| Synthesis of Novel Compounds with Benzimidazole and 1,2,3-Triazole Pharmacophores and Evaluation of their Antidiabetic Effects |
| کد مقاله : 1218-ICOC |
| نویسندگان |
|
مهدی حاتم فیاضی * دانشگاه آزاد اسلامی واحد تهران شمال |
| چکیده مقاله |
| A series of 16 novel benzimidazole-1,2,3-triazole derivatives (12a-p) were successfully designed and synthesized. These compounds were created by varying substituents on the phenyl ring of the N-phenylacetamide moiety, following a Knoevenagel reaction and a click reaction. All synthesized derivatives exhibited superior α-glucosidase inhibitory activity compared to the standard positive control, acarbose (IC50= 752.0 ± 2.0 µM). Compound 12m, bearing a 2-methyl-4-nitrophenyl group, emerged as the most potent derivative, displaying an IC50 value of 6.0 ± 0.2 µM. This represents an approximately 125-fold better activity than acarbose. Kinetic evaluation of compound 12m revealed that it acts as a reversible competitive inhibitor of α-glucosidase. The Lineweaver-Burk plot indicated that as the inhibitor concentration increased, the Michaelis-Menten constant (Km) progressively increased, while the maximum reaction rate (Vmax) remained unchanged, confirming competitive inhibition. The inhibition constant (Ki) for compound 12m was estimated to be 4.5 µM. Molecular docking studies confirmed improved anti-α-glucosidase activity for compound 12m, correlating with their in vitro data. Compound 12m showed a binding energy of -10.887 kcal/mol, consistent with its high potency. Key interactions included H-bonds with Asn241, Arg312, Phe157, and Gln350, as well as π-π stacking interactions with Phe310, His239, and Phe311. Molecular dynamics simulations confirmed the stability of the α-glucosidase-12m complex, with a low average RMSD value of 1.4 Å, indicating strong binding and low conformational flexibility of the protein in the complex. Intermolecular interactions for 12m over 100 ns simulation showed persistent contacts, including π-cation and π-π stacking with His279, H-bonds with Arg312 and His239, and interactions with Ser156 and Phe157. Compound 12m was evaluated for drug-likeness and ADME-T (absorption, distribution, metabolism, excretion, and toxicity) properties. In silico predictions indicated that 12m meets the ideal characteristics of an oral therapeutic agent, showing non-toxicity, metabolic stability, and bioavailability. In conclusion, this study successfully identified novel benzimidazole-1,2,3-triazole derivatives as potent α-glucosidase inhibitors, with compound 12m demonstrating exceptional activity, competitive inhibition, and favorable binding characteristics. Its promising in silico ADME-T profile further supports its potential as a lead candidate for anti-diabetic drug development. |
| کلیدواژه ها |
| Benzimidazole, 1,2,3-triazole, Click Reaction, α-glucosidase |
| وضعیت: پذیرفته شده |