Facultad de Ciencias Químicas, Universidad Autónoma "Benito Juárez" de Oaxaca, Oaxaca 68120, Mexico.
Departamento de Química, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740, C.P. 07000 CDMX, Mexico.
Bioorg Med Chem. 2021 Oct 15;48:116417. doi: 10.1016/j.bmc.2021.116417. Epub 2021 Sep 20.
Chagas disease is a health problem that affects millions of persons, currently Nifurtimox (Nfx) and Benznidazole (Bz) are the unique drugs to treat it. However, these drugs produce adverse effects and high toxicity, which has motivated the search for new candidate drugs. Based on reports about the extensive biological activity of steroidal nitrate esters, in this study three nitrate esters steroids (1b, 2b and 4b) were synthetized and characterized from Dehydroepiandrosterone (DHEA, 1a), 19-hydroxy-DHEA (2a), and Androst-5-en-3β,17β-diol (4a), respectively. In addition, compounds 3a and 3b were obtained by introducing an α-ethynyl and a β-hydroxyl groups at position 17 of 2b and further nitration of the hydroxyl group. The trypanocidal activity of these steroids was evaluated in vitro against the epimastigote stage of two T. cruzi strains, Ninoa and TH, and their cytotoxicity over J774.2 macrophage cell line was assayed. Compounds 3a, 3b, and 4a shown higher trypanocidal activity than Bz and Nfx against epimastigotes of Ninoa strain, whereas DHEA (1a) and its nitrate derivative 1b showed higher activity than the reference drugs against the TH strain epimastigote. None of the compounds showed activity in the ex vivo assays against the blood trypomastigote of both strains. Interestingly, the selectivity index of Androst-5-en-3β,17β-diol 4a was almost twice the value of Nfx and 50 times more than Bz, against Ninoa and TH strains, respectively. Therefore, compound 4a could represent a valuable starting point toward the optimization of steroid derivatives as trypanocidal agents.
恰加斯病是一种影响数百万人的健康问题，目前，硝呋莫司（Nfx）和苯唑硝唑（Bz）是唯一用于治疗该病的药物。然而，这些药物会产生不良反应和高毒性，这促使人们寻找新的候选药物。基于类固醇硝酸酯具有广泛的生物活性的报道，在这项研究中，从脱氢表雄酮（DHEA，1a）、19-羟基-DHEA（2a）和雄甾-5-烯-3β，17β-二醇（4a）分别合成并表征了三种硝酸酯类固醇（1b、2b 和 4b）。此外，通过在 2b 的 17 位引入α-乙炔基和β-羟基，并进一步硝化羟基，得到了化合物 3a 和 3b。这些类固醇的抗锥虫活性在体外对两种 T. cruzi 株，Ninoa 和 TH 的滋养体阶段进行了评估，并对 J774.2 巨噬细胞系的细胞毒性进行了测定。化合物 3a、3b 和 4a 对 Ninoa 株的滋养体表现出比 Bz 和 Nfx 更高的杀锥虫活性，而 DHEA（1a）及其硝酸盐衍生物 1b 对 TH 株滋养体的活性高于参考药物。在针对两种菌株的血液锥虫循环期的体外实验中，没有一种化合物表现出活性。有趣的是，Androst-5-en-3β，17β-二醇 4a 的选择性指数几乎是 Nfx 的两倍，对 Ninoa 和 TH 株的选择性指数分别是 Bz 的 50 倍。因此，化合物 4a 可能是作为抗锥虫剂优化类固醇衍生物的有价值的起点。
