School of Life Sciences, Jawaharlal Nehru University, 110067 New Delhi, India.
Grenoble Alpes University, Department of Molecular Pharmacochemistry (DPM), UMR 5063, 38041 Grenoble, France.
Future Med Chem. 2018 Sep 1;10(18):2177-2186. doi: 10.4155/fmc-2018-0081. Epub 2018 Jul 25.
Resistance against antifungals used for Candida albicans (Ca) treatment is mediated by two multidrug transporters, Mdr1p and Cdr1p, which are of enormous interest to the development of modulators combined with antifungals.
A set of chalcones was synthesized by condensation reactions in laboratory and was then subject to biological assays to evaluate the effects on different yeast strains. Results: The obtained chalcones were screened using the checkerboard liquid chemosensitization assays. Compounds 4, 10, 12 and 18, when combined with fluconazole, triggered strong sensitization on yeast strains overexpressing CaMdr1p and CaCdr1p, whereas displaying no cytotoxicity by themselves towards control strains and transporter-expressing yeast cells. In the Nile Red transport assay, the two most active compounds, 12 and 18 showed moderate-to-high accumulation of Nile Red with different behaviors towards the two transporters.
Chalcones are promising drug candidates for further development to make azole antifungals active again.
对抗真菌药物用于治疗白色念珠菌（Ca）的耐药性是由两种多药转运蛋白介导的，Mdr1p 和 Cdr1p，这对开发与抗真菌药物联合使用的调节剂具有重要意义。
一组查耳酮通过实验室中的缩合反应合成，然后进行生物测定以评估它们对不同酵母菌株的影响。
用棋盘微量稀释化学增敏试验筛选获得的查耳酮。化合物 4、10、12 和 18 与氟康唑联合使用时，对过度表达 CaMdr1p 和 CaCdr1p 的酵母菌株有强烈的增敏作用，而对对照菌株和转运蛋白表达的酵母细胞本身没有细胞毒性。在尼罗红转运试验中，两种最活跃的化合物 12 和 18 显示出对尼罗红的中等到高积累，对两种转运蛋白表现出不同的行为。
查耳酮是有前途的药物候选物，可进一步开发使唑类抗真菌药物重新发挥作用。
