2. Academic Validation
  3. Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors

Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors

  • J Med Chem. 2023 Dec 28;66(24):17059-17073. doi: 10.1021/acs.jmedchem.3c01898.
Vandna Sharma 1,  Valentina Noemi Madia 2,  Valeria Tudino 3,  Jennifer V Nguyen 1,  Anjan Debnath 1,  Antonella Messore 2,  Davide Ialongo 2,  Elisa Patacchini 2,  Irene Palenca 4,  Silvia Basili Franzin 4,  Luisa Seguella 4,  Giuseppe Esposito 4,  Rita Petrucci 5,  Paola Di Matteo 5,  Martina Bortolami 5,  Francesco Saccoliti 6,  Roberto Di Santo 2,  Luigi Scipione 2,  Roberta Costi 2,  Larissa M Podust 1
Affiliations

Affiliations

  • 1 Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, California 92093, United States.
  • 2 Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, p.le Aldo Moro 5, Rome I-00185, Italy.
  • 3 Dipartimento di Biotecnologie, Università degli Studi di Siena, Chimica e Farmacia via Aldo Moro 2, Siena 53100, Italy.
  • 4 Department of Physiology and Pharmacology "V. Erspamer", "Sapienza″ Università di Roma, p.le Aldo Moro 5, Rome I-00185, Italy.
  • 5 Dipartimento di Scienze di Base e Applicate per l'Ingegneria, "Sapienza" Università di Roma, Via Castro Laurenziano 7, Rome 00161, Italy.
  • 6 D3 PharmaChemistry, Italian Institute of Technology, Via Morego 30, Genova 16163, Italy.
PMID: 38085955 DOI: 10.1021/acs.jmedchem.3c01898
Abstract

Developing drugs for brain Infection by Naegleria fowleri is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to identify inhibitors that target an essential N. fowleri Enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected in silico were tested against N. fowleri. Nine primary hits with EC50 ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound 2a. The S-enantiomer of 2a produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the S-configuration over the R-configuration and the advantage of an ether linkage over an ester linkage. The two compounds, S-8b and S-9b, had an improved EC50 and KD compared to 2a. Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of S-9b was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.

Figures
Products