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

## TL;DR

This paper explores aryl guanyl hydrazones as promising building blocks for developing brain-penetrant drugs due to their favorable chemical properties and adaptability.

## Contribution

The paper introduces aryl guanyl hydrazones as a novel strategy for designing neuroactive compounds with improved blood-brain barrier permeability.

## Key findings

- Aryl guanyl hydrazones have lower pKa values, increasing lipophilicity and BBB permeability.
- Their tautomeric flexibility allows adaptation to binding site requirements for various targets.
- Synthetic methods and drug examples demonstrate their potential in CNS and PNS drug discovery.

## Abstract

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.