American Chemical Society
jm3c01898_si_002.pdf (1.78 MB)

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

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journal contribution
posted on 2023-12-12, 20:40 authored by Vandna Sharma, Valentina Noemi Madia, Valeria Tudino, Jennifer V. Nguyen, Anjan Debnath, Antonella Messore, Davide Ialongo, Elisa Patacchini, Irene Palenca, Silvia Basili Franzin, Luisa Seguella, Giuseppe Esposito, Rita Petrucci, Paola Di Matteo, Martina Bortolami, Francesco Saccoliti, Roberto Di Santo, Luigi Scipione, Roberta Costi, Larissa M. Podust
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.