2. Academic Validation
  3. Discovery of Lead 2-Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity

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

  • J Med Chem. 2023 Dec 8. doi: 10.1021/acs.jmedchem.3c01105.
Nereu Junio Cândido Oliveira 1,  Valtair Severino Dos Santos Júnior 1,  Isabella Campolina Pierotte 1,  Victor Augusto Teixeira Leocádio 2,  Luiz Felipe de Andrade Santana 2,  Gabriel Vitor de Lima Marques 1,  Ícaro Ferrari Protti 1,  Saulo Fehelberg Pinto Braga 3,  Markus Kohlhoff 4,  Túlio Resende Freitas 5,  Adriano de Paula Sabino 5,  Thales Kronenberger 6 7 8 9,  José Eduardo Gonçalves 1,  Susana Johann 2,  Daniel A Santos 2,  Isabela da Costa César 1,  Vinícius Gonçalves Maltarollo 1,  Renata Barbosa Oliveira 1
Affiliations

Affiliations

  • 1 Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
  • 2 Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
  • 3 Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais 35400-000, Brazil.
  • 4 Química de Produtos Naturais Bioativos (QPNB), Instituto René Rachou (IRR) - FIOCRUZ Minas, Belo Horizonte 30190-009, Brazil.
  • 5 Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
  • 6 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität, Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
  • 7 Tuebingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tuebingen, Germany.
  • 8 Excellence Cluster ″Controlling Microbes to Fight Infections″ (CMFI), 72076 Tübingen, Germany.
  • 9 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
PMID: 38064359 DOI: 10.1021/acs.jmedchem.3c01105
Abstract

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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