Antifungal Activity of N -(4-Halobenzyl)amides against Candida spp. and Molecular Modeling Studies

• Published in: International journal of molecular sciences 2021-12, Vol.23 (1), p.419
• Main Authors: Perez-Castillo, Yunierkis, Montes, Ricardo Carneiro, da Silva, Cecília Rocha, Neto, João Batista de Andrade, Dias, Celidarque da Silva, Brunna Sucupira Duarte, Allana, Júnior, Hélio Vitoriano Nobre, de Sousa, Damião Pergentino
• Format: Article
• Language: English
• Subjects: Amides; Amides - chemistry; Amides - pharmacology; Anti-Infective Agents - pharmacology; Antifungal activity; Antifungal agents; Antifungal Agents - pharmacology; Antimicrobial agents; Benzoic acid; Biological activity; Candida; Candida - drug effects; Candida krusei; Cell walls; Computer applications; Drug resistance; Fluconazole; Fungal infections; Fungicides; Halogenation; Hydrogen bonds; Ligands; Microbial Sensitivity Tests; Minimum inhibitory concentration; Models, Molecular; Molecular docking; Molecular dynamics; Molecular modelling; Protein folding; Proteins; Simulation; Thermodynamics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23010419

Fungal infections remain a high-incidence worldwide health problem that is aggravated by limited therapeutic options and the emergence of drug-resistant strains. Cinnamic and benzoic acid amides have previously shown bioactivity against different species belonging to the genus. Here, 20 cinnamic and benzoic acid amides were synthesized and tested for inhibition of ATCC 14243 and ATCC 22019. Five compounds inhibited the strains tested, with compound (MIC = 7.8 µg/mL) producing stronger antifungal activity than fluconazole (MIC = 16 µg/mL) against ATCC 14243. It was also tested against eight strains, including five clinical strains resistant to fluconazole, and showed an inhibitory effect against all strains tested (MIC = 85.3-341.3 µg/mL). The MIC value against ATCC 6258 was 85.3 mcg/mL, while against ATCC 14243, it was 10.9 times smaller. This strain had greater sensitivity to the antifungal action of compound . The inhibition of ATCC 14243 and ATCC 22019 was also achieved by compounds , , , and . Computational experiments combining target fishing, molecular docking and molecular dynamics simulations were performed to study the potential mechanism of action of compound against . From these, a multi-target mechanism of action is proposed for this compound that involves proteins related to critical cellular processes such as the redox balance, kinases-mediated signaling, protein folding and cell wall synthesis. The modeling results might guide future experiments focusing on the wet-lab investigation of the mechanism of action of this series of compounds, as well as on the optimization of their inhibitory potency.