posted on 2023-12-08, 18:08authored byNereu
Junio Cândido Oliveira, Valtair Severino dos Santos Júnior, Isabella Campolina Pierotte, Victor Augusto
Teixeira Leocádio, Luiz Felipe de
Andrade Santana, Gabriel Vitor de Lima Marques, Ícaro Ferrari Protti, Saulo Fehelberg
Pinto Braga, Markus Kohlhoff, Túlio Resende Freitas, Adriano de Paula Sabino, Thales Kronenberger, José Eduardo Gonçalves, Susana Johann, Daniel A. Santos, Isabela da Costa César, Vinícius Gonçalves Maltarollo, Renata Barbosa Oliveira
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.