Victor Mauricio M, Farias Ravir R, da Silva Danielle L, do Carmo Paulo H F, de Resende-Stoianoff Maria A, Viegas Cláudio, Espuri Patrícia F, Marques Marcos J
Department of Organic Chemistry, Chemistry Institute, Federal University of Bahia, Salvador 40170-115, BA, Brazil.
National Institute of Science and Technology for Energy and Environmental, Salvador 40170-115, BA, Brazil.
Med Chem. 2019;15(4):400-408. doi: 10.2174/1573406414666181024111522.
The trypanosomatids, such as the protozoan Leishmania spp., have a demand by ergosterol, which is not present in the membrane from mammal cells. The suppression of the synthesis of ergosterol would be a new target of compounds with leishmanicidal activity, and bistriazole has shown trypanocidal activity by this mechanism. The incidence of fungal infections has increased at an alarming rate over the last decades. This is related both to the growing population of immune-compromised individuals and to the emergence of strains that are resistant to available antifungals. Therefore, there is a challenge for the search of potential new antifungal agents.
The study aimed to synthesize 1,4-disubstituted-1,2,3-bistriazoles by optimized copper( I)-catalyzed alkyne-azide cycloaddition (CuAAC) and evaluate their antifungal and antitrypanosomastid activities.
The synthesis of symmetrical bistriazoles with diazides as spacers was planned to be performed following the CuAAC reaction strategy. For evaluation of best conditions for the synthesis of symmetrical bistriazoles hex-1-yne 2 was chosen as leading compound, and a variety of catalysts were employed, choosing (3:1) alkyne:diazide stoichiometric relationship employing CuSO4.5H2O as the best condition. For the preparation of diversity in the synthesis of symmetrical bistriazoles, a 1,3-diazide-propan-2-ol 1a and 1,3-diazidepropane 1b were reacted with seven different alkynes, furnishing eleven symmetrical bistriazoles 9-13a,b and 14a. All compounds were essayed to cultures of promastigotes of L. amazonensis (1 x 106 cells mL-1) in the range of 0.10 - 40.00 µg mL-1 and incubated at 25ºC. After 72 h of incubation, the surviving parasites were counted. For antifungal assay, the minimum inhibitory concentrations (MIC) for yeasts and filamentous fungi were determined. Each compound was tested in 10 serial final concentrations (64 to 0.125 µg mL-1).
Eleven 1,4-disubstituted-1,2,3-bistriazoles were synthesized and their structures were confirmed by IR, 1H and 13C-NMR and Mass spectral analysis. The antifungal and antitrypanosomastid activities were evaluated. The best result to antifungal activity was reached by bistriazole 11a that showed the same MIC of fluconazole (32 µg mL-1) against Candida krusei ATCC 6258, an emerging and potentially multidrug-resistant fungal pathogen. Due to their intrinsically biological activity versatility, five derivatives compounds showed leishmanicidal inhibitory activity between 15.0 and 20.0% at concentrations of 20 and 40.0 µg mL-1. Among these compounds the derivative 13a showed best IC50 value of 63.34 µg mL-1 (182.86 µM).
The preliminary and promising results suggest that bistriazole derivatives, especially compound 13a, could represent an innovative scaffold for further studies and development of new antifungal and anti-parasitic drug candidates.
锥虫，如原生动物利什曼原虫属，对麦角固醇有需求，而哺乳动物细胞的膜中不存在这种物质。抑制麦角固醇的合成可能成为具有杀利什曼原虫活性化合物的新靶点，双三唑已通过该机制显示出杀锥虫活性。在过去几十年中，真菌感染的发生率以惊人的速度上升。这既与免疫功能低下个体数量的增加有关，也与对现有抗真菌药物耐药的菌株的出现有关。因此，寻找潜在的新型抗真菌药物面临挑战。
本研究旨在通过优化的铜（I）催化炔烃 - 叠氮环加成反应（CuAAC）合成1,4 - 二取代 - 1,2,3 - 双三唑，并评估其抗真菌和抗锥虫活性。
计划按照CuAAC反应策略进行以二叠氮化物为间隔基的对称双三唑的合成。为评估对称双三唑合成的最佳条件，选择己 - 1 - 炔2作为先导化合物，并使用多种催化剂，选择（3:1）炔烃：二叠氮化物的化学计量关系，以五水硫酸铜作为最佳条件。为在对称双三唑的合成中实现多样性，使1,3 - 二叠氮基 - 丙 - 2 - 醇1a和1,3 - 二叠氮基丙烷1b与七种不同的炔烃反应，得到11种对称双三唑9 - 13a,b和14a。所有化合物在0.10 - 40.00μg mL - 1范围内对亚马逊利什曼原虫前鞭毛体培养物（1×106个细胞 mL - 1）进行测试，并在25℃下孵育。孵育72小时后，对存活的寄生虫进行计数。对于抗真菌试验，测定酵母和丝状真菌的最低抑菌浓度（MIC）。每种化合物在10个系列的终浓度（64至0.125μg mL - 1）下进行测试。
合成了11种1,4 - 二取代 - 1,2,3 - 双三唑，并通过红外光谱、1H和13C - NMR以及质谱分析确认了它们的结构。评估了它们的抗真菌和抗锥虫活性。双三唑11a对克鲁斯念珠菌ATCC 6258（一种新出现的、可能具有多重耐药性的真菌病原体）显示出与氟康唑相同的MIC（32μg mL - 1），在抗真菌活性方面取得了最佳结果。由于其固有的生物活性多样性，五种衍生物化合物在20和40.0μg mL - 1浓度下显示出15.0至20.0％的杀利什曼原虫抑制活性。在这些化合物中，衍生物13a显示出最佳的IC50值为63.34μg mL - 1（182.86μM）。
初步的有前景的结果表明，双三唑衍生物，特别是化合物13a，可能代表一种创新的骨架，用于进一步研究和开发新的抗真菌和抗寄生虫候选药物。
