Discovery of Lead 2‑Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity

Discovery of Lead 2‑Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity

Opportunistic fungal infections represent a global health problem, mainly for immunocompromised individuals. New therapeutical options are needed since several fungal strains show resistance to clinically available antifungal agents. 2-Thiazolylhydrazones are well-known as potent compounds against C...

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Published in:Journal of medicinal chemistry Vol. 66; no. 24; pp. 16628 - 16645
Main Authors: Oliveira, Nereu Junio Cândido, dos Santos Júnior, Valtair Severino, Pierotte, Isabella Campolina, Leocádio, Victor Augusto Teixeira, Santana, Luiz Felipe de Andrade, Marques, Gabriel Vitor de Lima, Protti, Ícaro Ferrari, Braga, Saulo Fehelberg Pinto, Kohlhoff, Markus, Freitas, Túlio Resende, Sabino, Adriano de Paula, Kronenberger, Thales, Gonçalves, José Eduardo, Johann, Susana, Santos, Daniel A., César, Isabela da Costa, Maltarollo, Vinícius Gonçalves, Oliveira, Renata Barbosa
Format: Journal Article
Language:English
Published: United States American Chemical Society 28-12-2023
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Summary:Opportunistic fungal infections represent a global health problem, mainly for immunocompromised individuals. New therapeutical options are needed since several fungal strains show resistance to clinically available antifungal agents. 2-Thiazolylhydrazones are well-known as potent compounds against Candida and Cryptococcus species. A scaffold-focused drug design using machine-learning models was established to optimize the 2-thiazolylhydrazone skeleton and obtain novel compounds with higher potency, better solubility in water, and enhanced absorption. Twenty-nine novel compounds were obtained and most showed low micromolar MIC values against different species of Candida and Cryptococcus spp., including Candida auris, an emerging multidrug-resistant yeast. Among the synthesized compounds, 2-thiazolylhydrazone 28 (MIC value ranging from 0.8 to 52.17 μM) was selected for further studies: cytotoxicity evaluation, permeability study in Caco-2 cell model, and in vivo efficacy against Cryptococcus neoformans in an invertebrate infection model. All results obtained indicate the great potential of 28 as a novel antifungal agent.
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c01105