Triazole-benzodiazepine derivatives: One-pot synthesis, characterization, hirshfeld surface analysis, and computational insights into anticancer potential as KIF11 inhibitors

In this study a [3 + 2] cycloaddition reaction of the benzodiazepine BZD1 with N-aryl-C-ethoxycarbonylnitrilimines 3(a-b) was explored. The reaction was carried out in a basic medium to obtain new triazole-benzodiazepine derivatives 4(a-b) with improved selectivity. Structural characterization was performed using ¹H, ¹³C NMR spectroscopy, as well as X-ray diffraction analysis. A comprehensive theoretical study was conducted to elucidate the electronic structure and reactivity of two newly synthesized triazole-benzodiazepine derivatives (4a and 4b). Frontier Molecular Orbital (FMO), Electrostatic Potential (ESP), Fukui function, and global descriptor analyses consistently revealed that the triazole-benzodiazepine core drives charge transfer, while the ester and triazole groups are the main sites of nucleophilic and electrophilic attacks. According to Hirshfeld surface analysis, there was no significant π–π stacking interactions were observed, and weak hydrogen bonding between oxygen and nitrogen atoms play a critical directing function, even if dispersion forces (H···H contacts) predominate. Drug similarity and in silico ADMET studies indicated that both compounds exhibit high predicted oral bioavailability, blood-brain barrier crossing, and good gastrointestinal absorption all of which suggest that the central nervous system may be activated. Docking simulation results demonstrated that both compounds represent promising prospects for the development of oral bioavailable KIF11 inhibitors with potential anticancer effects.