On-Resin Assembly of Macrocyclic Inhibitors of <i>Cryptococcus neoformans</i> May1: A Pathway to Potent Antifungal Agents
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 <i>Cryptococcus neoformans</i>, 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 <b>25</b> exhibited a <i>K</i><sub>i</sub> 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.
Authors
- Jan Konvalinka (ORCID: https://orcid.org/0000-0003-0695-9266)
- Pavel Šácha (ORCID: https://orcid.org/0000-0001-6198-9826)
- Karel Chalupský (ORCID: https://orcid.org/0000-0001-6890-6464)
- Eva Tloušťová
- Robin Kryštůfek (ORCID: https://orcid.org/0000-0003-4096-1159)
- J. Brynda (ORCID: https://orcid.org/0000-0003-3675-6769)
- Pavel Majer (ORCID: https://orcid.org/0000-0002-1804-6934)
- Adam Pecina (ORCID: https://orcid.org/0000-0003-3890-7831)
- Miroslav Hájek (ORCID: https://orcid.org/0000-0002-8906-243X)
- Hiten D. Madhani (ORCID: https://orcid.org/0000-0001-7400-6657)
- Martin Hadzima (ORCID: https://orcid.org/0000-0002-6479-3682)
- Jan Řezáč (ORCID: https://orcid.org/0000-0001-6849-7314)
- Alexandra Dvořáková
- Jana Starková
- Charles S. Craik (ORCID: https://orcid.org/0000-0001-7704-9185)
- Michael J. Boucher (ORCID: https://orcid.org/0000-0001-5725-7219)
- Václav Verner (ORCID: https://orcid.org/0009-0003-4190-4698)
- Filip Trajhan
Institutions
- University of California, San Francisco (US)
- Charles University (CZ)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00396
- Citations
- 1
- Primary Topic
- Fungal Infections and Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Ministerstvo Zdravotnictví Ceské Republiky
- National Institutes of Health