Design, Synthesis and Biopharmacological Profile Evaluation of New 2-((4- Chlorophenoxy)Methyl)-N-(Arylcarbamothioyl)Benzamides with Broad Spectrum Antifungal Activity

Abstract

The emerging antifungal resistance represents a major challenge for the treatment of severe fungal infections, highlighting the need to develop novel and efficient antifungal compounds. This study aimed to synthesize new title compounds and screen them for their antifungal activity in order to generate highly accurate structure - activity relationships of 2-((4-chlorophenoxy)methyl)-N-(arylcarbamothioyl)benzamides and their de novo derivatives and to unveil some of their mechanisms of action by flow cytometry and fluorescence microscopy. The presence of functional groups was confirmed for nine new 2-((4- chlorophenoxy) methyl)-N-(arylcarbamothioyl)benzamides, using experimental and in silico methods. The antifungal activity was assessed against a broad spectrum of 26 yeast and filamentous fungal strains, using qualitative and quantitative assays. The results showed that Candida kefyr has been the most susceptible to all tested compounds, while 1b and 1f induced a strong inhibitory effect on the filamentous fungi Alternaria rubi, Aspergillus ochraceus and A. niger strains growth. The derivative 1c in subinhibitory concentrations alsoincreased the susceptibility of Candida albicans clinical strains to azoles. Predicted drug likeness and pharmacokinetics profiles of most active compounds were compared with the standard antifungal ketoconazole. Furthermore, the potentially more potent 1c and 1f derivatives were designed and studied regarding the chemical structure-biological activity relationship and pharmacokinetics profiles versus ketoconazole. The study confirms that the new benzamide derivatives exhibited an improved pharmacokinetics profile and a good antifungal activity, acting at least by increasing membrane permeability of fungal cells. Our results are recommending them as promising candidates for the development of novel therapeutic alternatives.