Unravelling the potency of the 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile scaffold with <i>S</i>-arylamide hybrids as PIM-1 kinase inhibitors: synthesis, biological activity and <i>in silico</i> studies

PIM-1 is a type of serine/threonine kinase that plays a crucial role in controlling several vital processes, including proliferation and apoptosis. New synthetic <i>S</i>-amide tetrahydropyrimidinone derivatives were designed and synthesized as PIM-1 inhibitors with potential anticancer activity. Several biochemical assays were performed for anticancer assessment, including PIM-1 inhibitory assays, MTT, apoptosis and cell cycle, gene expression analysis, <i>c-MYC</i> analysis, and ATPase inhibitory assays. Compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibited strong <i>in vitro</i> broad antiproliferative activity against MCF-7, DU-145, and PC-3, with a relatively higher SI index suggesting minimal cytotoxicity to normal cells. Furthermore, these compounds induced mixed late apoptosis and necrosis with cell cycle arrest at the G2/M phase. Moreover, compounds 8b, 8f, 8g, 8k, and 8l showed potent inhibitory action against PIM-1 kinase, with corresponding IC₅₀ values of 660, 909, 373, 518, and 501 nM. <i>In silico</i> prediction studies of physiochemical properties, molecular dynamics, and induced fit docking studies were performed for these compounds to explain their potent biological activity. In conclusion, new pyrimidinone compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibit potential PIM-1 inhibitory activity and can be used as promising scaffolds for further optimization of new leads with selective PIM-inhibitors and anticancer activity.