a Faculdade de Ciências Farmacêuticas de Ribeirão Preto , USP , Av. do Café S/N, CEP: 14040-903, Ribeirão Preto , SP , Brazil.
b Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , c/ Campus de Cartuja s/n, Granada 18071 , Spain.
J Biomol Struct Dyn. 2017 Aug;35(11):2430-2440. doi: 10.1080/07391102.2016.1221364. Epub 2016 Sep 6.
Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D-QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic α6β3β4α5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays.
利什曼病是一组主要的被忽视热带病，由原生动物寄生虫利什曼原虫引起。在 98 个国家约有 1200 万人受到感染，全世界有 3.5 亿人面临感染风险。目前的利什曼病治疗方法依赖于相对较少的药物，包括两性霉素 B、喷他脒等，这些药物通常都有某种不便之处。最近，我们合成了抗利什曼病的双吡啶衍生物和对称的双吡啶环芳烃。这些化合物被认为是喷他脒的结构类似物，其中在生理 pH 下质子化的脒基部分被带正电荷的氮原子取代，形成吡啶环。在这项工作中，建立了一个基于 GRIND2 的统计学显著的 3D-QSAR 模型，并进行了生物活性预测，允许对最近获得的针对利什曼原虫（在利什曼原虫前鞭毛体中）的 19 种双吡啶化合物数据集的不同活性进行合理化。我们将强调最重要的结构要求，以提高生物活性，并可能与生物受体相互作用，作为先导和原型优化的指南。此外，由于没有提供关于该系列活性化合物实际生物靶标的信息，我们使用生物活性物质的活性光谱预测来提出我们的化合物作为潜在的烟碱α6β3β4α5 受体拮抗剂。这一建议得到了我们的化合物与目前临床使用的几种驱虫药物之间观察到的高度结构相似性的支持，这里预测的药物作用机制相同。这些新发现将通过进一步和额外的实验检测来证实。
