Background: In recent decades, Candida albicans has become a serious issue for public health. The worldwide rapid rise in drug resistance to conventional therapies is the main contributing reason. Moreover, because of their potent activity at low concentrations and apparent lack of toxicity, compounds originating from plants are used in therapeutic treatments because of their potent activity at low concentrations and apparent lack of toxicity. Particularly in immunocompromised people, Candida species can result in a wide range of ailments. Objectives: Present manuscript describes antifungal activity of an indole derivative 1-(4-((5- methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indol-1-yl) methyl) phenoxy)-N,N-dimethylethan-1- amine (7, 100DL-6) by using an in-silico and in-vitro anti-candidal activity against two Candida strains; Candida kefyr-DS-02 (ATCC-204093) and Candida albicans (AI-clinical isolate, AIIMS- Delhi). Methods: The synthetic strategy for the preparation of indole derivatives was modified through Fischer indole reaction. Antifungal activity of an indole derivative 1-(4-((5-methoxy-2-(3,4,5- trimethoxyphenyl)-1H-indol-1-yl) methyl) phenoxy)-N,N-dimethylethan-1-amine (7, 100DL-6) was done by using an in-silico and in-vitro anti-candidal activity against two Candida strains; Candida kefyr-DS-02 (ATCC-204093) and Candida albicans (AI-clinical isolate, AIIMS-Delhi). Compound 100DL-6 efficacy was determined by Combination synergy study, ergosterol binding assay, MTT toxicity study and Mutagenicity. Results: Compound 100DL-6 was obtained in 65% yield on desired motifs. Docking scores found were 100DL-6 (-8.7 kcal/mol) and Fluconazole (-7.6 kcal/mol). Further, RMSD were shown for 100DL6 (0.26 ± 0.23 nm) and fluconazole (1.2 ± 0.62 nm). Indole derivative 100DL-6 was active against the tested fungal pathogens and the total zone of inhibition was measured between 13-14 mm in diameter and MIC values between 31.25 μg/mL to 250 μg/mL and MFC values between 62.5 μg/mL to 500 μg/mL. In checkerboard assay synergistic mode of interaction of 100DL-6 with known antifungal drugs was observed. In the presence of ergosterol 100DL-6 and standard drug (s) increased their MIC values, demonstrating a considerable affinity for ergosterol. Compound 100DL-6 was considered to be less-cytotoxic to the cells as determined by MTT assay. Lead compound 100DL-6 was found to be non-mutagenic. Conclusion: In the present study, 100DL6 (indole derivatives) significantly abrupted the ergosterol biosynthetic pathway and showed moderate anti-candidal effects. These studies suggest that 100DL6 significantly enhances antifungal effect of clinical drug fluconazole synergistically and may be considered as in clinical trial prior to some extensive in-vivo validations.

中文翻译：

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没食子酸衍生的 1, 2-二芳基吲哚作为抗念珠菌菌株的潜在抗真菌剂

背景：近几十年来，白色念珠菌已成为公共卫生的一个严重问题。全球范围内对传统疗法的耐药性迅速上升是主要原因。此外，由于源自植物的化合物在低浓度下具有有效活性且明显无毒性，因此它们在低浓度下具有有效活性且明显无毒性而被用于治疗处理。特别是在免疫功能低下的人群中，念珠菌会导致多种疾病。目的：本手稿描述了吲哚衍生物 1-(4-((5-甲氧基-2-(3,4,5-三甲氧基苯基)-1H-吲哚-1-基)甲基)苯氧基)-N,N 的抗真菌活性-二甲基乙烷-1-胺 (7, 100DL-6)，通过使用针对两种念珠菌菌株的计算机内和体外抗念珠菌活性；念珠菌 kefyr-DS-02 (ATCC-204093) 和白色念珠菌（AI 临床分离株，AIIMS-德里）。方法：改进Fischer吲哚反应制备吲哚衍生物的合成策略。吲哚衍生物1-(4-((5-甲氧基-2-(3,4,5-三甲氧基苯基)-1H-吲哚-1-基)甲基)苯氧基)-N,N-二甲基乙烷-1-的抗真菌活性胺 (7, 100DL-6) 是通过使用针对两种念珠菌菌株的计算机内和体外抗念珠菌活性来完成的；念珠菌 kefyr-DS-02 (ATCC-204093) 和白色念珠菌（AI 临床分离株，AIIMS-德里）。通过组合协同作用研究、麦角甾醇结合测定、MTT毒性研究和致突变性来确定化合物100DL-6的功效。结果：在所需基序上以 65% 的产率获得了化合物 100DL-6。发现的对接分数为 100DL-6 (-8.7 kcal/mol) 和氟康唑 (-7.6 kcal/mol)。此外，还显示了 100DL6 (0.26 ± 0.23 nm) 和氟康唑 (1.2 ± 0.62 nm) 的 RMSD。吲哚衍生物 100DL-6 对测试的真菌病原体具有活性，测量的总抑制区直径在 13-14 mm 之间，MIC 值在 31.25 μg/mL 至 250 μg/mL 之间，MFC 值在 62.5 μg/mL 至 500 之间微克/毫升。在棋盘试验中，观察到 100DL-6 与已知抗真菌药物相互作用的协同模式。在麦角甾醇 100DL-6 和标准药物存在的情况下，它们的 MIC 值增加，表明对麦角甾醇具有相当大的亲和力。通过MTT测定确定，化合物100DL-6被认为对细胞的细胞毒性较小。先导化合物 100DL-6 被发现不具有诱变性。结论：在本研究中，100DL6（吲哚衍生物）显着中断麦角甾醇生物合成途径，并显示出中等的抗念珠菌作用。这些研究表明，100DL6 可以协同显着增强临床药物氟康唑的抗真菌作用，并且可以考虑在一些广泛的体内验证之前进行临床试验。