Advancements in designing hydroxamate-based urease inhibitors

Hydroxamic acids, strong Ni?? chelators, are longstanding scaffolds for urease inhibition. Clinically, urease drives ammonia production in Helicobacter pylori infection and contributes to urolithiasis; thus inhibitors have medical and agricultural value. Since the 1960s, > 350 derivatives have been explored across aliphatic, (hetero)aromatic, and peptide-based series, yielding sub-micromolar and, in some cases, nanomolar potencies. Yet acetohydroxamic acid (AHA) remains the sole approved drug, underscoring the potency-to-product gap. This review summarizes key developments in hydroxamate-based urease inhibitor research, with particular emphasis on recent advances in hybrid molecules that combine the hydroxamate moiety with complementary pharmacophores. These hybrids exhibit enhanced potency and novel mechanisms of action, representing a promising direction for the development of next-generation antiureolytic agents. Beyond summarizing prior work, this review (i) consolidates cross-scaffold SAR rules into a concise design ?playbook?; (ii) contrasts enzyme vs. whole-cell activities under differing assay conditions; (iii) identifies recurring liabilities (acid lability, off-target metal binding, mutagenicity) with mitigation tactics (hybridization, prodrugs); and (iv) proposes indication-specific decision points for H. pylori, urolithiasis, and agro uses.