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

Authors

Robin Kryštůfek, Václav Verner, Pavel Šácha, Martin Hadzima, Filip Trajhan, Jana Starková, Eva Tloušt'ová, Alexandra Dvořáková, Adam Pecina, Jiří Brynda, Karel Chalupský, Miroslav Hájek, Michael J Boucher, Pavel Majer, Jan Řezáč, Hiten D Madhani, Charles S Craik, Jan Konvalinka

Published in

Journal of medicinal chemistry. Apr 22, 2025. Epub Apr 22, 2025.

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 against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.

PMID:
40262033
Bibliographic data and abstract were imported from PubMed on 23 Apr 2025.

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