#143 Design, synthesis, induced-fit docking, DFT, molecular dynamics, and biological evaluation of some thiazolidine-4-ones as antidiabetic agent through PPAR-γ partial agonism

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Das, S. .; Joseph, A. . #143 Design, Synthesis, Induced-Fit Docking, DFT, Molecular Dynamics, and Biological Evaluation of Some Thiazolidine-4-Ones As Antidiabetic Agent through PPAR-γ Partial Agonism. J Pharm Chem 2022, 8.

Abstract

Diabetes is a metabolic disorder that affects roughly 463 million people, with the number expected to climb to 700 million by 2045. The most frequently observed adverse effects of antidiabetic drugs (e.g., thiazolidinedione) are weight gain and hepatotoxicity. This study aims to synthesize a series of novel thiazolidine-4-one ring-bearing molecules with improved antidiabetic activity with lesser side effects. Thiazolidine-4-one derivatives were synthesized using suitable synthetics scheme and characterized by IR, NMR (1H and 13C), mass spectroscopy, and elemental analysis studies. Synthesized compounds were then subjected to pharmacological evaluation as antidiabetic agents (OGTT, HbA1C) along with toxicity studies. Their unique selectivity toward the PPAR-γ was investigated using molecular modeling techniques (Molecular docking, ADMET, and molecular dynamics). All the synthesized compounds showed moderate to excellent antidiabetic activity. One synthesized compound 4h demonstrated an excellent antidiabetic activity by reducing blood glucose levels compared with the standard drug (Pioglitazone). It was encouraging to note that all the tested compounds have displayed no significant liver toxicity due to the partial activation of the PPAR-γ receptor. In molecular docking studies, compound 4 h shows hydrogen bond interaction with SER342 amino acid, an essential feature for PPAR-γ partial agonism, and retains the same binding during 100 ns molecular dynamics study. Compound 4h is less toxic, according to histopathology studies of the organs and regular body weight monitoring. Structural activity relationship study also reveals that the presence of the bulkier ring system significantly improves the antidiabetic activity. It can be concluded that the synthesized compound 4h has the potential for further development as a safer antidiabetic agent with fewer side effects.

References

Kharbanda C, Alam MS, Hamid H, Ali Y, Nazreen S, Dhulap A, Alam P, Pasha MA. (2021) In silico designing, in vitro and in vivo evaluation of potential PPAR-γ agonists derived from aryl propionic acid scaffold. Bioorg Chem 106:104458. DOI: https://doi.org/10.1016/j.bioorg.2020.104458

Sun J, Liu HY, Zhang YH, Fang ZY, Lv PC. (2021) Design, synthesis and bioactivity evaluation of thiazolidinedione derivatives as partial agonists targeting PPARγ. Bioorg Chem 116:105342. DOI: .https://doi.org/10.1016/j.bioorg.2021.105342

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