On-Resin Assembly of Macrocyclic Inhibitors of <i>Cryptococcus neoformans</i> May1: A Pathway to Potent Antifungal Agents.

ABSTRACT: Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a K_i of 180 pM, significant selectivity

SUBMITTER: Krystufek R 

PROVIDER: S-EPMC12067429 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature