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In silico ADMET, molecular docking study, and nano Sb2O3-catalyzed microwave-mediated synthesis of new α-aminophosphonates as potential anti-diabetic agents

  • Shaik Mohammad Altaff , Tiruveedula Raja Rajeswari EMAIL logo and Chennamsetty Subramanyam
Published/Copyright: November 8, 2022
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Main Group Metal Chemistry
From the journal Main Group Metal Chemistry Volume 45 Issue 1

Abstract

An efficient and greener method is developed for the synthesis of α-aminophosphonates via Kabachnik–Fields reaction in solvent free condition using microwave irradiation technique. For all of the compounds, an in silico ADMET and molecular docking study was conducted to get insight on the drug likeliness behavior as well as their ability to block the enzyme α-amylase. The compounds with significant binding affinity and significant pharmacokinetic characteristics were produced. The newly produced compounds were spectroscopically analyzed to confirm their structure, and in vitro α-amylase inhibitory activity was also tested for all of them. The compounds 8j (half-maximal inhibitory concentration (IC50), 100.5 ± 0.2 μg·mL−1) showed better inhibitory activity than the reference drug, acarbose. The compounds 8d (IC50, 108.6 ± 0.2 μg·mL−1), 8g (IC50, 110.9 ± 0.3 μg·mL−1), 8h (IC50, 115.0 ± 0.1 μg·mL−1), and 8f (IC50, 118.9 ± 0.2 μg·mL−1) have been reported to exhibit significant inhibition toward the target enzyme. All the leftover compounds displayed modest to excellent inhibition through IC50 values in the range from 122.3 ± 0.3 to 154.3 ± 0.6 μg·mL−1 while comparing with the reference drug, Acarbose (IC50, 103.2 ± 0.7 μg·mL−1). The results disclosed that the majority of these compounds exhibit significant α-amylase inhibitory activity.

Keywords: α-aminophosphonates; Kabachnik–Fields reaction; microwave irradiation; molecular docking; α-amylase

1 Introduction

Organophosphorus compounds have gained significance in industrial, agricultural, medicinal, and synthetic organic chemistry as a result of their distinct physical, chemical, and biological properties (Bagi et al., 2019; Basha et al., 2016; Jean-Luc, 2014; Shameem and Orthaber, 2016). α-Aminophosphonates (α-Aps), for instance, are an intriguing class of bioactive analogues that mimic active peptide transition states and have features similar to naturally occurring amino acids (Orsini et al., 2010). α-Aps possess broad range of applications in the field of medicine (Mucha et al., 2011, Naydenova et al., 2010), biology (Smith and Bartlett, 1998), and industry (Dhawan and Redmore, 1987). They are useful compounds as antibiotics (Hirschmann et al., 1994; Kuemin and Donk, 2010), fungicides (Yang et al., 2006), bactericides (Herczegh et al., 2002), herbicides (Maier, 1990), enzyme inhibitors (Allen et al., 1989), antitumor reagents (Huang et al., 2013; Kafarski and Lejczak, 2001), anti-cancer agents (Bhattacharya et al., 2013), anti-thrombotic agents (Meyer and Barlett, 1998), anti-inflammatory (Damiche and Chafaa, 2017; Sujatha et al., 2017), anti-oxidants (Mohan et al., 2016), antiviral agents (Xie et al., 2017), protease inhibitors (Miller et al., 1998), peptide mimetics (Natchev, 1988), glutamine synthetase (Bayer et al., 1972), plant growth regulators (Maheshwara Reddy et al., 2021), metal corrosion preventor (Kuznetsov et al., 2003), and anti-diabetic agents (Madhu Kumar Reddy et al., 2021).

The nucleophilic addition of phosphites to imines, i.e., the Kabachnik–Fields (K–F) reaction, was shown to be a convenient approach among the several synthetic processes proposed for the synthesis of α-Aps (Ordonez et al., 2009). Several papers have recently been published describing the synthesis of α-Aps employing Lewis acids (Ghafuri et al., 2016; Ghosh et al., 2004; Tang et al., 2011; Wang et al., 2015), Bronsted acids (Farahani and Akbari, 2017; Mitragotri et al., 2008; Mohammadiyan et al., 2017; Rostamizadeh et al., 2011; Vahdat et al., 2008), solid acids (Sreekanth Reddy et al., 2014), bases (Lewkowski et al., 2014; Motevalli et al., 2015), nano catalysts (Kaboudin et al., 2017; Ravikumar et al., 2018; Syama Sundar et al., 2014), and other catalysts in the K–F reaction (Azaam et al., 2018; Karimi-Jaberi and Amiri, 2010; Ningbo et al., 2014; Yu and Xu, 2015). Although these methods are suitable for the one-pot synthesis of α-Aps, they have at least one disadvantage, such as extended reaction periods, low product yields requiring stoichiometric concentrations of catalysts, excess phosphorus compounds, or the usage of additives.

Oxides of antimony (OA) play a key role among all the other metal oxides from V to VI groups in the field of chemical, sensing, and semiconductors (Brebua et al., 2007; Dzimitrowicz et al., 1982; Laachachi et al., 2004; Nalin et al., 2001; Ozawa et al., 1998; Xie et al., 2004). In comparison to bulk OA, literature shows that nanoparticles of OA have superior qualities, such as a higher refractive index (Nalin et al., 2001), stronger abrasion resistance, higher proton conductivity (Dzimitrowicz et al., 1982; Ozawa et al., 1998), excellent mechanical strength (Chang et al., 2009), and higher absorbability (Xie et al., 1999). They possess a remarkable catalytic property in poly(ethylene terephthalate) and organic synthesis industries (Duh, 2002; Matsumura et al., 2006; Nanda et al., 2002; Spengler et al., 2001). Especially, nano Sb2O3 possess low affinity to side products, easy recovery, insoluble in organic solvents, avoids unwanted color, and acts as a catalytic agent in organic synthesis (Liu and Iwasawa, 2002). Recently, it has been reported that nano Sb2O3 can be effective in the synthesis of α-Aps (Syamala, 2009).

On the other hand, microwave (MW) irradiation (Mohan et al., 2016) provided a new approach of energizing the reaction mixture since it involves the direct transfer of energy to the substrate molecules and will boost the rate of the reaction by rapid kinetic excitation of molecules. MW-assisted organic syntheses have attracted a lot of attention from chemists in recent years because of their benefits such as shorter reaction times, cleaner products, operational simplicity, higher yields, and the possibility of achieving effective synthesis of heterocyclic bioactive compounds (De la Hoz et al., 2005; Sujatha et al., 2017). The use of a solvent-free reaction state has been shown to be an effective method for a variety of chemical reactions (Tanaka, 2000). This is a perfect platform for the three components of the K–F reaction, which may all be done in one pot.

In the disciplines of medical, drug design, and agrochemicals, dyes, photochemistry, and combinatorial chemistry, molecules with heterocyclic ring structures have attracted a lot of interest (Shiro et al., 2015; Vorathavorn et al., 2013). Thiazolidinediones (TZDs) are a type of heterocyclic molecule having a wide range of biological functions (Angajala et al., 2014; Bozdag-Dündar et al., 2008; Ceriello, 2008; Eun et al., 2007; Mori et al., 2008; Sahu et al., 2007). TZDs are being used to treat a variety of diabetic problems in type 2 diabetes mellitus patients (Yoshioka et al., 1989). Our recent study demonstrated that organophosphorus compounds bearing TZD moiety would be effective as α-amylase and α-glucosidase inhibitors in the diabetic treatment (Altaff et al., 2021; Hidalgo-Figueroa et al., 2013; Ibrar et al., 2017; Kaur et al., 2018; Pavan Phani Kumar et al., 2021; Ramandeep et al., 2021; Senthil et al., 2019; Sujatha et al., 2020; Vijay et al., 2022; Wang et al., 2017). By considering the above facts and in continuation of our studies toward developing new methods for the synthesis of bioactive α-Aps (Haji basha et al., 2020; Ravikumar et al., 2018; Subramanyam et al., 2017; Sujatha et al., 2017), we decided to explore the possibility of implementing a MW-mediated one-pot three-component reaction for the preparation of α-Aps using nano Sb2O3 as catalyst under solvent-free condition.

2 Results and discussion

2.1 Chemistry

In the present work, we have designed and synthesized a series of α-Aps (8a–j) starting with 2,4-thiazolidine-dione with good yields (89–95%). The synthetic strategy of α-Aps (8a–j) is presented in Scheme 1.

Scheme 1 Microwave-assisted synthesis of α-Aps (8a–j).
Scheme 1

Microwave-assisted synthesis of α-Aps (8a–j).

Initially, a model reaction was carried out for this reaction involving a mixture of picolinaldehyde (6a), diethyl (4-(2,4-dichlorophenyl)thiazol-2-ylamino)(phenyl)methyl-phosphonate (5), and diethyl phosphite (7). At the beginning of investigation, the reaction was carried out using tetrahydrofuran (THF) as solvent at 40°C without using any catalyst. In this case, the model molecules were not able to undergo efficient reaction to give the desired product, diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(pyridin-2-yl)methylphosphonate (8a), and obtained very poor yield (30%) of the product (Table 1, entry 1). Then, the reaction was carried out in the presence of a catalyst. In search for an efficient catalyst, the model reaction was conducted using catalyst (10 mol%) such as NiBr2, ZnCl2, LaCl3, CuCl2, AlCl3, and BF3·Et2O. The results are presented in Table 1 (entries 2–7).

Table 1

Synthesis of compound 8a under various conditionsa

Entry Catalyst (mol%) Solvent Temp. (°C) Time Yieldb (%)
1 — THF 40 24 h 30
2 NiBr2 (10) THF 40 7 h 59
3 ZnCl2 (10) THF 40 6 h 63
4 LaCl3 (10) THF 40 6 h 60
5 CuCl2 (10) THF 40 5 h 65
6 AlCl3 (10) THF 40 5 h 60
7 BF3·Et2O (10) THF 40 4.5 h 69
8 Nano Sb2O3 (10) THF 40 3 h 78
9 Nano Sb2O3 (10) DCM 40 3.5 h 73
10 Nano Sb2O3 (10) Toluene 60 4 h 70
11 Nano Sb2O3 (10) Ethanol 40 3.5 h 71
12 Nano Sb2O3 (10) Solvent-free 40 2 h 89
13 Nano Sb2O3 (10) Solvent-free (MW) Room temp. 15 min 93

aReaction of picolinaldehyde, diethyl (4-(2,4-dichlorophenyl)thiazol-2-ylamino)(phenyl)methyl-phosphonate and diethyl phosphite were selected as models to optimize reaction conditions.

bIsolated yield.

It was observed that the yield of the product 8a was improved from 30% to the range of 59–69%, indicating that the catalyst plays a hopeful role in the process. On the other hand, OA especially, nano Sb2O3, play a key role as catalytic agent in organic synthesis. Hence, nano Sb2O3 (10 mol%) was utilized in the model reaction to prepare compound 8a. A good yield (78%) (Table 1, entry 8) of the compound 8a was obtained, when THF was used as solvent within 3 h. Additionally, the effect of solvent on the reaction was also analyzed by varying different solvents such as dichloromethane (DCM), toluene, and ethanol. No appreciable yield of the product (70–73%) was found (Table 1, entry 9–11). Then, we tried this reaction without solvent. In this case, a good yield (89%) of the product was obtained within 2 h (Table 1, entry 12). Further, to improve the reaction conditions and to reduce the time to complete the reaction, the reaction mixture was MW-irradiated (450 W) without solvent using nano Sb2O3 (10 mol%). In this case, we obtained better yield (93%) of 8a within 10 min (Table 1, entry 13).

Further, the role of catalyst amount (nano Sb2O3) on the model reaction was also studied with different catalyst amounts ranging from 1 to 12.5 mol% (Table 2, entry 1–6). But no appreciable yield of the compound 8a other than 10 mol% was found. Hence, 10 mol% of the catalyst was confirmed using MW irradiation under solvent-free situation. The obtained results are summarized in Table 2. The reusability of nano Sb2O3 (10 mol%) was also studied. The product was filtered and the residue was washed with chloroform after every run to take away stains from surface of the catalyst and then reused it up to five times to prepare compound 8a (Table 3, entry 1–5). Hence, nano Sb2O3 (10 mol%) might efficiently catalyze the reaction without solvent under MW irradiation.

Table 2

The effect of the amount of catalyst, Nano Sb2O3 (10 mol%), to promote the Kabachnik–Fields reactiona

Entry Amount of catalyst (mol%) Time (min) Yieldb (%)
1 1 15 60
2 2.5 15 64
3 5 15 69
4 7.5 15 80
5 10 15 93
6 12.5 15 92

aReaction of picolinaldehyde, diethyl (4-(2,4-dichlorophenyl)thiazol-2-ylamino)(phenyl)methyl-phosphonate and diethyl phosphite were selected as models to optimize reaction conditions.

bIsolated yield.

Table 3

Reusability of the catalyst, nano Sb2O3 (10 mol%), for the synthesis of compound 5aa

Entry Nano Sb2O3 (10 mol%) Time (min) Yieldb (%)
1 1st run 15 93
2 2nd run 15 92
3 3rd run 15 90
4 4th run 15 89
5 5th run 15 83

aReaction of picolinaldehyde, diethyl (4-(2,4-dichlorophenyl)thiazol-2-ylamino)(phenyl)methyl-phosphonate and diethyl phosphite were selected as models to optimize reaction conditions.

bIsolated yield.

Once the reaction conditions were optimized, the generality of this process to synthesize α-Aps (8b–j) (Scheme 1) was studied with numerous aldehydes (6b–j), amine (5), and diethyl phosphite (7) in the presence of nano Sb2O3 (10 mol%) without solvent using MWI technique and Table 4 depicted the summary of results of this study. The detailed mechanism to synthesize new α-Aps (8a–j) is presented in Figure S1. Initially the carbonyl group of aldehyde reacts with amine to form an intermediate imine (A). The activated intermediate imine then reacts with diethylphosphite to give the respective α-Aps (8a–j).

Table 4

MW-mediated synthesis of α-aminophosphonates (8a–j) a

Compound Aldehyde Time (min) Yieldb (%) Compound Aldehyde Time (min) Yieldb (%)
8a 10 93 8f 10 95
8b 13 92 8g 12 93
8c 12 94 8h 10 94
8d 15 90 8i 15 96
8e 11 92 8j 10 92

aReaction of substituted aldehyde, diethyl (4-(2,4-dichlorophenyl)thiazol-2-ylamino)(phenyl)methyl-phosphonate and diethyl phosphite in the presence of nano Sb2O3 (10 mol%) without solvent under MWI.

bIsolated yield.

Nuclear magnetic resonance (NMR) (31P, 1H, 13C), infrared (IR) spectroscopy, mass, and elemental studies were used to confirm the structures of the newly synthesized compounds 8a–j. For the compounds 8a–j, singlet 31P NMR signals were found in the range of 25.3–15.7 ppm (Altaff et al., 2021; Quin et al., 1994). The signal attributable to the N–H proton of the thiazolidinedione ring and the NH proton linked to the phenyl ring were seen at 11.52 and 5.71 ppm for 8a–j in their 1H-NMR spectra. The aromatic protons of 8a–j produced two doublets at 7.02 and 6.33 ppm. The proton signals of compounds 8a–j emerged as multiplets for methylene protons at 4.19 ppm and as triplets for methyl protons at 1.21 ppm. The signal for ethylene and methine proton was found at 7.12 and 3.90 ppm, respectively. In 13C NMR spectra, the chemical shifts for carbonyl, ethylene, methylene, and methyl carbons were found at 165.8–164.5, 141.3, 63.5, and 13.7 ppm, respectively, in compounds 8a–j. The remaining carbons’ chemical changes were observed within their respective ranges. An IR spectral investigation of the prepared compounds was conducted in order to confirm their functional groups. In IR spectra, the absorption band in the range of 3,372–3,136 cm−1 is assigned to secondary amines of the compounds 8a–j. The stretching vibrations for P═O and P–O–Calip were noticed at 1,221–1,210 and 1,012–1,004 cm−1, respectively. M+ ions were found as base peaks in all the title compounds, as well as isotopic cluster peaks with the predicted ratio. The estimated elemental analysis values for the synthesized compounds were quite close to the empirical values. The Supplementary Materials contained typical spectra (1H, 31P, 13C NMR, IR, mass, and CHN analyses) of compound 8a as representative of title compounds (Figures S2–S7).

2.2 Pharmacology

2.2.1 In silico ADME analysis

In the process of drug discovery and development, compounds with high bioactivity and low toxicity are likely to be favored. One of the best ways to design new drug candidates is to use in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) property screening based on molecular structure. The rate of pharmacokinetic failure in clinical stages during the discovery phase is greatly reduced when ADME features are predicted early in the drug development process (Hay et al., 2014). SwissADME, which can be found at http://www.swissadme.ch, was used to test the ADME parameters of the proposed compounds. The prediction was based on the moieties’ physicochemical and structural advantages. The physicochemical parameters of the molecules 8a–j are displayed in Table 5 (molecular weight, heavy atoms, aromatic heavy atoms, ratio of sp3 hybridized carbons over the total carbon number of the molecule, rotatable bonds, H-bond acceptors and donors, molar refractivity, lipophilicity, and water solubility). When compared to Acarbose, these metrics were in good agreement with the applied criteria for all the compounds 8a–j and exhibited a good bioavailability score. The ADME parameters of the newly developed compounds are shown in Table 6. The gastrointestinal (GI) absorption of all the compounds was found to be minimal. Both passive blood–brain barrier (BBB) permeability and human gastrointestinal absorption (HIA) are demonstrated in the BOILED-Egg model’s output (Daina and Zoete, 2016) (Figure S8). The reference drug, acarbose was found to be out of range and all the tested molecules were discovered outside the egg, indicating that they were not absorbed and hence were not BBB permeant. Knowledge of compounds that are non-substrate or substrate of the permeability glycoprotein (Pgp) is used to evaluate the active efflux in biological membranes, especially for incidence from the GI wall to the lumen (Montanari and Ecker, 2015). Molecules 1 (8a) and 7 (8g) (Pgp–, blue dots) were anticipated to be effluated from the central nervous system by the Pgp, whereas molecules 2 (8b), 3 (8c), 4 (8d), 5 (8e), 6 (8f), 8 (8h), and 10 (8j) (Pgp+, red dots) were predicted not to be effluated.

Table 5

Physicochemical properties of compounds 8a–j

Compound aMW Heavy atoms Aromatic heavy atoms bFraction C sp3 Rotatable bonds H-bond acceptors H-bond donors cMR dTPSA eiLOGP fSilicos-IT class
8a 447.44 30 12 0.25 9 6 2 120.78 141.73 2.87 Poorly soluble
8b 531.95 35 16 0.21 9 6 2 143.29 141.73 3.44 Poorly soluble
8c 497.5 34 16 0.21 9 6 2 138.28 141.73 3 Poorly soluble
8d 486.48 33 15 0.22 9 6 2 132.76 141.98 3.28 Poorly soluble
8e 499.52 34 15 0.25 9 5 2 139.74 133.77 3.26 Poorly soluble
8f 503.53 33 15 0.23 9 6 2 136.16 169.97 3.45 Poorly soluble
8g 485.49 33 15 0.22 9 5 3 134.84 144.63 2.64 Poorly soluble
8h 593.38 36 16 0.21 9 7 2 146.73 159.05 3.58 Poorly soluble
8i 532.48 36 16 0.21 9 8 2 138.98 159.05 3.48 Poorly soluble
8j 528.51 36 16 0.24 9 7 2 143.99 159.05 3.37 Poorly soluble
Acarbose 645.6 44 0 0.92 9 19 14 136.69 321.17 0.63 Soluble

aMolecular weight; bThe ratio of sp3 hybridized carbons over the total carbon count of the molecule; cMolar refractivity; dtopological polar surface area (Å2); elipophilicity; fwater solubility (SILICOS-IT).

Table 6

Pharmacokinetic/ADME properties of compounds 8a–j

Compound aGI absorption bBBB permeant cPgp substrate dCYP1A2 inhibitor eCYP2C19 inhibitor fCYP2C9 inhibitor gCYP2D6 inhibitor hCYP3A4 inhibitor ilog Kp (cm·s−1)
8a Low No Yes No Yes Yes Yes Yes −7.08
8b Low No No No Yes Yes No Yes −6.04
8c Low No No No Yes Yes No Yes −6.46
8d Low No No No Yes Yes No Yes −6.27
8e Low No No No Yes Yes Yes Yes −6.61
8f Low No No Yes Yes Yes No Yes −6.33
8g Low No Yes No Yes Yes No Yes −6.49
8h Low No No No Yes Yes No Yes −7
8i Low No No No Yes Yes No Yes −7.05
8j Low No No No Yes Yes No Yes −6.84
Acarbose Low No Yes No No No No No −16.29

aGastrointestinal absorption; bblood–brain barrier permeant; cp-glycoprotein substrate; dCYP1A2: Cytochrome P450 family 1 subfamily A member 2; eCYP2C19: Cytochrome P450 family 2 subfamily C member 19; fCYP2C9: Cytochrome P450 family 2 subfamily C member 9; gCYP2D6: Cytochrome P450 family 2 subfamily D member 6; hCYP3A4: Cytochrome P450 family 3 subfamily A member 4; iskin permeation in cm·s−1.

In a pharmacokinetic study, it is crucial to forecast if a chemical will cause significant drug interactions by inhibiting cytochromes (CYPs) such CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4, as well as which isoenzymes would be affected (Hollenberg, 2002; Huang et al., 2008). Except 8f, all other molecules were non-inhibitors of CYP1A2. The molecules 8a and 8e were found to be inhibitors of CYP2D6. The study further demonstrated that all the tested molecules were inhibitors of CYP2C19, CYP2C9, and CYP3A4. All these isoenzymes were shown to be non-inhibitors by the reference drug, acarbose. All the compounds had significant low skin permeability with high skin permeability coefficient (log Kp) values, with the reference medication having the least skin permeability and the highest log Kp of all the molecules examined (−16.29).

Predicting drug-likeness factors can aid qualitative identification of a compound that turns out to be an oral medication with high bioavailability. To assess the drug-likeness and oral bioavailability of the developed compounds, we used five rules: Lipinski (Lipinski et al., 2001), Ghose (Ghose et al., 1998), Veber (Veber et al., 2002), Egan (Egan and Lauri, 2002), and Muegge (Muegge et al., 2001). All the molecules have followed the five principles with few exceptions. Table 7 lists the features of compounds 8a–j that relate to drug similarity. The bioavailability scores of all the compounds studied were found to be 0.55 except for acarbose (0.17), indicating good compliance. The pan assay interference compounds (PAINS) warnings are zero, indicating that the lead molecules’ pharmacokinetic profile is favorable. When compared to the reference drug, acarbose, the majority of the compounds showed good physicochemical, pharmacokinetic, and drug likeliness features.

Table 7

Drug likeness properties of compounds 8a–j

Compound Lipinski violations Ghose violations Veber violations Egan violations Muegge violations Bioavailability score PAINS alerts Synthetic accessibility
8a 0 0 1 1 0 0.55 0 4.53
8b 1 2 1 1 0 0.55 0 4.73
8c 0 2 1 1 0 0.55 0 4.75
8d 0 2 1 1 0 0.55 0 4.81
8e 0 2 0 1 0 0.55 0 4.78
8f 1 2 1 1 1 0.55 0 4.69
8g 0 2 1 1 0 0.55 0 4.73
8h 1 2 1 1 1 0.55 0 5.04
8i 1 2 1 1 1 0.55 0 4.99
8j 1 2 1 1 1 0.55 0 5.16
Acarbose 3 4 1 1 5 0.17 0 7.34

2.2.2 In silico molecular docking study

All the designed molecules were screened further in silico for their ability to bind with pancreatic α-amylase enzyme using 1-click docking online server tool (http://mcule.com/apps/1-click-docking/) authorized by AutoDock Vina docking algorithm (Trott and Olson, 2010). The screening results depicted that all molecules showed better or nearly equal binding energies (−8.6 to −7.6 kcal·mol−1) on comparison with reference drug, acarbose (−8.2 kcal·mol−1). The comprehensive data of binding energies and the corresponding bonding pose of complexes are shown in Table S1.

All the screened molecules (8a–j) have shown good docking with binding energies in the range −7.9 to 8.6 kcal·mol−1. Among the 10 molecules in this series, the molecules 8b, 8d, 8f, 8i, and 8j have shown equal or greater binding energies when compared with reference drug (Table S1). In compound 8b, the iso-quinoline formed π–π stacking with His305. In addition, the molecule formed hydrophobic interactions with residues such as Leu237, Ile235, Trp58, Trp59, Ala198, Tyr 62, Leu165, Leu162, Ala307, and Tyr151. In molecule 8d, oxygen atom of thiazolidine-dione formed hydrogen bonding with Lys200. Additionally, the molecule also formed hydrophobic contacts with residues Tyr151, Ala198, Ile235, Trp58, Trp59, Tyr62, Leu165, and Leu162. In molecule 8f, the oxygen atom of thiazolidine-dione formed hydrogen bonding with Gln63. Additionally, the phenyl and benzothiazole rings have formed π–π stacking with the residues His305 and His201, respectively. The hydrophobic interactions are formed by this molecule with Tyr62, Tyr151, Trp59, Trp58, Ile235, Val234, Ala198, Leu162, and Leu165. In molecule 8i, oxygen atom of both chromone and thiazolidine-dione rings formed hydrogen bonding with His305 and Lys200, respectively. The molecule 8i also formed hydrophobic contacts with residues, namely, Tyr151, Ile235, Ala198, Trp58, Trp59, Tyr62, Leu165, and Leu162. The molecule 8j showed the best binding energy among the screened molecules. Hydrogen bonding is formed by both oxygen atoms of thiazolidine-dione ring with residues, namely, Lys200 and Tyr151. It is observed that, π–π stacking is formed between chromone ring and Trp59. Besides, this molecule also formed hydrophobic contacts with Leu165, Leu162, Ala198, Tyr62, Trp59, Trp58, Tyr151, and Ile235. In scientific literature, 2D diagrams are used to recognize the binding interactions of the target protein with the ligands. These 2D ligand diagrams of the molecules 8b, 8d, 8f, 8i, and 8j which depict their binding contacts with target enzyme are given in Table 8.

Table 8

2D LIGPLOT images of compounds 8b, 8d, 8e, 8i, and 8j

Compound 2D structure Compound 2D structure
8b 8i
8d 8j
8f

2.2.3 α-Amylase inhibitory activity

The synthesized compounds were screened in vitro for their ability to inhibit α-Amylase using a standard method (Nickavar and Amin, 2011; Patil et al., 2013) with slight amendments. The screening was carried out at concentrations of 25, 50, 100, 150, and 200 μg·mL−1. Majority of the compounds showed good inhibition towards the target enzyme. The compound 8j bearing with 6-methyl-4-oxo-4H-chromen-3-yl moiety has shown the highest inhibitory activity amongst the screened compounds with IC50 value of 100.5 ± 0.2 μg·mL−1. The compound 8d bearing benzofuran-2-yl substituent has shown the second highest inhibition with IC50 value of 108.6 ± 0.2 μg·mL−1. The 8g having 1H-indol-5-yl substituent has shown the third highest inhibition with IC50 value of 110.9 ± 0.3 μg·mL−1. The compounds 8h bearing 6-bromo-4-oxo-4H-chromen-3-yl moiety and 8f with benzothiazol-2-yl substituent have shown the inhibition next to these compounds with IC50 values of 115.0 ± 0.1 and 118.9 ± 0.2 μg·mL−1, respectively. The remaining compounds 8a, 8b, 8c, 8e, and 8i exhibited moderate inhibition on the enzyme with IC50 ranging from 122.3 ± 0.3 to 154.3 ± 0.6 μg·mL−1. The results pertaining to % inhibition and IC50 values of all the compounds 8a–j are presented in Figures 1 and 2, respectively.

Figure 1 α-Amylase inhibition activity results of compounds 8a–j.
Figure 1

α-Amylase inhibition activity results of compounds 8a–j.

Figure 2 IC50 values of compounds 8a–j.
Figure 2

IC50 values of compounds 8a–j.

3 Conclusion

A greener approach was developed for the synthesis of new α-Aps 8a–j via one pot K–F reaction in high yields under solvent free condition using nano Sb2O3 as reusable catalyst. Prior to synthesis, compounds were designed to mimic ADMET and molecular docking in order to identify the most promising candidates for subsequent drug development. Molecules 8a–j, which are predicted based on the five principles and have strong oral bioavailability, are identified in a library of tested molecules with drug-likeness and good oral bioavailability. All compounds are poorly absorbed through the GI tract and do not permeate the BBB, hence they are not a Pgp substrate. When compared to the reference drug, the PAINS warnings are zero, indicating that the lead compounds have an outstanding pharmacokinetic profile. The results of the molecular docking analysis revealed that all of the compounds examined showed effective inhibition of the target enzyme. The synthesis of compounds with good drug-like behavior and the ability to block the target enzyme, α-amylase, was prompted. This cut down on drug development time, expense, and chemical waste. The spectrophotometric technique was used to test in vitro α-amylase inhibitory activity for all the newly synthesized compounds. The compound 8j showed superior inhibition against the target enzyme than reference drug. The compounds 8d, 8g, 8h, and 8f exhibited close inhibitory activity in comparison with a standard. When compared to the conventional drug, acarbose, most of the compounds showed considerable inhibition of the target enzyme. The results of this study show that the synthesized compounds will be promising next-generation anti-diabetic medications that can be utilized to successfully treat symptoms of diabetes complications.

Experimental methods

Materials and characterization techniques

Using MarvinView software, the structures of all the compounds were sketched, optimized, and transferred into the appropriate format. The 1-Click docking software, which is driven by the AutoDock Vina docking algorithm, was used to conduct the in silico molecular docking study. The structures of all the compounds were drawn, optimized, and converted into the required format using MarvinView software. In silico molecular docking study was done using 1-Click docking software powered by AutoDock Vina docking algorithm. To calculate IC50 values and to draw the graphs related to the biological activity, GraphPad Prism 9 software was used. The chemicals were purchased from SD Fine Chem. Ltd, India, and only a small percentage of them were refined using normal methods. All the reactions took place on a magnetic agitator that also served as a hot plate. The purity of the compounds was checked by thin-layer chromatography (TLC) on an Al sheet of silica gel. NMR spectra of 31P (161.9 MHz), 1H (400 MHz), and 13C (100 MHz) were recorded using a Bruker AMX spectrometer. On the SHIMADZU 2010A, Liquid chromatography–mass spectrometry (LCMS) was recorded and CHN analysis was performed on the T. F. Flash 1112 apparatus. The IR spectra were documented using a Fourier transform infrared spectrometer (Bruker IFS 55, Equinox) in KBr. Chemical shift, coupling constants, and J values were all expressed in Hz and ppm, respectively. Peaks in NMR spectra were represented by the symbol “s” for singlet, “d” for doublet, “t” for triplet, and “m” for multiplet. Single-mode MW synthesis apparatus was used for MW irradiation experiments.

Procedure

Synthesis of 2,4-thiazolidinedione (3)

In a reaction vessel, a solution of chloroacetic acid (1) (4.73 g, 0.05 mol) in water (20 mL) and thiourea (2) (3.81 g, 0.05 mol) in water (20 mL) were mixed and agitated for 15 min to produce a white ppt on cooling. 5 mL of concentrated HCl was gently added using a dropping funnel, and the mixture was refluxed for 10–15 h at roughly 105°C. A cluster of white needle-shaped compound was obtained after cooling. HCl traces were eliminated by washing with water and drying. Finally, the pure compound (3) was obtained by recrystallizing from ethyl alcohol, with a melting point of 122–124°C (Prashantha Kumar et al., 2011).

Synthesis of (E)-5-(4-aminobenzylidene)thiazolidine-2,4-dione (5)

In the presence of a catalytic quantity of piperidine, p-amino benzaldehyde (4.85 g, 0.04 mol) (4) was added to 2,4-thiazolidinedione (3) (5.85 g, 0.05 mol) in toluene (20 mL) and refluxed at 110°C for roughly 6 h before cooling to room temperature to precipitate off the (E)-5-(4-aminobenzylidene)thiazolidine-2,4-dione (5). To check the progress of the process, TLC (eluent: ethyl acetate: n-hexane, 5:5) was utilized. (5): Solid; yield, 93%; melting point (MP): 187–189°C; δ H (DMSO-d 6): 12.23 (s, 1H, NH), 7.13 (s, 1H, = C–H), 7.09 (d, 2H, J = 7.6 Hz, Ar–H), 6.58 (d, 2H, J = 7.6 Hz, Ar–H), 3.86 (br-s, 2H, NH2); δ C (DMSO-d 6 ): 165.5 (C-1), 164.3 (C-3), 113.5 (C-5), 143.5 (C-6), 123.2 (C-7), 126.4 (C-8, C-12), 115.4 (C-9, C-11), 149.6 (C-10) (Kawade et al., 2017; Sujatha et al., 2020; Young et al., 2012).

MW-assisted synthesis of α-Aps (8a–j)

The mixture of picolinaldehyde (6a) (2.14 g, 0.020 mol), diethyl (4-(2,4-dichlorophenyl)thiazol-2-ylamino)(phenyl)methyl-phosphonate (5) (4.40 g, 0.020 mol), diethyl phosphite (7) (2.6 mL, 0.020 mol) were placed in a flat bottomed flask. To this mixture, nano Sb2O3 (10 mol%) was added and the mixture was MW irradiated at 450 W under solvent free condition at ambient temperature for about 15 min. The progress of the reaction was monitored by TLC (ethylacetate: n-hexane, 4:6). After completion of the reaction as checked by TLC, the reaction mixture was cooled to room temperature. DCM (15 mL) was added to the reaction content and stirred for 10 min. The catalyst, nano Sb2O3 was separated by filtration as residue, washed with DCM (2 mL × 10 mL) and the residue was dried under vacuum at 100°C to utilize in further studies. The combined organic layer was washed with water (15 mL), dried over anhydrous Na2SO4, and concentrated under vacuum at 50°C to obtain the crude product. The pure compound, diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(pyridin-2-yl)methylphosphonate (8a) was obtained by column chromatography using ethyl acetate: n-hexane (7:3) as eluent. The same procedure was used for the preparation of the remaining compounds 8b–j.

Characterization of title compounds 8a–j

The general structure of title compunds (8a–j) is presented in Figure 3.

Figure 3 General structure of title compounds 8a–j.
Figure 3

General structure of title compounds 8a–j.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(pyridin-2-yl)methylphosphonate (8a)

Yield: 89%; solid, MP 176–178°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 8.52 (d, J = 7.2 Hz, 1H, Py-H), 7.74 (t, J = 7.6 Hz, 1H, Py-H), 7.48 (d, J = 7.2 Hz, 1H, Py-H), 7.21 (t, J = 8.0 Hz, 1H, Py-H), 7.12 (s, 1H, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar-H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 157.4 (C-22), 147.8 (C-17), 120.7 (C-25), 137.4 (C-26), 125.7 (C-27); δ P (DMSO-d 6): 15.7 ppm; IR (KBr) (ν max cm−1): 3,330, 3,125 (NH), 1,206 (P═O), 1,017 (P–O–Calip); LCMS (m/z, %): 448 (M + H+, 100); For C20H22N3O5PS, calculated: C, 53.69%; H, 4.96%; N, 9.39%; found: C, 53.80%; H, 4.83%; N, 9.52%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(3-chloroisoquinolin-4-yl)methylphosphonate (8b)

Yield: 91%; solid, MP 182–184°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 9.10 (s, 1H, isoqui-H), 7.89 (d, 1H, isoqui-H), 7.80 (d, 1H, isoqui-H), 7.51 (t, 1H, isoqui-H), 7.42 (t, 1H, isoqui-H), 7.12 (s, 1H, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 125.3 (C-22), 133.4 (C-23), 127.5 (C-24), 151.3 (C-25), 149.2 (C-27), 120.5 (C-28), 129.8 (C-29), 125.6 (C-30), 127.8 (C-31); δ P (DMSO-d 6): 19.4 ppm; IR (KBr) (ν max cm−1): 3,295, 3,147 (NH), 1,210 (P═O), 1,004 (P–O–Calip); LCMS (m/z, %): 532 (M + H+, 100); For C24H23ClN3O5PS, calculated: C, 54.19%; H, 4.36%; N, 7.90%; found: C, 54.07%; H, 4.49%; N, 7.75%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(quinolin-4-yl)methylphosphonate (8c)

Yield: 90%; solid, MP 191–193°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 8.51 (d, 1H, Qui-H), 8.07 (d, 1H, Qui-H), 7.82 (d, 1H, Qui-H), 7.51 (t, 1H, Qui-H), 7.38 (t, 1H, Qui-H), 7.08 (d, 1H, Qui-H), 7.12 (s, 1H, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 140.3 (C-22), 126.6 (C-23), 147.3 (C-24), 151.5 (C-26), 123.2 (C-27), 123.5 (C-28), 127.4 (C-29), 128.8 (C-30), 128.6 (C-31); δ P (DMSO-d 6): 18.2 ppm; IR (KBr) (ν max cm−1): 3,331, 3,136 (NH), 1,215 (P═O), 1,008 (P–O–Calip); LCMS (m/z, %): 498 (M + H+, 100); For C24H24N3O5PS, calculated: C, 57.94%; H, 4.86%; N, 8.45%; found: C, 57.82%; H, 4.99%; N, 8.31%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(benzofuran-2-yl)methylphosphonate (8d)

Yield: 94%; solid, MP 231–233°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 7.42 (d, 1H, benzofuran-H), 7.37 (d, 1H, benzofuran-H), 7.23 (t, 1H, benzofuran-H), 7.14 (t, 1H, benzofuran-H), 7.12 (s, 1H, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.53 (t, 1H, benzofuran-H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 153.3 (C-22), 104.5 (C-23), 127.8 (C-24), 153.7 (C-25), 122.4 (C-27), 123.2 (C-28), 125.6 (C-29), 118.2 (C-30); δ P (DMSO-d 6): 21.4 ppm; IR (KBr) (ν max cm−1): 3,324, 3,188 (NH), 1,220 (P═O), 1,012 (P–O–Calip); LCMS (m/z, %): 487 (M + H+, 100); For C23H23N2O6PS, calculated: C, 56.78%; H, 4.77%; N, 5.76%; found: C, 56.91%; H, 4.64%; N, 5.89%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(1-methyl-1H-indol-3-yl)methylphosphonate (8e)

Yield: 92%; solid, MP 204–206°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 7.37 (s, 1H, indole-H), 7.29 (t, J = 7.2 Hz, 1H, indole-H), 7.21 (t, J = 7.2 Hz, 1H, indole-H), 7.12 (s, 1H, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.89 (d, J = 7.2 Hz, 1H, indole-H), 6.78 (d, J = 7.2 Hz, 1H, indole-H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 3.45 (s, 3H, –CH3), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18, C-21), 113.2 (C-22), 126.5 (C-23), 137.9 (C-24), 125.8 (C-26), 118.4 (C-27), 123.4 (C-28), 120.4 (C-29), 110.5 (C-30), 43.4 (C-31); δ P (DMSO-d 6): 17.9 ppm; IR (KBr) (ν max cm−1): 3,315, 3,145 (NH), 1,217 (P═O), 1,005 (P–O–Calip); LCMS (m/z, %): 500 (M + H+, 100); For C24H26N3O5PS, Calculated: C, 57.71%; H, 5.25%; N, 8.41%; found: C, 57.58%; H, 5.37%; N, 8.28%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(benzo[d]thiazol-2-yl)methylphosphonate (8f)

Yield: 90%; solid, MP 213–215°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 7.12 (s, 1H, ═CH), 8.17 (d, J = 7.2 Hz, 1H, Ar–H), 8.06 (d, J = 7.2 Hz, 1H, Ar–H), 7.43 (t, J = 7.2 Hz, 2H, Ar–H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 167.3 (C-22), 151.8 (C-24), 135.1 (C-25), 120.4 (C-27), 126.7 (C-28), 127.3 (C-29), 121.2 (C-30); δ P (DMSO-d 6): 25.3 ppm; IR (KBr) (ν max cm−1): 3,311, 3,166 (NH), 1,215 (P═O), 1,010 (P–O–Calip); LCMS (m/z, %): 504 (M + H+, 100); For C22H22N3O5PS2, calculated: C, 52.48%; H, 4.40%; N, 8.35%; found: C, 52.60%; H, 4.29%; N, 8.47%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(1H-indol-5-yl)methylphosphonate (8g)

Yield: 93%; solid, MP 166–168°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 7.32 (d, J = 7.2 Hz, 1H, indole-H), 7.26 (d, J = 7.2 Hz, 1H, indole-H), 7.17 (d, J = 7.2 Hz, 1H, indole-H), 7.12 (s, 1H, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.76 (d, J = 7.2 Hz, 1H, indole-H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 6.25 (d, J = 7.2 Hz, 1H, indole-H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18, C-21), 134.1 (C-22), 117.3 (C-23), 128.4 (C-24), 132.6 (C-25), 109.8 (C-26), 117.3 (C-27), 101.2 (C-28), 123.5 (C-29); δ P (DMSO-d 6): 22.6 ppm; IR (KBr) (ν max cm−1): 3,372, 3,292, 3,177 (NH), 1,218 (P═O), 1,011 (P–O–Calip); LCMS (m/z, %): 486 (M + H+, 100); For C23H24N3O5PS, calculated: C, 56.90%; H, 4.98%; N, 8.66%; found: C, 56.99%; H, 4.82%; N, 8.78%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(6-bromo-4-oxo-4H-chromen-3-yl)methylphosphonate (8h)

Yield: 89%; solid, MP 158–160°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 7.75 (s, 1H, Ar–H), 7.42 (d, J = 7.2 Hz, 1H, Ar–H), 7.15 (s, 1H, = C–H), 6.78 (d, J = 7.2 Hz, 1H, Ar–H), 7.12 (s, 1H, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 117.5 (C-22), 152.3 (C-23), 157.5 (C-25), 127.9 (C-26), 181.8 (C-27), 118.3 (C-28), 139.7 (C-29), 116.4 (C-30), 135.8 (C-31); δ P (DMSO-d 6): 18.7 ppm; IR (KBr) (ν max cm−1): 3,311, 3,159 (NH), 1,213 (P═O), 1,007 (P–O–Calip); LCMS (m/z, %): 593 (M + H+, 100); For C24H22BrN2O7PS, calculated: C, 48.58%; H, 3.74%; N, 4.72%; found: C, 48.70%; H, 3.60%; N, 4.85%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(6-fluoro-4-oxo-4H-chromen-3-yl)methylphosphonate (8i)

Yield: 95%; solid, MP 224–226°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 7.45 (s, 1H, Ar–H), 7.12 (s, 1H, ═CH), 7.18 (s, 1H, = C–H), 7.03 (d, J = 7.2 Hz, 1H, Ar–H), 6.72 (d, J = 7.2 Hz, 1H, Ar–H), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9, C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 117.5 (C-22), 152.3 (C-23), 157.5 (C-25), 127.9 (C-26), 181.8 (d, J = 242 Hz, C-27), 118.7 (C-28), 123.7 (C-29), 156.4 (C-30), 114.9 (C-31); δ P (DMSO-d 6): 20.9 ppm; IR (KBr) (ν max cm−1): 3,345, 3,192 (NH), 1,221 (P═O), 1,012 (P–O–Calip); LCMS (m/z, %): 533 (M + H+, 100); For C24H22FN2O7PS, calculated: C, 54.13%; H, 4.16%; N, 5.26%; found: C, 54.25%; H, 4.04%; N, 5.39%.

Diethyl (4-((E)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)(6-methyl-4-oxo-4H-chromen-3-yl)methylphosphonate (8j)

Yield: 94%; solid, MP 238–240°C; δ H (DMSO-d 6): 11.52 (s, 1H, –NH), 7.41 (s, 1H, Ar–H), 7.13 (d, J = 7.2 Hz, 1H, Ar–H), 7.18 (s, 1H, = C–H), 7.12 (s, ═CH), 7.02 (d, J = 7.2 Hz, 2H, Ar–H), 6.73 (d, J = 7.2 Hz, 1H, Ar–H), 2.26 (s, 3H, CH3), 6.33 (d, J = 7.6 Hz, 2H, Ar–H), 5.71 (d, 1H, N–H), 4.19 (q, 4H, O–CH 2CH 3 ), 3.90 (d, 1H, P–CH–), 1.21 (t, J = 6.8 Hz, 6H, O–CH2 CH 3 ); δ C (DMSO-d 6): 164.5 (C-1), 165.8 (C-3), 116.3 (C-5), 141.3 (C-6), 122.4 (C-7), 128.1 (C-8 and C-12), 112.7 (C-9 and, C-11), 145.9 (C-10), 54.6 (C-14), 63.5 (C-17 and C-20), 13.7 (C-18 and C-21), 117.5 (C-22), 152.3 (C-23), 157.2 (C-25), 123.9 (C-26), 181.8 (C-27), 118.3 (C-28), 138.6 (C-29), 132.6 (C-30), 131.3 (C-31), 25.5 (C-32); δ P (DMSO-d 6): 16.8 ppm; IR (KBr) (ν max cm−1): 3,305, 3,145 (NH), 1,210 (P═O), 1,005 (P–O–Calip);LCMS (m/z, %): 529 (M + H+, 100); For C25H25N2O7PS, calculated: C, 56.81%; H, 4.77%; N, 5.30%; found: C, 56.69%; H, 4.89%; N, 5.17%.

In silico analysis

Using the Swiss ADME tool from the Swiss Institute of Bioinformatics (http://www.sib.swiss), all the designed molecules were in silico predicted for their physicochemical, lipophilicity, water-solubility, pharmacokinetic/ADME, drug-likeness properties, and medicinal chemistry.

In silico molecular docking studies

The binding mechanism of 8a–j with the targeted enzyme, pancreatic α-amylase, was investigated using in silico molecular docking. The RCSB, Protein Data Bank, was used to obtain the crystal structure of this enzyme (PDB ID: 3IJ8). Water molecules, heteroatoms, and co-factors were removed from the structure to make it more efficient. Charges, hydrogen bonds, and atoms that were missing were added. The process of docking ligands with proteins and their interactions were investigated using the discovery studio visualizer V16.1.0.15350 (Madhu Kumar Reddy et al., 2019).

α-Amylase inhibitory activity

All the newly synthesized compounds were screened for their inhibitory activity against α-amylase using standard protocol through minor changes reported by Nickavar and Amin (2011) which was at first proposed by Patil et al. (2013) (see Supplementary material for detailed procedure).

One of the best measures of a drug’s efficiency is IC50 (half-maximal inhibitory concentration). It reflects the amount of drug required to block a biological process by half, and so serves as a measure of antagonist drug potency in pharmacological research. In the present study, the IC50 values were calculated by plotting the concentration (X-axis) vs the percent inhibitory activity (Y-axis). Using the linear (y = mx + c) equation on this graph for y = 50 value x point becomes IC50 value. All the experiments were performed in triplicates and the results are expressed as mean value ± SD.

Acknowledgments

Authors acknowledge Dr. C. Naga Raju, Department of Chemistry, S. V. University, Tirupati for his constant support to complete this work.

  1. Funding information: Authors state no funding involved.

  2. Author contributions: Shaik Mohammad Altaff: conceptualization, resources, methodology, and investigation; Tiruveedula Raja Rajeswari: methodology and writing – review and editing; Chennametty Subramanyam: validation, formal analysis, and writing – original draft.

  3. Conflict of interest: Authors state no conflict of interest.

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Received: 2021-11-27
Revised: 2022-10-13
Accepted: 2022-08-23
Published Online: 2022-11-08

© 2022 Shaik Mohammad Altaff et al., published by De Gruyter

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

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https://doi.org/10.1515/mgmc-2022-0023
Keywords for this article
α-aminophosphonates; Kabachnik–Fields reaction; microwave irradiation; molecular docking; α-amylase
Creative Commons
BY 4.0

Articles in the same Issue

  1. Embedded three spinel ferrite nanoparticles in PES-based nano filtration membranes with enhanced separation properties
  2. Research Articles
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