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
  • 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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