Due to the emergence of multi-drug resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase (CgHMGR), and thus affect ergosterol synthesis and yeast viability. One series of synthetic antifungal compounds were analogues to fibrates, a second series had substituted 1,2-dihydroquinolines and the third series included substituted pyrroles. α-asarone-related compounds 1c and 5b with a pyrrolic core were selected as the best antifungal candidates. Both inhibited the growth of fluconazole-resistant C. glabrata 43 and fluconazole-susceptible C. glabrata CBS 138. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 strain and after the 1c (versus 5b) treatment. Given that the compounds decreased the ergosterol concentration in the yeast strains, they probably target the ergosterol synthesis. According to the docking analysis, the inhibitory effect of the 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of CgHMGR. Since 1c displayed higher binding energy than α-asarone and 5b, it is a good candidate for further research, which should include structural modifications to increase its specificity and potency as well as in vivo studies on its effectiveness at a therapeutic dose.

中文翻译：

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基于贝特的化合物和取代吡咯的抗真菌活性抑制光滑念珠菌 (CgHMGR) 的酶 3-羟基-甲基-戊二酰-CoA 还原酶，并降低酵母活力和麦角甾醇合成

由于属于念珠菌属的多重耐药菌株的出现，迫切需要发现针对替代分子靶标的抗真菌剂。本研究的目的是评估合成化合物抑制光滑念珠菌的能力，称为 3-羟基-甲基-戊二酰辅酶 A 还原酶 (CgHMGR)，从而影响麦角甾醇合成和酵母活力。一系列合成抗真菌化合物类似于贝特类化合物，第二个系列含有取代的 1,2-二氢喹啉，第三个系列包括取代的吡咯。α-细辛酮相关化合物1c和5b吡咯核被选为最佳抗真菌候选药物。两者都抑制了耐氟康唑的C. glabrata 43 和对氟康唑敏感的C. glabrata CBS 138 的生长。基于添加外源麦角甾醇的酵母生长挽救实验表明，这些化合物通过抑制甲羟戊酸合成途径起作用。C. glabrata 43 菌株和1c（与5b相比）处理后酵母生长的恢复更大。鉴于这些化合物降低了酵母菌株中麦角甾醇的浓度，它们可能针对麦角甾醇的合成。根据对接分析，1c和5b的抑制作用可能是通过它们与 CgHMGR 催化位点的氨基酸残基的相互作用来介导的。由于1c显示出比 α-asarone 和5b更高的结合能，因此它是进一步研究的良好候选者，其中应包括结构修改以提高其特异性和效力，以及在治疗剂量下对其有效性进行体内研究。