Synthesis and in-vitro cytotoxicity activity of 1,3,4-oxa-diazolbenzamide derivatives and inhibition of human MAO-A enzyme: A in-silico approaches

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The report from the WHO, there are 2 million deaths in worldwide due to cancer in the year 2023. Due to increase death rate, the researchers need to find a new drug for targeting cancer. For the development of new medication for cancer, researcher now worked on the new target like MAO-A, because these group of enzymes are highly expressed in cancer cells. The present study deals with the designing of various substituted N-(1,3,4-oxadiazol- 2-yl) benzamide and it was synthesized. The docking studies revealed that, compound AA5 (-11.5 kcal/mol) showing similar binding affinity of standard molecule clorgyline towards the targeted protein and these molecules shows 2 conventional hydrogen bonds with Tyr 407 and Met 445 amino acid residues. The entire 10 synthesized compounds are evaluated their cytotoxicity activity by in-vitro MTT assay using MCF-7, A549 and the normal breast cell line MCF-10. The A549 cell line shows the most promising sensitivity towards all the synthesized molecules but the compound AA8 (31.546±0.71 nM), AA5 (34.969±0.53 nM), AA35 (37.733±0.78 nM) and AA6 (39.984±0.56 nM). In the MCF-7 cell line showed sensitivity towards the four derivatives such as AA5 (32.292±0.67 nM), AA35 (33.933±0.96 nM), AA7 (34.146±0.19 nM) and AA8 39.328±0.11 nM). In addition to this, the synthesized compounds are subjected to MAO-A enzyme inhibition assay. The results revealed that, the compound AA5 substituted with methyl group (28.00±0.3 nM) showed the highest substantial MAO-A inhibition, followed by compounds AA8 substituted with 2 pyridine moiety (29.28±0.4 nM) and AA35 substituted with furan and methyl group (31.04±0.4), showed significant MAO-A inhibition activity compared to other tested compounds. The both in-vitro cytotoxic studies and enzyme inhibition assay revealed that, compounds AA5, AA8 and AA35 are more sensitive towards tested cell line and MAO-A enzymes. Moreover, the results of cytotoxic activity of normal breast cell lines revealed that the entire tested compound less toxic to the tested cell lines. The designed compounds are also demonstrated a higher docking score and inhibition of human MAO-A enzyme. In addition, the in-silico ADMET screening revealed that all the designed compounds are low toxicity and have adequate pharmacokinetic properties.