Laboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of Alagoas, Maceió-AL 57072-900, Brazil | Institute of Chemistry and Biotechnology, Federal University of Alagoas, 57072-900, Maceió-AL, Brazil.
Laboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of Alagoas, Maceió-AL 57072-900, Brazil.
Med Chem. 2022;18(2):151-169. doi: 10.2174/1573406417666210216154428.
Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used in an urgent need. Aminoguanidine hydrazones (AGH's) have been explored for exhibiting a diverse spectrum of biological activities, in particular the antileishmanial activity of MGBG. The bioisosteres thiosemicarbazones (TSC's) offer a similar biological activity diversity, including antiprotozoal effects against Leishmania species and Trypanosoma cruzi.
Considering the impact of leishmaniasis worldwide, this work aimed to design, synthesize, and perform a screening upon L. chagasi amastigotes and for the cytotoxicity of the small "inhouse" library of both AGH and TSC derivatives and their structurally-related compounds.
A set of AGH's (3-7), TSC's (9, 10), and semicarbazones (11) were initially synthesized. Subsequently, different semi-constrained analogs were designed and also prepared, including thiazolidines (12), dihydrothiazines (13), imidazolines (15), pyrimidines (16, 18) azines (19, 20), and benzotriazepinones (23-25). All intermediates and target compounds were obtained with satisfactory yields and exhibited spectral data consistent with their structures. All final compounds were evaluated against L. chagasi amastigotes and J774.A1 cell line. Molecular docking was performed towards trypanothione reductase using GOLD software.
The AGH's 3i, 4a, and 5d, and the TSC's 9i, 9k, and 9o were selected as valuable hits. These compounds presented antileishmanial activity compared with pentamidine, showing ICvalues ranged from 0.6 to 7.27 μM, maximal effects up to 55.3%, and satisfactory SI values (ranged from 11 to 87). On the other hand, most of the resulting semi-constrained analogs were found cytotoxic or presented reduced antileishmanial activity. In general, TSC class is more promising than its isosteric AGH analogs, and the beneficial aromatic substituent effects are not similar in both series. In silico studies have suggested that these hits are capable of inhibiting the trypanothione reductase from the amastigote forms.
The promising antileishmanial activity of three AGH's and three TSC's was characterized. These compounds presented antileishmanial activity compared with PTD, showing IC50 values ranged from 0.6 to 7.27 μM, and satisfactory SI values. Further pharmacological assays involving other Leishmania strains are in progress, which will help choose the best hits for in vivo experiments.
利什曼病是一个全球性的健康问题，在发展中国家高度流行。在该疾病的四种主要临床形式中，内脏利什曼病最为严重，95%的病例是致命的。由于一线化疗存在不良的副作用，以及报道的耐药性，因此迫切需要寻找能够替代或补充目前使用的有效药物。氨基胍腙（AGH）因其具有多种生物活性而备受关注，特别是 MGBG 的抗利什曼原虫活性。生物等排物硫代氨基甲脒（TSC）具有相似的生物活性多样性，包括对利什曼原虫属和克氏锥虫的抗原生动物作用。
考虑到利什曼病在全球的影响，本工作旨在设计、合成并筛选小的内部文库中的 AGH 和 TSC 衍生物及其结构相关化合物对 L. chagasi 无鞭毛体的抗利什曼原虫活性和细胞毒性。
一组 AGH（3-7）、TSC（9、10）和半脒（11）最初被合成。随后，设计并制备了不同的半约束类似物，包括噻唑烷（12）、二氢噻嗪（13）、咪唑啉（15）、嘧啶（16、18）嗪（19、20）和苯并三唑并庚酮（23-25）。所有中间体和目标化合物均以满意的产率获得，并具有与其结构一致的光谱数据。所有终产物均针对 L. chagasi 无鞭毛体和 J774.A1 细胞系进行了评价。使用 GOLD 软件对 trypanothione reductase 进行分子对接。
AGH 的 3i、4a 和 5d 以及 TSC 的 9i、9k 和 9o 被选为有价值的候选物。与戊烷脒相比，这些化合物具有抗利什曼原虫活性，IC50 值范围为 0.6 至 7.27 μM，最大效应高达 55.3%，且 SI 值（11 至 87）令人满意。另一方面，大多数生成的半约束类似物被发现具有细胞毒性或表现出降低的抗利什曼原虫活性。一般来说，TSC 类比其等排物 AGH 类似物更有前途，并且两者系列中的芳香取代基效应并不相似。计算机研究表明，这些候选物能够抑制无鞭毛体形式的 trypanothione reductase。
对三种 AGH 和三种 TSC 的有前途的抗利什曼原虫活性进行了表征。与 PTD 相比，这些化合物具有抗利什曼原虫活性，IC50 值范围为 0.6 至 7.27 μM，SI 值令人满意。目前正在进行涉及其他利什曼原虫株的进一步药理学研究，这将有助于选择用于体内实验的最佳候选物。
