: Efficacy against esophageal squamous cell carcinoma
  109. Research on technological process for production of muskmelon juice (Cucumis melo L.)
  110. Physicochemical components, antioxidant activity, and predictive models for quality of soursop tea (Annona muricata L.) during heat pump drying
  111. Characterization and application of Fe1−xCoxFe2O4 nanoparticles in Direct Red 79 adsorption
  112. Torilis arvensis ethanolic extract: Phytochemical analysis, antifungal efficacy, and cytotoxicity properties
  113. Magnetite–poly-1H pyrrole dendritic nanocomposite seeded on poly-1H pyrrole: A promising photocathode for green hydrogen generation from sanitation water without using external sacrificing agent
  114. HPLC and GC–MS analyses of phytochemical compounds in Haloxylon salicornicum extract: Antibacterial and antifungal activity assessment of phytopathogens
  115. Efficient and stable to coking catalysts of ethanol steam reforming comprised of Ni + Ru loaded on MgAl2O4 + LnFe0.7Ni0.3O3 (Ln = La, Pr) nanocomposites prepared via cost-effective procedure with Pluronic P123 copolymer
  116. Nitrogen and boron co-doped carbon dots probe for selectively detecting Hg2+ in water samples and the detection mechanism
  117. Heavy metals in road dust from typical old industrial areas of Wuhan: Seasonal distribution and bioaccessibility-based health risk assessment
  118. Phytochemical profiling and bioactivity evaluation of CBD- and THC-enriched Cannabis sativa extracts: In vitro and in silico investigation of antioxidant and anti-inflammatory effects
  119. Investigating dye adsorption: The role of surface-modified montmorillonite nanoclay in kinetics, isotherms, and thermodynamics
  120. Antimicrobial activity, induction of ROS generation in HepG2 liver cancer cells, and chemical composition of Pterospermum heterophyllum
  121. Study on the performance of nanoparticle-modified PVDF membrane in delaying membrane aging
  122. Impact of cholesterol in encapsulated vitamin E acetate within cocoliposomes
  123. Review Articles
  124. Structural aspects of Pt(η3-X1N1X2)(PL) (X1,2 = O, C, or Se) and Pt(η3-N1N2X1)(PL) (X1 = C, S, or Se) derivatives
  125. Biosurfactants in biocorrosion and corrosion mitigation of metals: An overview
  126. Stimulus-responsive MOF–hydrogel composites: Classification, preparation, characterization, and their advancement in medical treatments
  127. Electrochemical dissolution of titanium under alternating current polarization to obtain its dioxide
  128. Special Issue on Recent Trends in Green Chemistry
  129. Phytochemical screening and antioxidant activity of Vitex agnus-castus L.
  130. Phytochemical study, antioxidant activity, and dermoprotective activity of Chenopodium ambrosioides (L.)
  131. Exploitation of mangliculous marine fungi, Amarenographium solium, for the green synthesis of silver nanoparticles and their activity against multiple drug-resistant bacteria
  132. Study of the phytotoxicity of margines on Pistia stratiotes L.
  133. Special Issue on Advanced Nanomaterials for Energy, Environmental and Biological Applications - Part III
  134. Impact of biogenic zinc oxide nanoparticles on growth, development, and antioxidant system of high protein content crop (Lablab purpureus L.) sweet
  135. Green synthesis, characterization, and application of iron and molybdenum nanoparticles and their composites for enhancing the growth of Solanum lycopersicum
  136. Green synthesis of silver nanoparticles from Olea europaea L. extracted polysaccharides, characterization, and its assessment as an antimicrobial agent against multiple pathogenic microbes
  137. Photocatalytic treatment of organic dyes using metal oxides and nanocomposites: A quantitative study
  138. Antifungal, antioxidant, and photocatalytic activities of greenly synthesized iron oxide nanoparticles
  139. Special Issue on Phytochemical and Pharmacological Scrutinization of Medicinal Plants
  140. Hepatoprotective effects of safranal on acetaminophen-induced hepatotoxicity in rats
  141. Chemical composition and biological properties of Thymus capitatus plants from Algerian high plains: A comparative and analytical study
  142. Chemical composition and bioactivities of the methanol root extracts of Saussurea costus
  143. In vivo protective effects of vitamin C against cyto-genotoxicity induced by Dysphania ambrosioides aqueous extract
  144. Insights about the deleterious impact of a carbamate pesticide on some metabolic immune and antioxidant functions and a focus on the protective ability of a Saharan shrub and its anti-edematous property
  145. A comprehensive review uncovering the anticancerous potential of genkwanin (plant-derived compound) in several human carcinomas
  146. A study to investigate the anticancer potential of carvacrol via targeting Notch signaling in breast cancer
  147. Assessment of anti-diabetic properties of Ziziphus oenopolia (L.) wild edible fruit extract: In vitro and in silico investigations through molecular docking analysis
  148. Optimization of polyphenol extraction, phenolic profile by LC-ESI-MS/MS, antioxidant, anti-enzymatic, and cytotoxic activities of Physalis acutifolia
  149. Phytochemical screening, antioxidant properties, and photo-protective activities of Salvia balansae de Noé ex Coss
  150. Antihyperglycemic, antiglycation, anti-hypercholesteremic, and toxicity evaluation with gas chromatography mass spectrometry profiling for Aloe armatissima leaves
  151. Phyto-fabrication and characterization of gold nanoparticles by using Timur (Zanthoxylum armatum DC) and their effect on wound healing
  152. Does Erodium trifolium (Cav.) Guitt exhibit medicinal properties? Response elements from phytochemical profiling, enzyme-inhibiting, and antioxidant and antimicrobial activities
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Heruntergeladen am 6.12.2025 von https://www.degruyterbrill.com/document/doi/10.1515/chem-2024-0086/html
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