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Abstract In this work, a novel series of quinoline-thiosemicarbazone-1,2,3-triazole-aceamide derivatives 10a-n as new potent α-glucosidase inhibitors was designed, synthesized, and evaluated. All the synthesized derivatives 10a-n were more potent than acarbose (positive control). Representatively, (E)-2-(4-(((3-((2-Carbamothioylhydrazineylidene)methyl)quinolin-2-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-phenethylacetamide (10n), as the most potent entry, with IC50 = 48.4 µM was 15.5-times more potent than acarbose. According to kinetic study, compound 10n was a competitive inhibitor against α-glucosidase. This compound formed the desired interactions with important residues of the binding pocket of α-glucosidase with favorable binding energy in the molecular docking and molecular dynamics. Compounds 10n, 10e, and 10 g as the most potent compounds among the synthesized compounds were evaluated in term of pharmacokinetics and toxicity via online servers. These evaluations predicted that compounds 10n, 10e, and 10 g had good pharmacokinetic properties and toxicity profile.

Abstract A new series of 2-amino-1,4-naphthoquinone-benzamides 5a-n was designed based on previously reported potent cytotoxic agents. These compounds were synthesized from the reaction of 1,4-naphthoquinone, 4-aminobenzoic acid, and appropriate amine derivatives in good yields. Cytotoxic activities of the target compounds 5a-n were evaluated against three cancer cell lines MDA-MB-231, SUIT-2, and HT-29 by MTT assay and the obtained in vitro data. All newly synthesized compounds were more potent than positive control cisplatin against MDA-MB-231 cell line and less potent than this control against SUIT-2 cell line. Moreover, most of the synthesized compounds were more potent than cisplatin against HT-29 cell line. Among the synthesized compounds, compound 5e was the most potent cytotoxic agent against all the three evaluated cell lines. Moreover, cell cycle analysis showed that derivatives 5f and 5l dose-dependently increase the percentage of sub-G1 cells. Induction of apoptosis as an important mechanism of anti-cancer drugs was confirmed morphologically in the most potent new compounds 5e, 5f, 5g, and 5l by Hoechst 33,258 staining.

Abstract In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure–activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.

Abstract In this work, a novel series of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives 5a–n were designed by consideration of the potent α-glucosidase inhibitors containing indole and carboxamide-1,2,3-triazole-N-phenylacetamide moieties. These compounds were synthesized by click reaction and evaluated against yeast α-glucosidase. All the newly title compounds demonstrated superior potency when compared with acarbose as a standard inhibitor. Particularly, compound 5k possessed the best inhibitory activity against α-glucosidase with around a 28-fold improvement in the inhibition effect in comparison standard inhibitor. This compound showed a competitive type of inhibition in the kinetics. The molecular docking and dynamics demonstrated that compound 5k with a favorable binding energy well occupied the active site of α-glucosidase.

Abstract Background Epilepsy is a common neurological disorder. The available drugs for this disease only control convulsions in nearly 70% of patients, while bearing many side effects. In this study, a new series of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids 8a-m was designed, synthesized, and evaluated as potent anticonvulsant agents. Methods Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid derivatives 8a-m were synthesized with well-known chemical reactions and anticonvulsant activity of them was determined by pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid scaffold has the necessary pharmacophores to be a benzodiazepine (BZD) receptor agonist, thus, the most potent anticonvulsant compounds were assayed in vivo and in silico as BZD receptor agonist. Furthermore, in vivo neurotoxicity evaluation and in silico physicochemical, pharmacokinetic, and toxicity study on the most potent compounds were also performed. Results Obtained results demonstrated that two compounds among the title new compounds have anticonvulsant activity in PTZ test while all of the new compounds are active in the MES test. The best anticonvulsant activities were obtained with nitro derivatives 8k and 8L. In vivo evaluation of flumazenil effect (a BZD receptor antagonist) on anticonvulsant activity of compound 8k confirmed that this compound is a BZD receptor agonist. The most potent compounds 8k and 8L interacted with the important residues of BZD-binding site of GABAA receptor. Furthermore, neurotoxicity of the latter compounds was lower than positive control diazepam. Conclusion According to these results, our designed scaffold can be a valuable lead structure for further structural developments and assessments to obtain a new potent anticonvulsant agent.

Abstract α-Glucosidase as a carbohydrate-hydrolase enzyme is a crucial therapeutic target for type 2 diabetes. In this work, benzo[d]imidazole-amide containing 1,2,3-triazole-N-arylacetamide derivatives 8a–n were synthesized and evaluated for their inhibitory activity against α-glucosidase. In vitro α-glucosidase inhibition assay demonstrated that more than half of the title compounds with IC50 values in the range of 49.0–668.5 μM were more potent than standard inhibitor acarbose (IC50 = 750.0 µM). The most promising inhibitor was N-2-methylphenylacetamid derivative 8c. Kinetic study revealed that compound 8c (Ki = 40.0 µM) is a competitive inhibitor against α-glucosidase. Significantly, molecular docking and molecular dynamics studies on the most potent compound showed that this compound with a proper binding energy interacted with important amino acids of the α-glucosidase active site. Study on cytotoxicity of the most potent compounds 8c, 8e, and 8g demonstrated that these compounds did not show cytotoxic activity against the cancer and normal cell lines MCF-7 and HDF, respectively. Furthermore, the ADMET study predicted that compound 8c is likely to be orally active and non-cytotoxic.

Abstract Background A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a–o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase. Methods The 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. Results All new derivatives 11a–o (IC50 values = 6.31 ± 0.03–49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound. Conclusion According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.

Abstract An important target in the treatment of type 2 diabetes is α-glucosidase. Inhibition of this enzyme led to delay in glucose absorption and decrease in postprandial hyperglycemia. A new series of phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides 11a–n were designed based on the reported potent α-glucosidase inhibitors. These compounds were synthesized and screened for their in vitro inhibitory activity against the latter enzyme. The majority of the evaluated compounds displayed high inhibition effects (IC50 values in the range of 45.26 ± 0.03–491.68 ± 0.11 µM) as compared to the positive control acarbose (IC50 value = 750.1 ± 0.23 µM). Among this series, compounds 11j and 11i represented the most potent α-glucosidase inhibitory activities with IC50 values of 45.26 ± 0.03 and 46.25 ± 0.89 µM. Kinetic analysis revealed that the compound 11j is a competitive inhibitor with a Ki of 50.4 µM. Furthermore, the binding interactions of the most potent compounds in α-glucosidase active site were studied through molecular docking and molecular dynamics. The latter studies confirmed the obtained results through in vitro experiments. Furthermore, in silico pharmacokinetic study of the most potent compounds was also performed.

Abstract Background A series of coumarin-indole hybrids was synthesized as the new α-glucosidase inhibitors. The title hybrids were considered as α-glucosidase inhibitors because had two active pharmacophores against α-glucosidase: coumarin and indole. Methods The thirteen various derivatives 4a–m were synthesized, purified, and fully characterized. These compounds were evaluated against α-glucosidase in vitro and in silico. In silico pharmacokinetic studies of the most potent compounds were also performed. Results Most of the title compounds exhibited high anti-α-glucosidase activity in comparison to standard drug acarbose. In particular, the phenoxy derivative 4d namely 3-((1H-indol-3-yl)(3-phenoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one showed promising activity. This compound is a competitive inhibitor against α-glucosidase and showed the lowest binding energy at the α-glucosidase active site in comparison to other potent synthesized compounds and acarbose. Conclusion Compound 4d can be a lead compound for further structural development to obtain effective and potent α-glucosidase inhibitors.

Abstract The control of postprandial hyperglycemia is an important target in the treatment of type 2 diabetes mellitus (T2DM). As a result, targeting α-glucosidase as the most important enzyme in the breakdown of carbohydrates to glucose that leads to an increase in postprandial hyperglycemia is one of the treatment processes of T2DM. In the present work, a new class of benzimidazole-Schiff base hybrids 8a–p has been developed based on the potent reported α-glucosidase inhibitors. These compounds were synthesized by sample recantations, characterized by 1H-NMR, 13C-NMR, FT-IR, and CHNS elemental analysis, and evaluated against α-glucosidase. All new compounds, with the exception of inactive compound 8g, showed excellent inhibitory activities (60.1 ± 3.6–287.1 ± 7.4 µM) in comparison to acarbose as the positive control (750.0 ± 10.5). Kinetic study of the most potent compound 8p showed a competitive type of inhibition (Ki value = 60 µM). In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the title new compounds over the active site of α-glucosidase. In silico druglikeness analysis and ADMET prediction of the most potent compounds demonstrated that these compounds were druglikeness and had satisfactory ADMET profile.

Abstract A new series of N-thioacylated ciprofloxacin 3a–n were designed and synthesized based on Willgerodt–Kindler reaction. The results of in vitro urease inhibitory assay indicated that almost all the synthesized compounds 3a–n (IC50 = 2.05 ± 0.03–32.49 ± 0.32 μM) were more potent than standard inhibitors, hydroxyurea (IC50 = 100 ± 2.5 μM) and thiourea (IC50 = 23 ± 0.84 μM). The study of antibacterial activity against Gram-positive species (S. aureus and S. epidermidis) revealed that the majority of compounds were more active than ciprofloxacin as the standard drug, and 3h derivative bearing 3-fluoro group had the same effect as ciprofloxacin against Gram-negative bacteria (P. aeruginosa and E. coli). Based on molecular dynamic simulations, compound 3n exhibited pronounced interactions with the critical residues of the urease active site and mobile flap pocket so that the quinolone ring coordinated toward the metal bi-nickel center and the essential residues at the flap site like His593, His594, and Arg609. These interactions caused blocking the active site and stabilized the movement of the mobile flap at the entrance of the active site channel, which significantly reduced the catalytic activity of urease. Noteworthy, 3n also exhibited IC50 values of 5.59 ± 2.38 and 5.72 ± 1.312 µg/ml to inhibit urease enzyme against C. neoformans and P. vulgaris in the ureolytic assay.

Abstract In the present work, a new series of 14 novel phthalimide-benzenesulfonamide derivatives 4a–n were synthesized, and their inhibitory activity against yeast α-glucosidase was screened. The obtained results indicated that most of the newly synthesized compounds showed prominent inhibitory activity against α-glucosidase. Among them, 4-phenylpiperazin derivative 4m exhibited the strongest inhibition with the IC50 value of 52.2 ± 0.1 µM. Enzyme kinetic study of compound 4m proved that its inhibition mode was competitive and Ki value of this compound was calculated to be 52.7 µM. In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the target compounds over the active site of α-glucosidase. Obtained date of these studies demonstrated that our new compounds interacted as well with the α-glucosidase active site with the acceptable binding energies. Furthermore, in silico druglikeness/ADME/Toxicity studies of compound 4m were performed and predicted that this compound is druglikeness and has good ADME and toxicity profiles.

Abstract In this study, 18 novel quinoline-based-benzo[d]imidazole derivatives were synthesized and screened for their α-glucosidase inhibitory potential. All compounds in the series except 9q showed a significant α-glucosidase inhibition with IC50 values in the range of 3.2 ± 0.3–185.0 ± 0.3 µM, as compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). A kinetic study indicated that compound 9d as the most potent derivative against α-glucosidase was a competitive type inhibitor. Furthermore, the molecular docking study revealed the effective binding interactions of 9d with the active site of the α-glucosidase enzyme. The results indicate that the designed compounds have the potential to be further studied as new anti-diabetic agents.