Irfan Mohammad, Alam Shadab, Manzoor Nikhat, Abid Mohammad
Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Medical Mycology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
PLoS One. 2017 Apr 21;12(4):e0175710. doi: 10.1371/journal.pone.0175710. eCollection 2017.
Candida albicans, along with some other non-albicans Candida species, is a group of yeast, which causes serious infections in humans that can be both systemic and superficial. Despite the fact that extensive efforts have been put into the discovery of novel antifungal agents, the frequency of these fungal infections has increased drastically worldwide. In our quest for the discovery of novel antifungal compounds, we had previously synthesized and screened quinoline containing 1,2,3-triazole (3a) as a potent Candida spp inhibitor. In the present study, two structural analogues of 3a (3b and 3c) have been synthesized to determine the role of quinoline and their anti-Candida activities have been evaluated. Preliminary results helped us to determine 3a and 3b as lead inhibitors. The IC50 values of compound 3a for C. albicans ATCC 90028 (standard) and C. albicans (fluconazole resistant) strains were 0.044 and 2.3 μg/ml, respectively while compound 3b gave 25.4 and 32.8 μg/ml values for the same strains. Disk diffusion, growth and time kill curve assays showed significant inhibition of C. albicans in the presence of compounds 3a and 3b. Moreover, 3a showed fungicidal nature while 3b was fungistatic. Both the test compounds significantly lower the secretion of proteinases and phospholipases. While, 3a inhibited proteinase secretion in C. albicans (resistant strain) by 45%, 3b reduced phospholipase secretion by 68% in C. albicans ATCC90028 at their respective MIC values. Proton extrusion and intracellular pH measurement studies suggested that both compounds potentially inhibit the activity of H+ ATPase, a membrane protein that is crucial for various cell functions. Similarly, 95-97% reduction in ergosterol content was measured in the presence of the test compounds at MIC and MIC/2. The study led to identification of two quinoline based potent inhibitors of C. albicans for further structural optimization and pharmacological investigation.
白色念珠菌与其他一些非白色念珠菌属物种一样，是一类酵母菌，可引发人类严重感染，包括全身性感染和浅表性感染。尽管人们已付出巨大努力来发现新型抗真菌药物，但在全球范围内，这些真菌感染的发生率仍急剧上升。在探寻新型抗真菌化合物的过程中，我们之前合成并筛选了含1,2,3 - 三唑的喹啉（3a），它是一种有效的念珠菌属抑制剂。在本研究中，我们合成了3a的两种结构类似物（3b和3c），以确定喹啉的作用，并评估了它们的抗念珠菌活性。初步结果帮助我们确定3a和3b为先导抑制剂。化合物3a对白色念珠菌ATCC 90028（标准菌株）和白色念珠菌（氟康唑耐药）菌株的IC50值分别为0.044和2.3μg/ml，而化合物3b对相同菌株的值为25.4和32.8μg/ml。纸片扩散法、生长曲线和时间杀菌曲线试验表明，在化合物3a和3b存在的情况下，白色念珠菌受到显著抑制。此外，3a表现出杀菌特性，而3b具有抑菌作用。两种受试化合物均显著降低了蛋白酶和磷脂酶的分泌。在各自的MIC值下，3a使白色念珠菌（耐药菌株）中的蛋白酶分泌减少45%，3b使白色念珠菌ATCC90028中的磷脂酶分泌减少68%。质子外排和细胞内pH测量研究表明，这两种化合物都可能抑制H + ATPase的活性，H + ATPase是一种对各种细胞功能至关重要的膜蛋白。同样，在MIC和MIC/2浓度的受试化合物存在下，麦角固醇含量降低了95 - 97%。该研究鉴定出两种基于喹啉的白色念珠菌有效抑制剂，用于进一步的结构优化和药理研究。
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