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Aryl Guanyl Hydrazones: A Viable Strategy for Designing BBB-Permeable, Neuroactive Compounds?
Eleonora Colombo1,2, Leonardo Maiorana1, Greta Donati3
1Chemistry Department, Università degli Studi di Milano, Via Golgi 19, 20133 Milan, Italy.
ACS Chemical Neuroscience
|July 22, 2025
Summary
Aryl guanyl hydrazones offer tunable properties for drug discovery, enhancing blood-brain barrier permeability due to their lipophilicity at physiological pH. Their adaptable charge distribution aids in binding to diverse biological targets.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Pharmacology
Background:
- Guanyl hydrazones are versatile functional groups with tunable properties.
- Aryl guanyl hydrazones possess lower pKa values than aliphatic counterparts, promoting ionization at physiological pH.
- This ionization state increases lipophilicity and blood-brain barrier (BBB) permeability.
Purpose of the Study:
- To review (hetero)aromatic drugs, clinical candidates, leads, and hits containing guanyl hydrazone moieties.
- To discuss their mechanisms of action, in vitro, and in vivo potency.
- To explore synthetic routes and future trends for aryl guanyl hydrazones in CNS and PNS drug discovery.
Main Methods:
- Literature review of existing drugs and drug candidates.
- Analysis of structure-activity relationships related to guanyl hydrazone functional groups.
- Brief presentation of synthetic methodologies for guanyl hydrazone synthesis.
Main Results:
- Aryl guanyl hydrazones demonstrate significant potential in drug discovery due to their favorable physicochemical properties.
- Their tautomeric equilibria allow for flexible charge allocation, enhancing binding to protein and nucleic acid targets.
- Examples of successful drug candidates incorporating these moieties were identified.
Conclusions:
- Aryl guanyl hydrazones are promising scaffolds for developing novel therapeutics, particularly for central nervous system (CNS) and peripheral nervous system (PNS) disorders.
- Their unique properties facilitate improved drug delivery and target engagement.
- Further research into synthetic strategies and biological applications is warranted.
