Synthesis and Antifungal Activity of 1-[(2-Benzyloxy)Phenyl]-2-(Azol-1-yl)Ethanone Derivatives: Exploring the Scaffold Flexibility

Based on the N‐(phenethyl)azole backbone of azole antifungals, we designed 1‐[(2‐benzyloxy)phenyl]‐2‐(azol‐1‐yl)ethanone derivatives 2 and 3, containing benzyloxyphenyl scaffold of croconazole. Also these compounds can be considered as flexible analogs, resulted from C2–C3 disconnection of 3′‐chloro‐3‐imidazolylflavanone 1, recently described as antifungal agent. Thus, in this report, we describe the synthesis of 1‐[(2‐benzyloxy)phenyl]‐2‐(azol‐1‐yl)ethanone derivatives 2 and 3 and their biological evaluation against different pathogenic fungi. By comparing the antifungal activity profile of flexible compounds 2 and 3 with that of rigid analog 1, it can be inferred that lower susceptibilities (higher minimum inhibitory concentrations) were observed with flexible compounds. However, among the synthesized compounds, 1‐[2‐(2,4‐dichlorobenzyloxy)phenyl]‐2‐(1H‐imidazol‐1‐yl)ethanone hydrochloride (2g) showed comparable or more potent antifungal activity in comparison with fluconazole as a standard drug. Based on the N‐(phenethyl)azole backbone of azole antifungals, we designed 1‐[(2‐benzyloxy)phenyl]‐2‐(azol‐1‐yl)ethanone derivatives 2 and 3, containing benzyloxyphenyl scaffold of croconazole. Among the synthesized compounds, 1‐[2‐(2,4‐dichlorobenzyloxy)phenyl]‐2‐(1H‐imidazol‐1‐yl)ethanone hydrochloride (2g) showed comparable or more potent antifungal activity in comparison with fluconazole as a standard drug.