Hydroxamic Acid Scaffolds as Metalloenzyme Inhibitors: Advances in Chemistry and Drug Discovery

Abstract

Hydroxamic acids are among the most widely used metal-chelating pharmacophores in medicinal chemistry, with diverse applications ranging from oncology and infectious diseases to inflammation and parasitic infections. Their strong affinity toward Zn2+, Fe3+, Mn2+, and Mg2+ underlies their utility in modulating metalloenzymes, including HDACs, MMPs, ADAMs, LpxC, and DXR. This review summarizes approximately two decades of research progress, covering more than 350 small molecules and key natural or synthetic derivatives. The mechanistic basis of metal chelation is discussed alongside structure-activity relationships, challenges in isoform selectivity, and contemporary drug design strategies. Methodologically, the review applies systematic literature selection using PubMed, Scopus, Web of Science, and SciFinder, retrieving studies published between January 2000 and December 2024. Critical inclusion criteria encompassed experimental or computational analysis of hydroxamate-containing scaffolds, reported biological activity, and relevance to medicinal chemistry. Gaps identified in current research include limited isoform-specific targeting, insufficient quantitative comparisons across inhibitor classes, inadequate pharmacokinetic profiling, and persistent concerns about the mutagenicity of the hydroxamate moiety. Recent methodological advancements, such as microwave-assisted synthesis, continuous-flow chemistry, and biocatalytic enzyme engineering, have significantly improved access to structurally diverse hydroxamic acids. The review also highlights clinical successes and failures, as well as the need for next generation bioisosteres with improved safety and stability. Overall, hydroxamic acids remain indispensable tools in drug discovery, but overcoming their pharmacokinetic and toxicological limitations will be essential for broader therapeutic impact.