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

Abstract Among the nitrogen-containing heterocyclic compounds proposed as selective modulators of γ-aminobutyric acid type A (GABA A ) 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 LUMO , E HOMO , ΔE (LUMO–HOMO) , 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).