Bioisosteric modification on benzylidene‐carbonyl compounds improved the drug‐likeness and maintained the antifungal activity against Sporothrix brasiliensis

• Published in: Chemical biology & drug design 2022-03, Vol.99 (3), p.391-397
• Main Authors: Waller, Stefanie Bressan, Cleff, Marlete Brum, Ripoll, Márcia Kutscher, Meireles, Mário Carlos Araújo, Ferrarini, Márcio, Varela, Marina Themoteo, Fernandes, João Paulo S.
• Format: Article
• Language: English
• Subjects: Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; antifungal resistance; Benzylidene Compounds - chemistry; bioisosterism; coumaric acid derivatives; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; itraconazole; Itraconazole - chemical synthesis; Itraconazole - chemistry; Itraconazole - pharmacology; Ketones - chemistry; Microbial Sensitivity Tests; mycosis; Sporothrix - drug effects; Sporothrix brasiliensis; sporotrichosis; Structure-Activity Relationship
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13994

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. New 19 benzylidene‐carbonyl compounds were tested against Sporothrix brasiliensis, including itraconazole‐resistant isolates (CLSI M38‐A2). 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) derivatives. Compound 3e (4‐methoxy‐N‐butylcinnamamide) was the most potent, showing that the modification of benzylidene‐ketone motif represented a strategy to achieve active compounds.