Find in Library

A newly synthetized series of <i>N</i>-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against <i>Candida</i> strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone (<b>5d</b>), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone (<b>5i</b>), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone (<b>5k</b>) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone (<b>6a</b>) showed anti-<i>C. albicans</i> SC5314 activity, where <b>5d</b> displayed MIC_T = 16 µg/mL (%R = 100) and a weak anti-proliferative activity against the clinical strains: <i>C. albicans</i> resistant to azoles (Itr and Flu) and <i>C. glabrata</i>. Derivatives <b>5k</b> and <b>6a</b> displayed MIC_P = 16 µg/mL and %R = 64.2 ± 10.6, %R = 88.0 ± 9.7, respectively, against the <i>C. albicans</i> isolate. Derivative <b>5i</b> was the most active against <i>C. glabrata</i> (%R = 53.0 ± 3.5 at 16 µg/mL). Benzoxazoles displayed no MIC against <i>C. glabrata</i>. Benzoxazoles showed a pleiotropic action mode: (<b>1</b>) the total sterols content was perturbed; (<b>2</b>) 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4-dichlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichlorophenyl)ethanol (<b>8h</b>–<b>i</b>) at the lowest fungistatic conc. inhibited the efflux of the Rho123 tracker during the membrane transport process; (<b>3</b>) mitochondrial respiration was affected/inhibited by the benzoxazoles: 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-chlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanol <b>8c</b>–<b>d</b> and <b>8i</b>. Benzoxazoles showed comparable activity to commercially available azoles due to (<b>1</b>) the interaction with exogenous ergosterol, (<b>2</b>) endogenous ergosterol synthesis blocking as well as (<b>3</b>) membrane permeabilizing properties typical of AmB. Benzoxazoles display a broad spectrum of anti-<i>Candida</i> activity and action mode towards the membrane without cross-resistance with AmB; furthermore, they are safe to mammals.