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
  • 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.

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