Efficacy of novel eugenol tosylate congeners as antifungal compounds in combination with fluconazole against Candida albicans

The incidences of Candida albicans infections and their changing drug resistance patterns have drastically increased in recent years. Therefore, new drugs and alternative treatment strategies are promptly required. Combination therapy and the use of natural products have been extensively studied as alternative treatment. In this study, we synthesized Eugenol Tosylate Congeners (ETCs 1–6) and evaluated their antifungal activity profile alone and in combination with fluconazole (FLC) against four FLC susceptible and three FLC resistant clinical isolates of Candida albicans isolates according to CLSI guidelines. For insight mechanism of antifungal action of ETCs, activity of plasma membrane H+-ATPase pump of these C. albicans isolates was determined by monitoring the pH of the external medium. ETC 1 and ETC 4 were the most active congeners against the resistant isolates with the MIC ranging from 125 to 250 µg ml−1. The MFC of ETCs ranged from 1000 µg ml−1 to 2000 µg ml−1. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms showed 36 % of synergy, 29 % of additive, 33 % of indifferent and 2 % of antagonistic interactions. These compounds also inhibit H+efflux activity of H+-ATPase pump at varying degrees. Our results suggest that these ETCs may be directly binding to this pump and thereby inhibiting H+-efflux in Candida cells. These results advocate the potential of these compounds in developing new antifungal drugs; however, further studies are required to understand the other mechanisms involved and in vivo efficacy and toxicity of these compounds.