Anticonvulsant activity of aza-Biginelli derivatives related to JM-II-43A and HSAB-based rationalization of their pharmacological profile.

Among the nitrogen-containing heterocyclic compounds proposed as selective modulators of γ-aminobutyric acid type A (GABA) receptor subtype, dihydropyrimidinone JM-II-43A figures as a promising probe molecule for the study of neurological disorders. In this work, its anticonvulsant activity was examined in vivo, in addition to its HSAB parameters as a prospective biological predictor to compared them with its racemic aza-Biginelli homologous (11a-i) containing π - donor, σ-acceptor and σ-neutral substituents as key modulators of the physicochemical parameters. To rationalize structure-property relationships and predict trends in global chemical reactivity, their paramount global chemical reactivity descriptors (E, E, ΔE, IP, EA, η, χ, σ, μ, and ω) were determined using quantum chemical calculations performed at DFT B3LYP/6-311 + + G (**) levels of theory. Additionally, its anticonvulsant activity was assessed in CF1 male mice using PTZ pharmacological model. Overall, the aza-Biginelli compounds 11a (f) exhibited the most pronounced seizure-inhibitory response at 10 mg/kg, outperforming the reference compound JM-II-43A at this dose. Although the overall anticonvulsant potency was moderate, all aza-Biginelli products tested showed a favorable safety profile (LD50 > 1000 mg/kg).