Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Curr Drug Targets. 2021;22(4):379-398. doi: 10.2174/1389450121666201228122239.
Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas diseases are among the most severe NTDs, and are caused by the Leishmania sp and Trypanosoma cruzi, respectively. Glucantime, pentamidine, and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance and severe side effects. Hence, the development of synthetic products, especially those containing N0, F, or Cl, are known to improve biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluorosynthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand-searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC/EC values in in vitro studies. It is worth mentioning that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro-, and chloro-groups in the compound backbone. All in all, nitro and halogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as the baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts in in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.
被忽视的热带病（NTDs）每年导致超过 500,000 人死亡，其特征是多种残疾。利什曼病和恰加斯病是最严重的 NTDs 之一，分别由利什曼原虫和克氏锥虫引起。葡萄糖酸锑钠、戊烷脒和米替福新通常用于治疗利什曼病，而硝呋替莫和苯硝唑是目前治疗恰加斯病的方法。然而，这些治疗方法与药物耐药性和严重的副作用有关。因此，开发合成产品，特别是含有 N0、F 或 Cl 的产品，被认为可以提高生物活性。本工作总结了有关硝基、氯和氟合成衍生物的抗利什曼原虫和抗锥虫活性的信息。在 SciFinder、Wiley、Science Direct、PubMed、ACS、Springer、Scielo 等数据库中，手工搜索了与抗利什曼原虫和抗锥虫活性有关的卤代衍生物的科学出版物。根据文献信息，超过 90 种化合物被预测为具有参考价值的先导分子，其在体外研究中的 IC/EC 值。值得一提的是，本研究仅考虑了对哺乳动物细胞具有已知细胞毒性作用的活性化合物。观察到的活性归因于化合物骨架中存在硝基、氟和氯基团。总之，硝基和卤代衍生物是活性抗利什曼原虫和抗锥虫化合物，可以作为开发针对利什曼病和恰加斯病的新药的基础。然而，仍然需要进行体外和体内毒性研究。需要探索有前途的化合物的药代动力学研究和作用机制。使用新的催化剂和化学转化可以提供具有改善的抗利什曼原虫和抗锥虫活性的未探索的卤代化合物。
