Aug 2026· Journal of Visualized Experiments· Vol 234· 0 citations
Medicine
TL;DR
Experimental findings identify compounds 8c and 9e as promising lead scaffolds for the development of next-generation inhibitors of urease and α-glucosidase.
Abstract
This study investigated the therapeutic potential of novel 1,2,4-triazole- and 1,3,4-oxadiazole-based acetamide derivatives as dual-target inhibitors of urease and α-glucosidase, two enzymes implicated in gastrointestinal disorders and type 2 diabetes, respectively. An integrated approach combining multistep organic synthesis, in vitro biological evaluation, molecular docking, in silico ADME prediction, and density functional theory (DFT) analysis was employed to identify potent lead compounds with favorable pharmacokinetic properties. Starting from benzoic acid, a series of 1,2,4-triazole derivatives (8a-c) and 1,3,4-oxadiazole derivatives (9d-f) bearing substituted acetamide moieties were successfully synthesized. All compounds exhibited inhibitory activity against both target enzymes. Compound 8c was the most potent urease inhibitor (IC₅₀ = 6.14 ± 1.06 µM), while compound 9e showed the strongest α-glucosidase inhibition (IC₅₀ = 27.29 ± 0.41 µM), surpassing the reference inhibitor acarbose (IC₅₀ = 38.25 ± 0.12 µM). Computational analyses supported the experimental findings: ADME predictions indicated favorable drug-like properties, and molecular docking demonstrated strong binding interactions, with compound 8a exhibiting the highest affinity for α-glucosidase (-7.165 kcal/mol) and compound 9e showing the strongest binding to urease (-7.30 kcal/mol). DFT calculations further correlated biological activity with electronic properties, revealing relatively small HOMO-LUMO energy gaps for the most active compounds, 8c (0.14831 a.u.) and 9e (0.14302 a.u.). Collectively, these findings identify compounds 8c and 9e as promising lead scaffolds for the development of next-generation inhibitors of urease and α-glucosidase.
α-Glucosidase is a key therapeutic target for treating type 2 diabetes mellitus. A new series of novel diazene-tri(phenoxy-1,2,3-triazole-acetamide) derivatives 9a–p was designed by hybridizing previously reported potent α-glucosidase inhibitors. The target compounds were successfully synthesized and structurally characterized by 1H NMR, 13C NMR, and elemental analysis. All synthesized compounds were evaluated for their anti-α-glucosidase efficacy and exhibited excellent inhibitory effects, with IC50 values ranging from 0.10 to 10.9 µM, which are approximately 69- to 7500-fold more potent than the reference drug acarbose (IC50 = 750.0 µM). Among this series, compound 9f showed the most potent activity. Kinetic enzyme assays revealed that compound 9f acts as a competitive inhibitor of α-glucosidase, competing with the natural substrate for binding to the active site, with a Ki value of 100 nM. To gain mechanistic insight into the binding mode and the stability of the inhibitor–enzyme complex, molecular docking and molecular dynamics (MD) simulations were performed for compound 9f in the α-glucosidase active site. Furthermore, pharmacokinetic predictions using SwissADME and admetSAR showed that compound 9f exhibits a bioavailability radar and drug-likeness profile similar to that of acarbose. Based on the promising in vitro and in silico results, compound 9f represents a valuable lead compound for further structural optimization and development of efficient and potent new α-glucosidase inhibitors.
Shahab Kermaninia, M. Sayahi, Mohammad Halimi et al.· RSC Advances· 0 citations
Overall, the newly synthesized compounds demonstrated pronounced AR inhibitory activity and notable α-GLY inhibition and may therefore be considered potential candidates for further investigation as anti-diabetic agents.
Mesut Işık, Abdüllatif Karakaya, U. A. Çevi̇k et al.· Molecules· 0 citations
A novel series of 5,6-diphenyl-1,2,4-triazine-3-yl-thioacetamide-chalcone hybrids (9a-n) was designed, synthesized, and evaluated for their antidiabetic potential. All derivatives exhibited potent in vitro α-glucosidase inhibitory activity (IC50 = 0.2-112 μM) compared with acarbose (IC50 = 750.0 μM). The most potent compound, 9b (IC50 = 0.2 μM), acted as a competitive inhibitor with a Ki value of 200 nM and demonstrated significant glucose-lowering activity in a zebrafish model. In addition, compound 9b effectively inhibited bovine serum albumin (BSA) glycation relative to aminoguanidine. Molecular docking and molecular dynamics revealed stable binding of compound 9b within the α-glucosidase active site, with a binding energy of -9.2 kcal/mol, compared with -4.04 kcal/mol for acarbose. According to the in silico ADMET analysis, compound 9b showed oral bioavailability comparable to acarbose, together with improved drug-like properties. Overall, these findings identify compound 9b as a promising lead α-glucosidase inhibitor with potent in vitro and in vivo antihyperglycemic activity, warranting further investigation for the treatment of type 2 diabetes.
Elika Salehi Ghalehsefid, Mohammad Halimi, Hassan Mohammadi et al.· European journal of medicina...· 0 citations
Background/Objectives: The thiazole ring is one of the core structures frequently favored in the design of new active compounds. Methods: A series of thiazole derivatives bearing a benzodioxole scaffold (1-9) were synthesized and evaluated for their antioxidant, anticholinesterase, and antidiabetic activities. Results: Antioxidant assays (ABTS and DPPH) revealed that compounds bearing 4-trifluoromethyl (compound 8) and phenyl (compound 9) moieties exhibited the strongest radical scavenging activities, attributed to efficient hydrogen atom transfer and extended π-conjugation, respectively. Enzyme inhibition studies showed that electron-withdrawing substituents such as 4-SO2CH3 (compound 3) and 3,4-diCl (compound 5) enhanced both AChE/BChE and α-amylase/α-glucosidase inhibition, surpassing the activity of acarbose in antidiabetic assays, while electron-donating groups reduced potency. Molecular docking and MD studies have shed light on the interactions of the active compounds. In addition, in silico ADMET predictions for the compounds have been performed. Conclusions: These results indicate that the thiazole-benzodioxole scaffold is a promising framework for developing multifunctional agents with combined neuroprotective, antidiabetic, and antioxidant activities.
Tuğçe Çaklılı, Yusuf Sıcak, Somdatta Y. Chaudhari et al.· Pharmaceuticals· 0 citations
Herein, we report the synthesis of new 1,4-benzothiazine-1,1-dioxide derivatives bearing bis(1,2,3-triazole) moieties via click chemistry in good to high yields and fully characterized by 1H NMR, 13C NMR and HRMS. The compounds were evaluated using a combined in silico approach, including physicochemical, pharmacokinetic and toxicity analysis, molecular docking and molecular dynamics studies. Drug-like properties of all compounds were favourable. Molecular docking against SRC kinase suggested binding affinities ranging from -7.14 to -8.13 kcal/mol. Compound 11 displayed the most favorable docking score (-8.13 kcal/mol), comparable to that of bosutinib (-8.54 kcal/mol), and formed key interactions within the active site. This finding was consistent with the 100 ns molecular dynamics simulations, which indicated that the SRC-compound 11 complex remained structurally stable and maintained key interactions with residues such as Met341, Tyr340 and Lys295. Despite showing conformational flexibility than bosutinib, compound 11 maintained stable binding throughout the simulation. Overall, compound 11 showed favorable predicted binding toward SRC kinase, suggesting that these bis-triazole derivatives may represent potential leads for future anticancer investigation.
Ezaddine Irrou, Chagaleti Bharath Kumar, Y. Riadi et al.· Computational biology and ch...· 0 citations
α-Glucosidase is an intestinal membrane-bound enzyme that catalyzes the final step in the digestion of carbohydrates. It cleaves the glycosidic bonds of oligosaccharides to release glucose and its inhibition results in delayed glucose absorption, thereby inhibiting post-prandial hyperglycemia and hyperinsulinemia in patients with type 2 diabetes. Therefore, in view of the biological role of α-glucosidase as an antidiabetic drug target, a series of 5-(substituted)-1,3-thiazolidine-2,4-diones (C1-C6) were designed, synthesized and characterized by FT-IR, 1H NMR, 13C NMR and mass spectral analyses. All the compounds were subjected to in vitro α-glucosidase inhibitory evaluation. Among the compounds tested for α-glucosidase inhibitory activity, compounds C1 and C3 exhibited significant inhibition, with IC50 values of 0.1363 ± 0.00085 µM and 3.63780 ± 0.00005 µM, respectively. Structure-activity relationship (SAR) analysis of the test compounds revealed the positive contribution of the 1,3-thiazolidine-2,4-dione moiety and the phenyl ring substituents at the 5-position of the 1,3-thiazolidine-2,4-dione scaffold towards the observed activity.
Lay Hsien Tan, Lai-Chun Wong, V. Avupati· Asian Journal of Chemistry· 0 citations
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