
Bioorganic Chemistry p. 77 - 90 (2016)
Update date:2022-08-17
Topics:
Alam, Raquib
Wahi, Divya
Singh, Raja
Sinha, Devapriya
Tandon, Vibha
Grover, Abhinav
Rahisuddin
In an attempt to find potential anticancer agents, a series of novel ethyl 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-(pyridin-3-yl)cyclohex-3-enecarboxylates 5a-i and 5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamides 6a-i were designed, synthesized and evaluated for their topoisomerase IIα inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Molecular docking studies of all the synthesized compounds into the binding site of topoisomerase IIα protein (PDB ID: 1ZXM) were performed to gain a comprehensive understanding into plausible binding modes. These compounds were also screened for in silico drug-likeliness properties on the basis of the absorption, distribution, metabolism and excretion (ADME) prediction. Among all the synthesized compounds, analogue 5d showed superior cytotoxicity with an IC50 value of 7.01?±?0.60?μM for HeLa, 8.55?±?0.35?μM for NCI-H460 and 14.31?±?0.90 for MCF-7 cancer cell lines. Further, compound 5d showed 70.82% inhibition of topoisomerase IIα at a concentration of 100?μM with maximum docking score of ?8.24. Results of ADME prediction revealed that most of these compounds showed in silico drug-likeliness properties within the ideal range.
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Doi:10.1080/10426500307819
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