Design, synthesis and biological evaluation of novel 5-(4-chlorophenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols as an anticancer agent

Cellular tumor antigen p53 is significant for cancer prevention and its mutation is most documented genomic change in human cancers. Thus, restoration of p53 function by interruption of the p53-MDM2 interaction opens up a prospect for a nongenotoxic anticancer therapeutic strategy. A novel series of molecules comprising 1,2,4-triazole-3-thiol scaffold were successfully discovered by structure-based designing approach. In silico modules predicted that 5-(4-chlorophenyl)-4-phenyl-4H-1,2,4-triazole-3-thiol derivatives have draggability and ability to mimic critical binding residues of p53. All target compounds were assayed for their in vitro antiproliferative activity against A549, U87 and HL60 cell lines. Twelve out of sixteen compounds exhibited good in vitro inhibitory activity in micromolar range. Especially, compound 6h possessed acute antitumor activity with IC50 values 3.854, 4.151 and 17.522 mu M against three tested cell lines. It represents as a promising lead for further optimization and a template for development of novel antitumor agents. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The p53 protein is crucial for cancer prevention, and restoring p53 function through disrupting the p53-MDM2 interaction shows promise as a non-genotoxic anticancer therapeutic strategy. A novel series of molecules with a 1,2,4-triazole-3-thiol scaffold was successfully discovered, with some compounds exhibiting good inhibitory activity and one compound showing strong antitumor activity.