Triazole-linked piperidinyl Glyoxamides with anticancer potential: Integrating synthesis, docking, MD simulation,...

The advancement of new oncological therapeutics remains a core objective in medicinal chemistry, especially for combating aggressive and drug-resistant tumours, including breast, cervical and colorectal cancers. In this paper, we report a new series of triazole-linked piperidinyl glyoxamide hybrids, synthesized via a piperidine mediated transformation of isatin derivatives followed by Cu(I)-catalysed azide-alkyne cycloaddition, designed to identify promising anticancer leads. A multimodal evaluation approach, comprising in-silico molecular docking, molecular dynamics (MD) simulations, ADMET analysis and in vitro cytotoxic screening was used to assess their anticancer efficacy. Molecular docking against EGFR tyrosine kinase and human topoisomerase IIα, support their significance in cancer related inflammatory and RAS-associated pathways. Compound 35 identified as the lead candidate with highest binding affinity across the series, further supported by molecular dynamics simulations. In vitro cytotoxicity profile of compound 35 against MCF-7, HeLa and HCT-116 cells having IC₅₀ values 1.21, 1.08, and 1.34 μM, respectively showing it is more potent than standard drug doxorubicin, especially in MCF-7 and HeLa cells. These outcomes paved a way for triazole-linked piperidinyl glyoxamide hybrids as promising lead candidates for further advancement in anticancer drug discovery.