Aryl Guanyl Hydrazones: A Viable Strategy for Designing BBB-Permeable, Neuroactive Compounds?

Guanyl hydrazones are emerging as valuable, target-tunable functional groups. In particular, aryl guanyl hydrazones, owing to extensive conjugation with aromatic rings, exhibit lower pK_a values compared to their aliphatic counterparts, so that, at physiological pH, a substantial proportion of them remains in a nonionized or partially protonated form, thereby increasing their lipophilicity and enhancing BBB permeability. Intriguingly, their tautomeric equilibria provide flexible charge allocation, adapting to binding site demands for protein and nucleic acid target species. Herein, (hetero)aromatic drugs, clinical candidates, leads and hits bearing one or more guanyl hydrazones are presented in terms of mechanism of action, in vitro and in vivo potency. Synthetic access to guanyl hydrazone-containing molecules, through complementary and simple routes, is briefly presented. Future trends for aryl guanyl hydrazones in CNS and PNS drug discovery are critically discussed.