Startseite Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
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Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds

  • Raed A. Al-Qawasmeh EMAIL logo , Louy A. Al-Nazer , Sarah A. Dawlat-Kari , Luay Abu-Qatouseh , Salim S. Sabri , Murad A. AlDamen und Mutasem Sinnokrot
Veröffentlicht/Copyright: 25. März 2020
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Open Chemistry
Aus der Zeitschrift Open Chemistry Band 18 Heft 1

Abstract

Sixteen new isoxazole tagged indole compounds have been synthesized via copper (I) catalyzed click chemistry of the aryl hydroxamoyl chloride and an indole containing alkyne moiety. The chemical structure of the synthesized compounds has been established using various physicochemical techniques. X-ray single crystal analysis of Ethyl 1-((3-phenylisoxazol-5-yl) methyl)-1H-indole-2-carboxylate (8a) has been analyzed. All compounds were tested for their antibacterial and anticancer activities. The activities for the new compounds were weak against both bacterial strains and the cancer cell lines.

Keywords: isoxazole; indole; click chemistry; 1,3-dipolar cycloaddition; Alkyne; Copper (I)

1 Introduction

Indole derivatives, either synthetic or natural, are considered as privileged scaffolds in medicinal chemistry [1, 2, 3, 4]. Many of them are the soul of an important class of therapeutic agents, including anticancer [5], antioxidant [6], antirheumatoidal [7], and anti-HIV [8, 9, 10] agents. They can also play a vital role in drugs targeting the immune system [11] and as tubulin polymerization inhibitors [12]. In view of the importance of the indole containing compounds, there is an ever-increasing demand to introduce new compounds based on indole moiety.

Isoxazole and their derivatives, on the other hand, have received comparable attention to the indole containing moieties. This is due to their diverse biological activities, which include, but are not limited to, their role as antiplatelet agents [13], antiviral and anti-HIV [14,15], anti-diabetic [16] anti-Alzheimer, anti-cancer and anti-inflammatory agents [17,18].

The nature and the fast pace of chemical research forced scientists to cope by creating reaction conditions that subjugate to its nature. Hence, the relatively new “click chemistry” reactions have been originated by Sharpless and coworkers in 2001 [19,20]. Many reactions were found to satisfy the “click” criteria, the most notable of which are the cycloaddition reactions [21]. The superiority of the click methodology over the traditional Huisgen thermal process is the introduction of metal catalysts such as Cu(I), with the possibility of using other metal catalysts (Ru, Ni, Pt, Pd), within the reaction system at room temperature, rather than resorting to elevated temperatures. This introduction led to an enhancement of the regioselectivity of the product with respect to the Huisgen thermal process [22].

Inspired by the above facts, and in pursuit of our research group theme, which targets research in the realms of drug design and discovery, we report herein, the synthesis of new hybrid scaffolds combining indole and substituted isoxazole based on the well-established “click chemistry” methodology. We are hereby successfully reporting potent antimicrobial agents based on the indole moiety hybridization with other heterocyclic systems, such as triazine [23] and imidazole [24]. The latter-mentioned scaffolds have been reported to be active against various bacterial strains as well as cancer cell lines. (Figure 1)

2 Results, Experimental Procedure, and Discussion

The newly-designed compounds were synthesized from the commercially available 1-H-indole-2-carboxylic acid (1). In detail, we utilized both the carboxylic acid and the NH of the indole moiety to introduce our click precursors (2) and (3), as shown in Scheme 1. The precursor (2) was synthesized in a quantitative yield through the reaction with propargyl bromide in the presence of potassium carbonate in dry DMF. For precursor (3) the carboxylic acid group was protected with ethyl ester before reacting it with sodium hydride in dry DMF, and thereafter with propargyl bromide. Both 1H and 13C-NMR analyses for (2) and (3) clearly depict the characteristic features of the propargyl moiety along with the indole part.

Scheme 1 Synthesis of the click precursors (2) and (3); i- Propargyl bromide, K2CO3/DMF, 0 ̊C., ii- EtOH/H2SO4 reflux 4h’s. iii- Propargyl bromide, NaH/DMF, 0 ̊C.
Scheme 1

Synthesis of the click precursors (2) and (3); i- Propargyl bromide, K2CO3/DMF, 0 ̊C., ii- EtOH/H2SO4 reflux 4h’s. iii- Propargyl bromide, NaH/DMF, 0 ̊C.

Having the first click precursor in hand, the second precursor was synthesized via a two-step process. Initially, a selected set of aldehydes (4a-h) were condensed with hydroxyl amine [25]. This was followed by a reaction with N-chlorosuccinimide in dry DMF to give the pure hydroxyimoyl chloride (6a-h), as shown in Scheme 2.

Scheme 2 Synthesis of second click precursor the hydroxamoyl chloride 6a-h; i- Hydroxylamine hydrochloride, Ar-aldehyde, H2O/EtOH, 50 % NaOH, 1h, HCl (conc.). ii- oxime, DMF/NCS 2-6 h’s.
Scheme 2

Synthesis of second click precursor the hydroxamoyl chloride 6a-h; i- Hydroxylamine hydrochloride, Ar-aldehyde, H2O/EtOH, 50 % NaOH, 1h, HCl (conc.). ii- oxime, DMF/NCS 2-6 h’s.

Figure 1 Structure of indole hybridized with triazine (I) and imidazole (II).
Figure 1

Structure of indole hybridized with triazine (I) and imidazole (II).

1,3-dipolar cycloaddition was then realized with the dipolarophile (2) and (3) with the nitrile oxide generated in situ from (6a-h) upon the action of base directly before the reaction. This will serve to prevent dimerization to furoxans. Clicking both precursors shown in Scheme 1 produced the desired new compounds (7a-h) and (8a-h) (Scheme 3). All the new compounds were fully characterized using 1H, 13C and 2D-NMR techniques along with HRMS (ESI). In series (7) the 1H-NMR shows a clear singlet for 2H resonating around δ = 6.0 ppm assigned for the methylene CH2 protons, where a 0.5-0.7 down field shift were observed for all the synthesized compounds from the propargylated starting compound (2). Additionally, the new singlet signal assigned for CH in the isoxazole appeared around 6.9-7.5 ppm which was correlated with the signal for the carbon at 100-112 ppm in the 13C-NMR spectrum. In the other series, the compounds show two CH2 signals, the first signal belongs to the methylene protons of the ester (OCH2CH3) at about 4.3 ppm, while the second one belongs to the methylene protons of the carbon attached to indole nitrogen (NCH2-isoxazole) at about 6.0 ppm. It was also observed that the CH of the isoxazole resonated in the same region as in the first series for both proton and carbon.

Scheme 3 Synthesis of compound (7a to h) and (8a to h); i- CuI, toluene/Et3N overnight.
Scheme 3

Synthesis of compound (7a to h) and (8a to h); i- CuI, toluene/Et3N overnight.

HRMS-ESI analysis gave exact molecular ions for all the compounds. The structures of the new derivatives were determined from their corresponding 1H and 13C-NMR spectra. The formation of the isoxazole moiety was characterized via the methine proton signal, that resonates as a singlet at δ = 7.07-7.43 ppm. The singlet at δ = 7.39 ppm was assigned to H-3 of the indole moiety. All compounds show the features of a para-substituted aromatic system along with the aromatic signals of the indole. 13C-NMR, on the other hand, clearly indicates all the features of the synthesized compounds. HMQC, HMBC and DEPT experiments allow us to fully assign all protons and carbons for the new compounds. The NH protons in compounds (3) and (7a-h) of the indole moiety appeared at 11.90-12.00 ppm for all the synthesized compounds.

X-ray structure determination was performed to further confirm the indole- hybrid system, with compound (8a) selected as a representative example of this new class of hybrid system (Figure 2). The molecule crystallizes in a monoclinic chiral space group P21. A summary of data collection and refinement parameters are given in Table 1. Figure 2 of compound (8a) shows that the indole along with the carboxylate moieties is in one plane with the CH2-isoxazole plane. Additionally, the isoxazole ring is connected to the indole via the CH2 moiety with angle N1C12C13 of 110.7(3)°. An insight into intermolecular interactions can be obtained by electrostatic potential map and two-dimensional fingerprint plots mapped in the Hirschfeld surface, analyzed by CrystalExplorer 17.5 [26, 27, 28]. The electrostatic potential of compound (8a) (Figure 3a) shows that the isoxazole plane is almost negative towards the oxygen atoms while the indole plane is positive. This makes the molecule neutral with non-favorable intermolecular interactions. The two dimensional fingerprint plots and the contributions of individual interatomic contacts toward the overall crystal packing are shown in Figure 3b. Several directional contacts can be observed, such as C–C (1.8%), C–H (16.4%), N–H (4.2%), O–H (7.8%) along with H–H (66.7%). These intermolecular atom-atom contacts contribute to the stability of the crystal packing of compound (8a).

Figure 2 Molecular structure and atom numbering scheme of 8a. Thermal ellipsoids are drawn at 30% probability level.
Figure 2

Molecular structure and atom numbering scheme of 8a. Thermal ellipsoids are drawn at 30% probability level.

Figure 3 a) Compound (8a) mapped over the Hirschfeld surface with a scale of -0.07 a.u. (red) through 0.0 (white) to +0.04 a.u. (blue); b) Two-dimensional full fingerprint plots and decomposed fingerprint plots over the Hirschfeld surface for various intermolecular atom–atom contacts in compound (8a). The numbers in brackets indicate the percentage contributions of each contact.
Figure 3

a) Compound (8a) mapped over the Hirschfeld surface with a scale of -0.07 a.u. (red) through 0.0 (white) to +0.04 a.u. (blue); b) Two-dimensional full fingerprint plots and decomposed fingerprint plots over the Hirschfeld surface for various intermolecular atom–atom contacts in compound (8a). The numbers in brackets indicate the percentage contributions of each contact.

Table 1

Crystal data and structure refinement for compound 8a.

Empirical formulaC21H18N2O3
Formula weight346.37
AppearanceBlock, colorless
Crystal systemMonoclinic,
Space groupP21
Temperature291 K°
A/å6.7129 (4)
B/å12.5657 (8)
C/å1610.8955 (9)
β/°104.802 (7)°
Volume/å3888.57 (11)
Z2
Ρcalcmg/mm31.295
μ/mm‑10.09
F(000)364
Θ range for data collection3.2–29.4°
Index ranges-29 ≤ h ≤ 27, -28 ≤ k ≤ 29, -21 ≤ l ≤ 10
Reflections collected4257
Independent reflections2979 [R(int) 0.017]
Data/restraints/parameters3501/0/209
Goof on f21.063
Final r indexesR1 = 0.038
[i>=2σ (i)], wR2 = 0.1029
Final r indexes [all data]R1 = 0.0487, wR2 = 0.1097*
Largest diff. Peak/hole/eå-33.08 /-1.28

Ethical approval: The conducted research is not related to either human or animal use.

2.1 Biological Activities

Indole derivatives have shown various antibacterial and anticancer activities. In regards to the antimicrobial activity, this study reported weak in vitro antibacterial activity against both Gram positive and Gram negative bacteria. In addition, no significant activity was reported against pathogenic yeast and fungi. By the initial screening against selected pathogenic bacteria including Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, the minimal inhibitory concentrations of the tested compounds were higher than 1 mg / ml.

For the anticancer activity testing of the synthetic compounds, the inhibitory concentrations and percentage of killing of the tested compounds were measured using three human cancer cell lines: Leukemic cells (Hela), breast cancer cells (MCF-7), and epiglottis cancer cells (Hep-2) in addition to a non-human Chinese hamster ovary (CHO) cell lines. A concentration range of 100-500 ug/mL was used for all cells, and cell viability assay MTT was performed. A weak anticancer activity was observed for the tested compounds. Furthermore, Hela cell lines showed the highest sensitivity to all chemicals (% of killing equals to 20-34), whereas Hep-2 and MCF-7 cells were the least sensitive (% of killing equals to 5-11).

2.2 Experimental

1H-NMR spectra were recorded in hexadeuterodimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) on a Bruker Avance III-300 MHz and III-500 MHz Spectrometer with TMS as an internal standard. 13C-NMR spectra were obtained at 75 MHz and 125 MHz on the same instruments, respectively. Chemical shifts were reported as δ-values in ppm. High resolution Mass spectra (HRMS) were recorded in positive ion mode by Electro Spray Ionization (ESI) using a Bruker Daltonics Apex IV, 7.0 T Ultra Shield Plus. The samples were dissolved in chloroform, diluted in spray solution (methanol / water 1:1 v/v + 0.1% formic acid) and infused using a syringe pump with a flow rate of 2 μL / min. External calibration was conducted using arginine cluster in a mass range m/z 175-871. For all HRMS data, mass error falls in the range of 0.00–0.50 ppm. Melting points (m.p.) were determined on an Electrothermal Melting Point Apparatus and were uncorrected in °C. Solvents used in this study were obtained from Scharlau, Fluka, Acros, and Aldrich. All reactions were monitored by thin layer chromatography (TLC) using Merck aluminum plates pre-coated with silica gel PF254; 20 × 20 × 0.25 mm, and detected by visualization of the plate under UV lamp (λ = 254 or 365 nm ). Spots were also detected by spraying with anisaldehyde- sulphuric acid in ethanol, followed by heating to 140°C [35].

2.2.1 X-Ray Crystallography

Compound (8a) was recrystallized from hot DMF/benzene after cooling to room tempetaure. Small amount of ice was added to produce a fine colorless block crystalline solid. The compound crystallized in monoclinic chiral space group P21. A summary of the crystallographic data and structure refinement parameters is given in Table 1.

Single-crystal X-ray diffraction data were collected using an Oxford Diffraction XCalibur, equipped with (Mo) X-ray Source (λ = 0.71073 Å) at room temperature (293(2) K). Data collection, reduction, and cell refinement were performed using the software package CrysAlisPro [29]. Analytical absorption corrections were applied using spherical harmonics implemented in SCALE3 (ABSPACK) scaling algorithm. Crystal structure was solved by direct methods, using the program OLEX2, followed by Fourier synthesis, and refined on F2 with SHELXL implemented in OLEX2 [30,31]. Anisotropic least-squares refinement of non-H atoms was applied. All crystallographic plots were obtained using the CrystalMaker program [32].

2.2.2 Prop-2-yn-1-yl 1H-indole-2-carboxylate (2)

1H-indole-2-carboxylic acid (1) 1.0 g (6.20 mmol) was dissolved in 10 ml DMF, and 5 equivalent of K2CO3, 4.28 g (31 mmol), were added at 0˚C. After 30 minutes, propargyl bromide (1.5 ml, 19 mmol) was added to the reaction mixture. After two hours, TLC confirmed the completion of the reaction; which was poured over crushed ice. The white precipitate that formed was collected and recrystallized from hot ethyl acetate. The product was produced with a high yield of 90.0%, and a melting point range of 136-138˚C.

2.2.3 Ethyl-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylate (3)

1-H-indole-2-carboxylic acid (1) was transformed into ethyl 1-H-indole-2-carboxylate using general method of esterification, where the indole acid was refluxed in ethanol in the presence of concentrated sulfuric acid (H2SO4) to produce indole ester with a high yield of 93.5% as a white solid after work up with water. The reaction of the ethyl 1-H-indole-2-carboxylate (3) with propargyl bromide was performed under an inert gas mixture (N2, Ar) in the presence of sodium hydride (NaH) and DMF as a solvent, to produce the ethyl-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylate as a white solid. This white solid was then recrystallized from hot EtOH. The product was obtained with a high yield of 80.7% and melting point range of 65-67˚C.

2.2.4 General Procedure for the Synthesis of Aryl Oximes (5a-h)

The designed oximes were prepared according to the general procedure described herein. Hydroxylamine hydrochloride (0.55 mol) was added to a mixture of aryl aldehyde (5a-h) (0.25 mol) dissolved in 30 ml H2O/EtOH (1:1) and 30 ml of ice. Afterwards, 0.63 mol of 50.0% NaOH was added dropwise and the reaction was stirred at room temperature for approximately one hour, and monitored by TLC in chloroform (CHCl3). After completion of the reaction, neutralization was accomplished using a concentrated HCl solution. Solid oximes were collected by suction filtration while liquid oximes were extracted with CHCl3 (20mL×2), dried over MgSO4. The solvent was evaporator; the aryl oximes were produced with high yields (74 – 93%) [27].

2.2.5 General Procedure for the Synthesis of Hydroxamoyl Chloride (6a-h)

To a stirred solution of 1.0 g of oxime (6a-h) in 15 ml DMF at room temperature, 1.3 mol equivalent of NCS was added. The initial addition (about 1/10 of the mass) results in a slight increase of temperature. In case that does not happen, then the solution is heated to 45°C to initiate the reaction. Once the reaction is initiated, the rest of NCS was added portion wise and the temperature was kept under 35°C. The mixture was stirred for 3-6 hours, and monitored by TLC (in CHCl3). After completion of the reaction, the mixture was poured over crushed ice and the resultant product was filtrated as a solid. In the case of liquid products, they were extracted using CHCl3 (20 mL×2) dried over MgSO4, and the solvent was removed using rotary evaporator. All hydroxamoyl chloride compounds (6a-h) were used in situ directly without further purification.

2.2.6 General Procedure for the Synthesis of Series (7) and (8)

A mixture of compound 3 (1.0 mmol) with 0.019 g copper (I) Iodide, CuI, (10 mmol) in the presence of Et3N (4.07 mmol) was stirred for 30 minutes. After that, 5-7 ml of toluene was added and the solution was stirred for an additional 30 minutes. To this solution, 1.3 mol equivalent of the corresponding hydroxamoyl chloride (7a-h) was added. The reaction mixture was stirred for 17-24 h. and monitored by TLC. After completion, 25 ml of EtOAc was added with stirring and the copper salt was removed by filtration. The filtrate was extracted and the combined organic layer was dried over Na2SO4. The solvent was evaporated and the product was purified using normal thin layer chromatography with Hexane/ethyl acetate as mobile phase (the ratio depended on the product polarity). Figure 4 shows the numbering system adopted in this study with compounds 7a and 8a used as representatives for this order.

Figure 4 structure and numbering of compounds (7a) and (8a).
Figure 4

structure and numbering of compounds (7a) and (8a).

(3-phenylisoxazol-5-yl)methyl 1H-indole-2-carboxylate (7a)

Yield: 57%; white solid; m.p: 196 - 198°C. 1H NMR (500 MHz, DMSO-d6) δ 5.53 (s, 2H, H-9), 7.05 (pseudo t, H-5), 7.19 (s, H-4’), 7.24 (s, H-3), 7.25 (pseudo t, H-6), 7.43 (d, J = 8.3 Hz, H-7), 7.47 (m, H-4’’), 7.48 (m, H-3’’, H-5’’ ),7.65 (d, J = 8.1 Hz, H-4), 7.86 (m, H-2’’, H-6’’), 11.90 (s, NH). 13C NMR (125 MHz, DMSO-d6): 57.1 (C-9), 103.0 (C-4’), 109.4 (C-3), 113.1 (C-7), 120.8 (C-5), 122.7 (C-4), 125.5 (C-6), 126.6 (C-2), 126.8 (C-3a), 127.1 (C-2’’, C-6’’), 128.7 (C-1’’), 129.6 (C-3’’, C-5’’), 130.9 (C-4’’), 138.2 (C-7a), 161.0 (C-5’), 163.0 (C-3’), 168.2 (C-8). HRMS (ESI) m/z: Calcd. For C19H14N2O3Na [M + Na]+ 341.09021. Found: 341.08966.

(3-(4-fluorophenyl)isoxazol-5-yl)methyl 1H-indole-2-carboxylate (7b)

Yield: 52%; White solid; mp: 155 - 157°C. 1H NMR (500 MHz, DMSO-d6): δ 5.58 (s, 2H, H-9), 7.10 (pseudo t, H-5), 7.27 (s, H-4’), 7.29 (s, H-3), 7.29 (pseudo t, H-6), 7.37 (pseudo t, H-2’’, H-6’’), 7.48 (d, J = 8.3 Hz, H-7), 7.68 (d, J = 8.1 Hz, H-4), 7.99 (dd, J H-H = 8.6 Hz , J H-F = 14.2 Hz, H-3’’, H-5’’), 11.99 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 57.0 (C-9), 102.9 (C-4’), 109.3 (C-3), 113.1 (C-7), 116.7 (2J C-F = 21.9 Hz, C-3’’, C-5’’), 120.5 (C-5), 122.4 (C-4), 125.2 (C-6), 126.6 (C-3a), 127.1 (C-2), 129.5 (C-1’’), 129.7 (3J C-F = 8.7 Hz, C-2’’, C-6’’), 138.1 (C-7a), 160.9 (C-5’), 161.6 (C-3’), 163.8 (1J C-F = 247.6 Hz, C-4’’), 168.5 (C-8). HRMS (ESI) m/z: Calcd. For C19H12FN2O3 [M - H]+ 335.08320. Found: 335.08374.

(3-(4-chlorophenyl)isoxazol-5-yl)methyl 1H-indole-2-carboxylate (7c)

Yield 54%; White solid; mp: 180 - 182°C. 1H NMR (500 MHz, DMSO-d6): δ 9.53 (bs, 1H), 7.77 (bd, J = 8Hz, 1H), 7.69 (m, 1H), 7.48-7.60 (m, 9H); 7.34-7.37 (m, 1H), 7.19-7.22 (m, 1H). 13C NMR (125 MHz, DMSO-d6): δ 57.0 (C-9), 102.9 (C-4’), 109.4 (C-3), 113.1 (C-7), 120.8 (C-5), 122.6 (C-4), 125.5 (C-6), 126.5 (C-3a), 127.1 (C-2), 127.5 (C-1’’), 128.6 (C-3’’, C-5’’), 129.4 (C-2’’, C-6’’), 135.5 (C-4’’), 138.1 (C-7a), 160.9 (C-5’), 161.7 (C-3’), 168.5 (C-8). HRMS (ESI) m/z: Calcd. for C19H13ClN2O3Na [M + Na]+ 375.05124. Found: 375.05069.

(3-(4-bromophenyl)isoxazol-5-yl)methyl 1H-indole-2-carboxylate (7d)

Yield 46%; White solid; mp: 165 - 168°C. 1H NMR (500 MHz, DMSO-d6): δ 5.59 (s, 2H, H-9), 7.10 (pseudo t, H-5), 7.29 (s, H-3), 7.29 (pseudo t, H-6), 7.29 (s, H-4’), 7.48 (d, J = 8.2 Hz, H-7), 7.68 (d, J = 8.0 Hz, H-4), 7.74 (d, J = 8.4 Hz, H-2’’, H-6’’), 7.87 (d, J = 8.4 Hz, H-3’’, H-5’’), 11.99 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 57.1 (C-9), 103.0 (C-4’), 109.4 (C-3), 113.1 (C-7), 120.8 (C-5), 122.7 (C-4), 124.3 (C-4’’), 125.5 (C-6), 126.5 (C-3a), 127.1 (C-2), 127.9 (C-1’’), 129.2 (C-2’’, C-6’’), 132.6 (C-3’’, C-5’’), 138.1 (C-7a), 160.9 (C-5’), 161.7 (C-3’), 168.6 (C-8).

(3-(4-cyanophenyl)isoxazol-5-yl)methyl 1H-indole-2-carboxylate (7e)

Yield 34%; White solid; mp: 162 - 164°C. 1H NMR (500 MHz, DMSO-d6): δ 5.63 (s, 2H, H-9), 7.10 (pseudo t, H-5), 7.29 (s, H-3), 7.29 (pseudo t, H-6), 7.40 (s, H-4’), 7.48 (d, J = 8.2 Hz, H-7), 7.68 (d, J = 8.0 Hz, H-4), 8.01 (d, J = 8.2 Hz, H-3’’, H-5’’), 8.15 (d, J = 8.2 Hz, H-2’’, H-6’’), 12.00 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 57.1 (C-9), 103.3 (C-4’), 109.4 (C-3), 113.1 (C-7), 113.3 (C-4’’), 118.8 (CN), 120.8 (C-5), 122.6 (C-4), 125.5 (C-6), 126.5 (C-3a), 127.1 (C-2), 127.9 (C-2’’, C-6’’), 133.0 (C-1’’), 133.6 (C-3’’, C-5’’), 138.2 (C-7a), 160.9 (C-5’), 161.4 (C-3’), 169.0 (C-8). HRMS (ESI) m/z: Calcd. For C20H12N3O3 [M - H]+ 342.08787. Found: 342.08763.

(3-(p-tolyl)isoxazol-5-yl)methyl 1H-indole-2-carboxylate (7f)

Yield 35%; White solid; mp: 165 - 167°C. 1H NMR (500 MHz, DMSO-d6): δ 2.38 (s, 3H, CH3), 5.57 (s, 2H, H-9), 7.10 (pseudo t, H-5), 7.21 (s, H-4’), 7.29 (s, H-3), 7.29 (pseudo t, H-6), 7.34 (d, J = 7.9 Hz, H-3’’, H-5’’),7.48 (d, J = 8.2 Hz, H-7), 7.68 (d, J = 8.0 Hz, H-4), 7.79 (d, J = 7.9 Hz, H-2’’, H-6’’), 11.90 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 21.4 (CH3), 57.1 (C-9), 102.8 (C-4’), 109.3 (C-3), 113.1 (C-7), 120.8 (C-5), 122.6 (C-4), 125.5 (C-6), 125.9 (C-2), 126.5 (C-3a), 127.0 (C-2’’, C-6’’), 127.1 (C-4’’), 130.1 (C-3’’, C-5’’), 138.1 (C-7a), 140.5 (C-1’’), 160.9 (C-5’), 162.4 (C-3’), 168.0 (C-8). HRMS (ESI) m/z: Calcd. For C20H15N2O3 [M - H]+ 333.12392. Found: 333.12337.

(3-(4-nitrophenyl)isoxazol-5-yl)methyl 1H-indole-2-carboxylate (7g)

Yield 22%; Off-white solid; mp: 150 - 153°C. 1H NMR (500 MHz, DMSO-d6): δ 5.62 (s, 2H, H-9), 7.10 (pseudo t, H-5), 7.29 (s, H-3), 7.29 (pseudo t, H-6), 7.43 (s, H-4’), 7.48 (d, J = 8.3 Hz, H-7), 7.68 (d, J = 8.0 Hz, H-4), 8.20 (d, J = 8.7 Hz, H-2’’, H-6’’), 8.37 (d, J = 8.7 Hz, H-3’’, H-5’’), 12.00 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 21.4 (CH3), 57.1 (C-9), 102.8 (C-4’), 109.3 (C-3), 113.1 (C-7), 120.8 (C-5), 122.6 (C-4), 125.5 (C-6), 125.9 (C-2), 126.5 (C-3a), 127.0 (C-2’’, C-6’’), 127.1 (C-4’’), 130.1 (C-3’’, C-5’’), 138.1 (C-7a), 140.5 (C-1’’), 160.9 (C-5’), 162.4 (C-3’), 168.0 (C-8). HRMS (ESI) m/z: Calcd. for C19H13N3O5 [M - H]+ 362.07770 .Found: 362.7824.

(3-(4-methoxyphenyl)isoxazol-5-yl)methyl 1H-indole-2-carboxylate (7h)

Yield 36%; white solid; mp: 146 - 149°C. 1H NMR (500 MHz, DMSO-d6): δ 3.83 (s, 3H, OCH3), 5.56 (s, 2H, H-9), 7.07 (d, J = 8.6 Hz, H-3’’, H-5’’), 7.10 (pseudo t, H-5), 7.19 (s, H-4’), 7.29 (s, H-3), 7.29 (pseudo t, H-6), 7.48 (d, J = 8.3 Hz, H-7), 7.68 (d, J = 8.0 Hz, H-4), 7.84 (d, J = 8.6 Hz, H-2’’, H-6’’), 11.99 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 55.8 (OCH3), 57.0 (C-9), 102.7 (C-4’), 109.3 (C-3), 113.1 (C-7), 115.0 (C-3’’, C-5’’), 120.8 (C-5), 121.6 (C-1’’), 122.6 (C-4), 125.5 (C-6), 126.6 (C-3a), 127.1 (C-2), 128.4 (C-2’’, C-6’’), 138.1 (C-7a), 160.9 (C-5’), 161.1 (C-3’), 162.1 (C-4’’), 167.8 (C-8). HRMS (ESI) m/z: Calcd. for C20H15N2O3 [M - H]+ 347.10373. Found: 347.10372.

Ethyl 1-((3-phenylisoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8a)

Yield 60.5%; white solid; mp: 112 – 113°C. 1H NMR (500 MHz, DMSO-d6): δ 1.33 (t, J = 7.10 Hz, CH2CH3), 4.34 (q, J = 7.10 Hz, OCH2CH3), 6.08 (s, NCH2C), 6.79 (s, H-4’), 6.89 (s, H-3), 7.19 – 7.81 (m, H-4, H-5, H-6, H-7, H-2”, H-3”, H-4”, H-5”, H-6”). 13C NMR (125 MHz, DMSO-d6): δ = 14.6 (CH2CH3), 40.4 (NCH2C), 61.1 (OCH2CH3),100.8 (C-4’), 111.6 (C-7), 111.7 (C-3), 121.7 (C-5), 123.1 (C-4), 126.0 (C-6), 126.1 (C-3a), 127.1 (C-2”, C-6”), 127.5 (C-2), 128.7 (C-4”), 129.5 (C-3”, C-5”), 130.7 (C-1”), 139.4 (C-7a), 161.6 (C-5’), 162.3 (Ar-COO), 170.1 (C-3’). HRMS (ESI) m/z: Calcd. for C21H18N2O3+ [M+H]+ 347.13902. Found: 347.13903

Ethyl 1-((3-(4-fluorophenyl)isoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8b)

Yield 41.2%; white solid; mp: 109 – 110°C. 1H NMR (500 MHz, DMSO-d6): δ 1.33 (t, J = 6.5 Hz, CH2CH3), 4.34 (q, J = 6.5 Hz, OCH2CH3), 6.07 (s, NCH2C), 6.80 (s, H-4’), 7.20 (overlapped dd, J = 7.1, 6.9, H-5), 7.31 (overlapped dd, J = 8.1, 8.2 Hz, H-3”, H-5”), 7.41 (m, H-3, H-6), 7.76 (m, H-4, H-7), 7.87 (m, H-2”, H-6”). 13C NMR (125 MHz, DMSO-d6): δ = 14.6 (CH2CH3), 40.4 (NCH2C), 61.1 (OCH2CH3), 100.8 (C-4’), 111.6 (C-3), 111.7 (C-7), 116.6 (2J C-F = 21.9 Hz, C-3”, C-5”), 121.67 (C-5), 123.1 (C-4), 125.3 (4J C-F = 3.2 Hz, C-1”), 126.0 (C-6), 126.1 (C-3a), 127.4 (C-2), 129.5 (3J C-F = 8.6 Hz, C-2”, C-6”), 139.5 (C-7a), 161.5 (Ar-COO), 161.6 (C-5’), 163.7 (1J C-F = 247.8 Hz, C-4”), 170.3 (C-3’). HRMS (ESI) m/z: Calcd. for C21H17FN2O3+ [M+H]+ 387.11154. Found: 387.11145.

Ethyl 1-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8c)

Yield 21.1%; white solid; mp: 117 – 119°C. 1H NMR (300 MHz, DMSO-d6): δ 1.39 (t, J = 7.1 Hz, CH2CH3), 4.37 (q, J = 7.1 Hz, OCH2CH3), 5.95 (s, NCH2C), 6.22 (s, H-4’), 7.19 (overlapped dd, J = 7.8, 7.2 Hz, H-5), 7.34 (d, J = 8.3 Hz, H-3”, H-5”) ,7.39 (m, H-3, H-6), 7.49 (d, J = 8.5 Hz, H-4), 7.62 (d, J = 8.3 Hz, H-2”, H-6”), 7.69 (d, J = 7.8 Hz, H-7). 13C NMR (75 MHz, CDCl3): δ = 14.4 (CH2CH3), 40.2 (NCH2C), 60.9 (OCH2CH3), 100.3 (C-4’), 110.4 (C-3), 111.8 (C-7), 121.5 (C-5), 122.9 (C-4), 125.9 (C-6), 126.2 (C-3a), 127.1 (C-1”), 127.3 (C-2), 128.1 (C-2”, C-6”), 129.1 (C-3”, C-5”), 136.1 (C-4”), 139.2 (C-7a), 161.6 (C-5’), 162.0 (Ar-COO), 169.7 (C-3’). HRMS (ESI) m/z: Calcd. for C21H17ClN2O3+[M+H]+ 381.10005. Found: 381.10003.

Ethyl 1-((3-(4-bromophenyl)isoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8d)

Yield 52.7%; white solid; mp: 108 – 109°C. 1H NMR (300 MHz, DMSO-d6): δ 1.27 (t, J = 7.1 Hz, CH2CH3), 4.29 (q, J = 7.1 Hz, OCH2CH3), 6.02 (s, NCH2C), 6.77 (s, H-4’), 7.15 (overlapped dd, J = 7.4, 7.7 Hz, H-5), 7.27 – 7.73 (m, 8H, ArH). 13C NMR (75 MHz, DMSO-d6): δ = 14.6 (CH2CH3), 40.4 (NCH2C), 61.1 (OCH2CH3), 100.8 (C-4’), 111.6 (C-3), 111.7 (C-7), 121.7 (C-5), 123.1 (C-4), 124.2 (C-6), 126.1 (C-3a), 127.5 (C-1”), 127.9 (C-2), 129.1 (C-2”, C-6”), 132.6 (C-3”, C-5”), 130.7 (C-4”), 139.5 (C-7a), 161.6 (C-5’), 161.6 (Ar-COO), 170.5 (C-3’). HRMS (ESI) m/z: Calcd. for C21H17BrN2O3Na + [M+Na]+ 447.03148. Found: 447.03236.

Ethyl 1-((3-(4-cyanophenyl)isoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8e)

Yield 50.3%; white solid; mp: 154 – 158°C. 1H NMR (300 MHz, DMSO-d6): δ 1.27 (t, J = 7.1 Hz, CH2CH3), 4.29 (q, J = 7.1 Hz, OCH2CH3), 5.51 (s, NCH2C), 6.05 (s, H-4’), 6.89 (s, H-3), 7.16 (pseudo t, J = 7.8 Hz, H-5), 7.27 – 7.74 (m, H-4, H-6, H-7), 7.90 (d, J = 8.4 Hz, H-3”, H-5”), 7.98 (d, J = 8.4 Hz, H-2”, H-5”). 13C NMR (75 MHz, DMSO-d6): δ = 14.6 (CH2CH3), 40.6 (NCH2C), 61.2 (OCH2CH3), 101.2 (C-4’), 111.6 (C-3), 111.8 (C-7), 113.2 (C-4”), 118.9 (C≡N), 121.7 (C-5), 126.1 (C-4), 127.0 (C-6), 127.5 (C-3a), 128.0 (C-2”, C-6”), 133.0 (C-2), 133.5 (C-3”, C-5”), 139.0 (C-1”), 139. 5 (C-7a), 161.3 (C-5’), 161.6 (Ar-COO), 171.0 (C-3’). HRMS (ESI) m/z: Calcd. for C22H17N3O3+[M+H]+ 372.13427. Found: 372.13426.

Ethyl 1-((3-(p-tolyl)isoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8f)

Yield 59.5%; white solid; mp: 80 – 81°C. 1H NMR (300 MHz, DMSO-d6) : δ = 1.28 (t, J = 7.1 Hz, CH2CH3), 2.29 (s, Ar-CH3), 4.29 (q, J = 7.1 Hz, OCH2CH3), 6.01 (s, NCH2C), 6.68 (s, H-4’), 7.13 (overlapped dd, J = 7.4, 7.3 Hz, H-5), 7.22 (d, J =7.8 Hz, H-3”, H-5”), 7.30 – 7.43 (m, H-3, H-6), 7.64 (d, J = 7.8 Hz, H-2”, H-6”), 7.70 (d, J = 7.8, H-4, H-7). 13C NMR (75 MHz, DMSO-d6) : δ = 14.8 (CH2CH3), 21.4 (Ar-CH3), 40.5 (NCH2C), 61.1 (OCH2CH3), 100.7 (C-4’), 111.6 (C-3), 111.7 (C-7), 121.7 ( C-5 ), 123.1 (C-4), 125.9 (C-2), 126.1 (C-6), 127.0 (C-2”, C-6”), 127.5 (C-1”), 130.1 (C-3”, C-5”), 139.5 (C-7a), 140.5 (C-4”), 161.6 (C-5’), 162.3 (Ar-COO), 169.9 (C-3’). HRMS (ESI) m/z: Calcd. for C22H20N2O3+[M+H]+ 361.15467. Found: 361.15450.

Ethyl 1-((3-(4-nitrophenyl)isoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8g)

Yield 57.4%; green solid; mp: 111 – 114°C. 1H NMR (500 MHz, DMSO-d6): δ = 1.32 (t, J = 7.0 Hz, CH2CH3), 4.34 (q, J = 7.0 Hz, OCH2CH3), 6.11 (s, NCH2C), 6.96 (s, H-4’), 7.21 (overlapped dd, J = 6.9, 7.7 Hz, H-5), 7.39 (m, H-3, H-6) ,7.77 (m, H-4, H-7), 8.11 (d, J = 7.4 Hz, H-2”, H-6”), 8.31 (d, J = 7.4 Hz, H-3”, H-5”). 13C NMR (125 MHz, DMSO-d6) : δ = 14.6 (CH2CH3) , 40.6 (NCH2C), 61.1 (OCH2CH3), 101.3 (C-4’), 111.5 (C-3), 111.8 (C-7), 121.7 ( C-5 ), 123.1 (C-4), 124.7 (C-3”, C-5” ), 126.1 (C-6), 127.4 (C-2), 128.4 (C-3a), 128.8 (C-2”, C-6”), 134.7 (C-1”), 139.4 (C-7a), 148.8 (C-4”), 161.0 (C-5’), 161.6 (Ar-COO), 171.1 (C-3’). HRMS (ESI) m/z: Calcd. for C21H17N3O5+[M+H]+ 392.12410. Found: 392.12397.

Ethyl 1-((3-(4-methoxyphenyl)isoxazol-5-yl)methyl)-1H-indole-2-carboxylate (8h)

Yield 31.8%; yellow solid; m.p: 144 – 146°C. 1H NMR (300 MHz, DMSO-d6): δ = 1.27 (t, J = 7.1 Hz, CH2CH3), 3.84 (s, Ar-OCH3), 4.29 (q, J = 7.1 Hz, OCH2CH3), 5.99 (s, NCH2C), 6.76 (s, H-4’), 7.07 – 7.38 (m, H-6, H-3’’, H-5”), 7.65 -7.74 (m, H-3, H-6), 7.82 (d, J = 2.1 Hz, H-2”, H-6”). 13C NMR (75 MHz, DMSO-d6): δ = 14.6 (CH2CH3), 40.7 (NCH2C), 56.8 (OCH3), 61.2 (OCH2CH3), 100.7 (C-4’), 111.5 (C-3), 111.7 (C-7), 113.7 (C-3”, C-5”), 121.7 (C-5), 122.0 (C-4), 122.2 (C-1”), 123.1 (C-6), 126.1 (C-2”, C-6”), 127.3 (C-3a), 127.5 (C-2), 139.4 (C-7a), 156.4 (C-5’), 161.1 (Ar-COO), 161.6 (C-4”), 170.2 (C-3’). HRMS (ESI) m/z: Calcd. for C22H20N2O4+[M+H]+ 377.14958. Found: 377.14969.

2.2.7 Grwoth and Maintainance of Microorganisms and Cancer Cell Lines

The synthesized compounds were tested against Gram-positive strains namely; Methicillin-sensitive Staphylococcus aureus NCTC 10788 (MSSA), methicillin-resistant Staphylococcus aureus ATCC 33591 (MRSA), two standard Gram-negative bacterial strains namely; Escherichia coli NCTC 12923, Pseudomonas aeruginosa NCTC 12924 along with the two fungi Candida albicans (NCPF 3179) and Aspergillus brasiliences (NCPF 2275). The microorganisms were inoculated into Trypticase soy broth and Sabaroud dextrose broth for bacteria and fungi respectively and the pH of the medium was adjusted to 7.3 with sterile phosphate buffered saline. The cultures were subsequently incubated at 37°C for 24-48 hours except for Aspergillus which was incubated at 25°C for 5-7 days. The optical density (OD) of the bacteria from mid-log phase of growth was measured at 600 nm and to obtain an optical density of 0.4 (corresponding to 1.5×108 colony forming units/mL).

MCF-7 (human breast adenocarcinoma), Hep2 (human epiglottis cancer), and Hela (cervical cancer cells) cell cultures were kindly provided by Jordan Company for Antibody Production (MONOJO, Amman, Jordan). The cell lines were cultured in growth medium (RPMI-1640medium, pH7.4), supplemented with 15% fetal bovine serum (FBS) and antibiotics [(penicillin (100 units/mL) and streptomycin (100 ug/mL)]. The cell lines were maintained at 37°C in a 5% CO2 atmosphere with 95% humidity [33].

2.2.8 Antimicrobial Susceptibility Testing

The stock suspensions of microorganisms were prepared to the standard McFarlands (0.5) and subsequently uniformly spread on a solid growth medium in a Petri dish. Sterile paper disks (6 mm in diameter; Becton, Dickinson & Co.) were placed on the agar plates and impregnated with 30 uL solution of each compound. Plates were incubated for the recommended time periods (24–48 h and up to 7 days for Aspergillus) under appropriate cultivation conditions. Antimicrobial activity was determined if the tested compound produced an inhibition zone around the impregnated disk. Disks impregnated with sterile DMSO served as negative controls and disks with standard antibiotics (vancomycin, ciprofloxacin, and clarithromycin (Oxoid, UK)) served as positive controls. Measurements at each concentration were performed in triplicates [36]. For MIC determination, 200 μL of diluted microbial suspension was added, (0.2500 μg/50 μL) of the synthesized compounds and standard antibiotics (Cephtriaxone, Gentamycin and Levofloxacin) in 20% H2O/DMSO were added to wells of ELISA plates, and subsequently incubated at conditions described above. The effect of the tested compounds on the growth of microorganisms was monitored by measuring the optical density at 600 nm using an ELISA reader. The MIC was defined as the lowest concentration of the tested compounds allowing no visible growth. All measurements of MIC values were repeated in triplicate.

Antimicrobial interactions between the tested compounds conventional antimicrobial agents like cefzolidin and amoxicillin against MRSA were evaluated by the standard checkerboard titration method [34]. The bacterial suspensions, growth media, and culture conditions were the same as those described for the MIC determination mentioned above. Experiments were performed in triplicate. The fractional inhibitory concentrations (FICs) were calculated as follows:

FIC = (MIC of drug A in combination/MIC of drug A alone) + (MIC of drug B in combination/MIC of drug B alone).

The FIC indices were interpreted as follows: ≤0.5, synergy; 0.5–1, additive; 1–4.0, indifference; >4.0, antagonism [37].

2.2.9 Cell Cytotoxicity for Anticancer Activity Testing

Microculture tetrazolium (MTT) assay was used to evaluate cell vitality. Briefly, monolayers of each cell line were trypsinized and the cells were seeded in 96-well plates at the density of 5 x105 cell/well (100 μL/well) in a culture medium and incubated for 24 h at 37oC, with 5% CO2 in a humidified atmosphere. The medium was subsequently removed and fresh growth medium containing different concentrations of tested compounds (concentration range of 5-500 μg/mL) were separately added. Control cells were supplemented only with a medium and colchicine was used as a positive control. 20 μL of 5 mg / mL MTT (pH 7.4) in 180 μL media was added per well and incubated for another 4 h. The plates were then centrifuged and supernatants were removed to all the addition of 100 μL of 1:1 ethanol: DMSO. The absorbance was then measured by an ELISA reader Bio-Rad, USA) at a wavelength of 570 nm. The values are presented as means of duplicate analyses. The activity of the tested compounds on the proliferation of cancer cells was expressed as the % of cytotoxicity [36].

3 Conclusion

In summary, sixteen new hybrid compounds were synthesized featuring the indole and the isoxazole moieties. All new compounds were identified and tested against three bacterial strains and three cancer cell lines. It was found through this research work that these newly-synthesized compounds did not show any promising activities. Single X-ray crystal structure was determined for a representative compound of these new hybrid systems.

Acknowledgments

This work was supported by grants (1015-1014\19) from the Deanship of Scientific Research-the University of Jordan, Amman 11942, Jordan.

  1. Conflict of interest: Authors declare no conflict of interest.

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Received: 2018-10-22
Accepted: 2019-10-02
Published Online: 2020-03-25

© 2020 Raed A. Al-Qawasmeh et al., published by De Gruyter

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

Artikel in diesem Heft

  1. Regular Articles
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  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
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  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
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https://doi.org/10.1515/chem-2020-0017
Schlagwörter für diesen Artikel
isoxazole; indole; click chemistry; 1,3-dipolar cycloaddition; Alkyne; Copper (I)
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
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  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
  50. Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique
  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
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  60. DFT investigations on arylsulphonyl pyrazole derivatives as potential ligands of selected kinases
  61. Treatment of Parkinson’s disease using focused ultrasound with GDNF retrovirus-loaded microbubbles to open the blood–brain barrier
  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
  67. Design, synthesis and pharmacological profile of (−)-verbenone hydrazones
  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
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  75. Electrochemical evaluation of the antioxidant capacity of natural compounds on glassy carbon electrode modified with guanine-, polythionine-, and nitrogen-doped graphene
  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
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  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
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  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
  125. Special Issue on 13th JCC 2018
  126. The Role of H2C2O4 and Na2CO3 as Precipitating Agents on The Physichochemical Properties and Photocatalytic Activity of Bismuth Oxide
  127. Preparation of magnetite-silica–cetyltrimethylammonium for phenol removal based on adsolubilization
  128. Topical Issue on Agriculture
  129. Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions
  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
  132. Lycopene in tomatoes and tomato products
  133. Fluorescence in the assessment of the share of a key component in the mixing of feed
  134. Sulfur application alleviates chromium stress in maize and wheat
  135. Effectiveness of removal of sulphur compounds from the air after 3 years of biofiltration with a mixture of compost soil, peat, coconut fibre and oak bark
  136. Special Issue on the 4th Green Chemistry 2018
  137. Study and fire test of banana fibre reinforced composites with flame retardance properties
  138. Special Issue on the International conference CosCI 2018
  139. Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide
  140. Synthesis of amorphous aluminosilicate from impure Indonesian kaolin
  141. Special Issue on the International Conf on Science, Applied Science, Teaching and Education 2019
  142. Functionalization of Congo red dye as a light harvester on solar cell
  143. The effect of nitrite food preservatives added to se’i meat on the expression of wild-type p53 protein
  144. Biocompatibility and osteoconductivity of scaffold porous composite collagen–hydroxyapatite based coral for bone regeneration
  145. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  146. Effect of natural boron mineral use on the essential oil ratio and components of Musk Sage (Salvia sclarea L.)
  147. A theoretical and experimental study of the adsorptive removal of hexavalent chromium ions using graphene oxide as an adsorbent
  148. A study on the bacterial adhesion of Streptococcus mutans in various dental ceramics: In vitro study
  149. Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study
  150. Special Issue on Chemistry Today for Tomorrow 2019
  151. Diabetes mellitus type 2: Exploratory data analysis based on clinical reading
  152. Multivariate analysis for the classification of copper–lead and copper–zinc glasses
  153. Special Issue on Advances in Chemistry and Polymers
  154. The spatial and temporal distribution of cationic and anionic radicals in early embryo implantation
  155. Special Issue on 3rd IC3PE 2020
  156. Magnetic iron oxide/clay nanocomposites for adsorption and catalytic oxidation in water treatment applications
  157. Special Issue on IC3PE 2018/2019 Conference
  158. Exergy analysis of conventional and hydrothermal liquefaction–esterification processes of microalgae for biodiesel production
  159. Advancing biodiesel production from microalgae Spirulina sp. by a simultaneous extraction–transesterification process using palm oil as a co-solvent of methanol
  160. Topical Issue on Applications of Mathematics in Chemistry
  161. Omega and the related counting polynomials of some chemical structures
  162. M-polynomial and topological indices of zigzag edge coronoid fused by starphene
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