Anticonvulsant Activity of Aza-Biginelli Derivatives Related to JM-II-43A and HSAB-Based Rationalization of Their Pharmacological Profile

Among nitrogen containing heterocyclic compounds proposed as selective modulators of γ-aminobutyric acid type A (GABA _A) receptor subtype, the dihydropyrimidinone JM-II-43A has emerged as a relevant probe molecule for the study of neurological disorders. In this work, its anticonvulsant activity was evaluated in vivo together with a series of racemic aza-Biginelli homologues ( 11a – 11i ) bearing π-donor, σ-acceptor, and σ-neutral substituents at the para-aryl position. To rationalize structure–activity relationships, key global reactivity descriptors (E _LUMO , E _HOMO , ΔE _(L–H), IP, EA, η, χ, σ, μ, and ω) were determined using density functional theory (DFT) at the B3LYP/6–311++G(**) level. Anticonvulsant activity was assessed in the pentylenetetrazole (PTZ)-induced seizure model in CF1 male mice. Compounds 11a and 11f exhibited the most pronounced seizure-inhibitory response at 10 mg/kg, surpassing the reference compound JM-II-43A at this dose. Although the overall anticonvulsant potency was moderate, all derivatives displayed a favorable safety profile (LD ₅₀ > 1000 mg/kg). Within the Hard and Soft Acids and Bases (HSAB) framework, increased electronic softness and enhanced π-donor character at the para-aryl moiety were associated with improved biological response. These findings demonstrate that conceptual DFT descriptors provide a consistent electronic basis for interpreting substituent effects and support their utility in guiding the electronic modulation and rational design of neuroactive aza-Biginelli scaffolds.