Pyrithione: A Privileged Structure with the Essential Pharmacophore for Inhibiting Zinc Metalloenzymes.

Zinc Pyrithione is a naturally occurring zinc complex well-known as an antifungal agent, used in the treatment of dandruff and other scalp-related diseases for more than half a century. Pyrithione has been exploited as a potential antimicrobial and anticancer agent with other clinical applications for treating glaucoma, epilepsy, and neurological conditions. The market for zinc pyrithione has been steadily increasing over the last two decades and is estimated to exceed $1 billion in 2024 alone. Pyrithione is one of the forgotten privileged structures in drug discovery. It is a zinc-specific chelate that possesses the essential pharmacophore for inhibiting zinc metalloenzymes. Its potential has been revisited recently for a variety of zinc metalloenzyme targets containing one or two zinc atoms. In this review, we describe the broad-spectrum inhibitory activities and the exact mechanism of action of pyrithione against validated and promising zinc metalloenzyme drug targets, including vancomycin-resistant element VanX, Histone deacetylases (HDAC) 6 and 8 in cancer treatment, carbonic anhydrase for the treatment of pediatric obstructive sleep apnea and glaucoma, and metallo beta-lactamases for overcoming beta-lactam antibiotic-resistant infections. Continuing the enrichment of pyrithione analogues to reduce off-target activities, improve inhibitory potency, and increase metabolic stability could revitalize their relevance in drug discovery.