IN SILICO DESIGN, SYNTHESIS AND EVALUATION OF IN VITRO GLUCOSE UPTAKE, GENE EXPRESSION, AND α-GLUCOSIDASE INHIBITORY ACTIVITY OF NOVEL 2-AMINOBENZIMIDAZOLE DERIVATIVES
Objective: The present study was aimed to design and evaluate the antidiabetic potential of novel 2-aminobenzimidazole derivatives by in silico method.
Materials and Methods: Various in silico tools such as Chemsketch, Molinspiration, Prediction of activity spectra for substances, OpenBabel, Discovery Studio was used in the designing and evaluation of the biological activity. The retrieved hits were further filtered by absorption, distribution, metabolism, and excretion descriptors. The designed molecules having required physicochemical properties, drug-likeness, and obeying Lipinski’s rule of five were selected for the synthesis. The synthesized compounds were subjected to determination of yield, melting point and characterized by infrared, 1HNMR, 13CNMR, and mass spectroscopic methods. The selected derivatives were subjected to in vitro glucose uptake, 50% lethal dose (LD50) determination, gene expression analysis, and α-glucosidase inhibitory assay.
Results: Totally, 32 novel analogs of 2-aminobenzimidazole were designed and 17 compounds were selected for docking analysis; and finally, five derivatives (3a, 3c, 3e, 3f, and 3h) were selected for synthesis. Among them, the compounds 3a and 3f were selected for in vitro glucose uptake analysis. Finally, the compound 3f was selected for LD50 determination, gene expression analysis, and α-glucosidase inhibitory assay. The selected derivative 3f showed a significant α-glucosidase inhibitory activity compared with the standard drug acarbose.
Conclusion: These results are useful for further investigation in the future, and hopefully, these studies could discover a new specific leads in antidiabetic category as α-glucosidase inhibitor.
2. Amuthalakshmi S, Smith AA, Manavalan R. Modeling assisted in silico design of ligand molecule for DPP IV in Type II diabetes mellitus. Lett Drug Des Discov 2012;9:764-6.
3. Singh RJ, Gupta AK, Kohli K. Diabetes mellitus: A review with edge of SGLT2 inhibitors. Int J Curr Pharm Res 2018;10:1-2.
4. Kim HI, Ahn YH. Role of peroxisome proliferator-activated receptor-gamma in the glucose-sensing apparatus of liver and beta-cells. Diabetes 2004;53 Suppl 1:S60-5.
5. Vinodkumar R, Vaidya SD, Siva Kumar BV, Bhise UN, Bhirud SB, Mashelkar UC, et al. Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of novel N-substituted-2-(4-phenylethynyl-phenyl)-1H-benzimidazoles and N-substituted 2[4-(4,4-dimethyl-thiochroman-6-yl-ethynyl)-phenyl)-1H-benzimidazoles. Eur J Med Chem 2008;43:986-95.
6. Aboul-Enein HY, EI Rashedy AA. Benzimidazole derivatives as anti-diabetic agents. Med Chem 2015;5:318-25.
7. Kang SM, Heo SJ, Kim KN, Lee SH, Yang HM, Kim AD, et al. Molecular docking studies of a phlorotannin, dieckol isolated from Ecklonia cava with tyrosinase inhibitory activity. Bioorg Med Chem 2012;20:311-6.
8. Arul K, Sunisha KS. In silico design, synthesis and in vitro anticancer and anti-tubercular activity of novel azetidinone containing isatin derivatives. Int J Pharm Pharm Sci 2014;6:506-13.
9. Kavitha R, Karunagaran S, Chandrabose SS, Lee KW, Meganathan C. Pharmacophore modeling, virtual screening, molecular docking studies and density functional theory approaches to identify novel ketohexokinase (KHK) inhibitors. Biosystems 2015;138:39-52.
10. Arul K, Smith AA. In silico design, synthesis and in vivo anti-inflammatory evaluation of novel 1, 2, 4 triazole derivatives. Int J Pharm Sci Rev Res 2017;47:95-9.
11. Irwin JJ, Shoichet BK. Docking screens for novel ligands conferring new biology. J Med Chem 2016;59:4103-20.
12. Khatri DK, Juvekar AR. ?-glucosidase and ?-amylase inhibitory activity of Indigofera cordifolia seeds and leaves extract. Int J Pharm Pharm Sci 2014;6:152-5.
13. Bachhawat JA, Shihabudeen MS, Thirumurugan K. Screening of fifteen Indian ayurvedic plants for alpha-glucosidase inhibitory activity and enzyme kinetics. Int J Pharm Pharm Sci 2011;3:267-74.
14. Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: Methods and applications. Nat Rev Drug Discov 2004;3:935-49.
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