1,4-dihydropyridine–hydrazone hybrids as novel scaffold for serine protease inhibitors: Synthesis, in vitro and in silico drug-likeness studies

1,4-Dihydropyridines (1,4-DHPs) are well established as antagonists of L-type Ca 2+ channels, thereby exerting potent vasodilatory effects. Nifedipine is regarded as the prototypical representative of this pharmacological class. Calcium signalling plays a critical role in the inflammatory response by activating multiple pro-inflammatory enzymes and mediators. Consequently, modulation or inhibition of this signalling cascade represents a compelling therapeutic approach for the development of novel anti-inflammatory agents. The hydrazone moiety is known to display a wide spectrum of biological activities, among which, its anti-inflammatory potential is particularly significant. In the present study, we report the rational design and synthesis of a series of 1,4-DHP–hydrazone hybrid derivatives (HA-1,4-DHPs) as prospective inhibitors of two inflammation-associated serine proteases, thrombin and trypsin. The target compounds were synthesized in good yields using benzotriazole-based one-dimensional Cu(II) coordination materials as catalytic systems and subsequently subjected to comprehensive in-vitro biological evaluation. The experimental outcomes were analyzed in relation to structure–activity relationships (SAR), providing insights into the key structural determinants of biological efficacy. Moreover, in silico drug-likeness assessments highlighted favorable pharmacokinetic and physicochemical properties, underscoring the drug-ability of the synthesized hybrids. Collectively, the experimental and computational findings provide a robust foundation for further optimization and development of 1,4-DHP–hydrazone hybrids as potential anti-inflammatory agents.