Identification of pyrazole-acrylonitrile derivatives as potential anticancer agents and mechanistic insights

Developing highly effective anticancer drugs remains a primary focus for drug designers worldwide. In this investigation, we designed and developed novel pyrazole-acrylonitriles incorporating various N-heterocyclic groups and evaluated their anticancer properties. Comprehensive in vitro profiling included evaluation of cell cytotoxicity, colony formation and cell adhesion in 3D cultures, cell cycle analysis, DNA damage induction, and apoptosis. Among the synthesized compounds, 8b and 8c demonstrated enhanced sensitivity and potency with IC₅₀ values of 2.58 ± 0.053 μM and 2.34 ± 0.074 μM, respectively, against the MCF7 cell line. Furthermore, compounds 8e and 9c exhibited IC₅₀ values of 2.09 ± 0.464 μM and 1.65 ± 0.006 μM against A549, while compounds 9b and 9f displayed values of 4.84 ± 0.035 μM and 4.89 ± 0.053 μM on the HCT116 cell line. All these compounds exhibited greater potency than the standard drug, cisplatin. Our findings suggest that potent pyrazole derivatives effectively inhibited cell proliferation by inducing cell cycle arrest, promoted significant DNA fragmentation, and demonstrated superior apoptotic activity compared to the standard drug Etoposide. Moreover, In silico studies revealed favorable pharmacokinetic profiles and non-carcinogenicity for all potent compounds. Therefore, the potent pyrazole-acrylonitriles can serve as lead compounds for further in vivo investigations and the design and development of new drug candidates.