Benzoxaboroles in medicinal chemistry: A structure-guided perspective on next-generation therapeutics.

Benzoxaboroles have emerged as a chemically versatile and pharmacologically rich class of boron-containing heterocycles with broad-spectrum therapeutic potential. This review provides a comprehensive and systematically organized account of BBZ-based drug discovery, spanning antifungal, antibacterial, antiviral, antiparasitic, and enzyme inhibition domains, with an emphasis on mechanistic insights, structure-activity relationships (SAR), and scaffold optimization strategies. Unlike previous reviews, which often present BBZ pharmacology in a generalized or disease-specific manner, this work uniquely integrates cross-disciplinary advances from medicinal chemistry and structural biology to computational modelling, while mapping chemical evolution across therapeutic areas. The SAR studies mapped how specific substitutions on the BBZ scaffold influence potency and selectivity across pathogen classes. Special attention is given to translationally relevant examples, including FDA-approved drugs such as Tavaborole, investigational clinical candidates, and novel hybrid scaffolds that exploit BBZ's covalent and reversible binding capabilities. Distinguishing features of this review include (a) a residue-level analysis of target-ligand interactions, particularly for LeuRS and β-carbonic anhydrase enzymes, (b) a critical discussion of physicochemical parameters such as pKa modulation for activity tuning, (c) an exploration of hybrid chemotypes (e.g., Amp-B-BBZ conjugates), for overcoming resistance and toxicity, and (d) future opportunities for targeting neglected pathogens. By consolidating dispersed literature and integrating structure-guided design principles, this review not only serves as a reference for the current state of BBZ-based therapeutics but also outlines rational strategies for the next generation of boron-based drugs, thereby addressing gaps in scope and depth left by prior publications.