Mollineda-Diogo Niurka, Chaviano-Montes de Oca Claudia Sissely, Sifontes-Rodríguez Sergio, Espinosa-Buitrago Teresa, Monzote-Fidalgo Lianet, Meneses-Marcel Alfredo, Morales-Helguera Aliuska, Perez-Castillo Yunierkis, Arán-Redó Vicente
Universidad Central "Marta Abreu" de Las Villas, Centro de Bioactivos Químicos, Carretera a Camajuaní Km. 5 ½, Santa Clara, Villa Clara, Cuba.
Universidad Central "Marta Abreu" de Las Villas, Centro de Bioactivos Químicos, Villa Clara, Cuba.
Ther Adv Infect Dis. 2023 Oct 30;10:20499361231208294. doi: 10.1177/20499361231208294. eCollection 2023 Jan-Dec.
Currently, there is no safe and effective vaccine against leishmaniasis and existing therapies are inadequate due to high toxicity, cost and decreased efficacy caused by the emergence of resistant parasite strains. Some indazole derivatives have shown and activity against and . On that basis, 20 indazole derivatives were tested against .
To evaluate the activity of twenty 2-benzyl-5-nitroindazolin-3-one derivatives against .
For the selection of promising compounds, it is necessary to evaluate the indicators for activity. For this aim, a battery of studies for antileishmanial activity and cytotoxicity were implemented. These results enabled the determination of the substituents in the indazole derivatives responsible for activity and selectivity, through the analysis of the structure-activity relationship (SAR).
cytotoxicity against mouse peritoneal macrophages and growth inhibitory activity in promastigotes were evaluated for 20 compounds. Compounds that showed adequate selectivity were tested against intracellular amastigotes. The SAR from the results in promastigotes was represented using the SARANEA software.
Eight compounds showed selectivity index >10% and 50% inhibitory concentration <1 µM against the promastigote stage. Against intracellular amastigotes, four were as active as Amphotericin B. The best results were obtained for 2-(benzyl-2,3-dihydro-5-nitro-3-oxoindazol-1-yl) ethyl acetate, with 50% inhibitory concentration of 0.46 ± 0.01 µM against amastigotes and a selectivity index of 875. The SAR study showed the positive effect on the selectivity of the hydrophilic fragments substituted in position 1 of 2-benzyl-5- nitroindazolin-3-one, which played a key role in improving the selectivity profile of this series of compounds.
2-bencyl-5-nitroindazolin-3-one derivatives showed selective and potent activity, supporting further investigations on this family of compounds as potential antileishmanial hits.
目前，尚无针对利什曼病的安全有效的疫苗，且现有疗法因毒性高、成本高以及耐药寄生虫菌株的出现导致疗效降低而存在不足。一些吲唑衍生物已显示出对[具体对象1]和[具体对象2]的[具体活性1]和[具体活性2]。在此基础上，对20种吲唑衍生物进行了针对[具体对象3]的测试。
评估20种2-苄基-5-硝基吲唑啉-3-酮衍生物对[具体对象3]的[具体活性]。
为了筛选出有前景的化合物，有必要评估[具体活性]的指标。为此，开展了一系列抗利什曼原虫活性和细胞毒性研究。通过分析构效关系（SAR），这些结果能够确定吲唑衍生物中负责活性和选择性的取代基。
评估了20种化合物对小鼠腹腔巨噬细胞的细胞毒性以及对前鞭毛体的生长抑制活性。对显示出足够选择性的化合物进行了针对细胞内无鞭毛体的测试。使用SARANEA软件从前鞭毛体的结果中呈现构效关系。
8种化合物对前鞭毛体阶段的选择性指数>10%，50%抑制浓度<1μM。针对细胞内无鞭毛体，4种化合物的活性与两性霉素B相当。2-(苄基-2,3-二氢-5-硝基-3-氧代吲唑-1-基)乙酸乙酯的效果最佳，对无鞭毛体的50%抑制浓度为0.46±0.01μM，选择性指数为875。构效关系研究表明，2-苄基-5-硝基吲唑啉-3-酮1位取代的亲水性片段对选择性有积极影响，这在改善该系列化合物的选择性方面起关键作用。
2-苄基-5-硝基吲唑啉-3-酮衍生物显示出选择性和强效的[具体活性]，支持对该类化合物作为潜在抗利什曼原虫药物进行进一步研究。
