ioisosteric modification on benzylidene-carbonyl compounds improved the drug-likeness and maintained the antifungal activity against Sporothrix brasiliensi

Author(s)

Waller, Stefanie Bressan ^{[1, 2]} ; Cleff, Marlete Brum ^[2] ; Ripoll, Marcia Kutscher ^[1] ; Araujo Meireles, Mario Carlos ^[1] ; Ferrarini, Marcio ^[3] ; Varela, Marina Themoteo ^[3] ; Fernandes, Joao Paulo S. ^[3]

Affiliation

^[1] Univ Fed Pelotas, Fac Vet, Dept Prevent Vet, Pelotas, RS - Brazil

^[2] Univ Fed Pelotas, Fac Vet, Dept Vet Clin, Pelotas, RS - Brazil

^[3] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, Dept Pharmaceut Sci, Diadema, SP - Brazil

• Document type: Journal article
• Source: CHEMICAL BIOLOGY & DRUG DESIGN; v. 99, n. 3 DEC 2021.
• Web of Science Citations: 0

Abstract

Considering the emergence of antifungal resistance on Sporothrix brasiliensis, we aimed to assess new benzylidene-carbonyl compounds against feline-borne S. brasiliensis isolates. The compounds were designed as bioisosteres from previously reported benzylidene-ketones generating the p-coumaric (1), cinnamic (2), p-methoxycinnamic (3) and caffeic acid (4) analogues. The corresponding compounds were tested against feline isolates of S. brasiliensis with sensitivity (n = 4) and resistance (n = 5) to itraconazole (ITZ), following the M38-A2 protocol (CLSI, Reference method for broth dilution antifungal susceptibility testing of filamentous fungi M38-A2 Guideline, 2008). Eleven analogues showed activity against all fungal strains with minimum inhibitory concentrations (MIC) <= 1 mg/ml (1a-d, 2e, 3b, 3e, 4, 4a and 5e) and fungicidal concentrations (MFC) <= 1 mg/ml (1b, 1d, 3e and 4a), whereas 3 was the less active with both MIC and MFC values above 1 mg/ml. Compound 3e (4-methoxy-N-butylcinnamamide) was the most potent (MICrange 0.08-0.16 mg/ml; MFCrange 0.32-0.64 mg/ml) from the set, suggesting a different role of the substituents in ester and amide derivatives. The designed compounds proved to be important prototypes with improved drug-likeness to achieve compounds with higher activity against ITZ-resistant S. brasiliensis. (AU)

• FAPESP's process: 18/03918-2 - Evaluation of the antiparasitic activity and cytotoxicity of natural products derivatives in Trypanosoma cruzi: design and synthesis of analogues potentially superior
• Grantee: Marina Themoteo Varela
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/24028-8 - Substituted aryl-alkylamide-piperazines as multitarget ligands: synthesis and assessment of the activity on relevant targets for the treatment of CNS disorders
• Grantee: João Paulo dos Santos Fernandes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
• Grantee: João Paulo dos Santos Fernandes
• Support Opportunities: Regular Research Grants