Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2‐substituted‐1H‐benzo[d]imidazole derivatives (9a–d) showing affinity in the submicromolar range (K_i = 0.15–0.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of Leishmania infantum with the best result being obtained with derivative 9d (IC₅₀ = 6.8 μM), although with some degree of cytotoxicity (CC₅₀ = 8.0 μM on PMM and CC₅₀ = 32.0 μM on MCR‐5). In silico molecular docking studies and ADME‐Tox properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug‐likeness of these derivatives.

中文翻译：

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发现基于苯并咪唑的墨西哥利什曼原虫半胱氨酸蛋白酶CPB2.8ΔCTE抑制剂可作为利什曼病的潜在疗法

化学疗法是目前治疗所有形式的利什曼病的唯一有效方法。然而，由于高毒性，长治疗时间，耐药性或给药方式不足，其有效性受到严重限制。结果，需要鉴定新的分子支架和靶标作为用于治疗该疾病的潜在疗法。我们报告了一系列小的1,2-取代-1 H-苯并[ d ]咪唑衍生物（9a–d），显示在亚微 摩尔范围内（K _i = 0.15–0.69μM）对墨西哥利什曼原虫CPB2.8ΔCTE，抗衰老药物设计的最有希望的目标之一。化合物确认了对细胞内无鞭毛体的体外活性婴儿利什曼原虫的最佳效果与衍生物而得到9d中（IC ₅₀  = 6.8μM），虽然具有一定程度的细胞毒性（CC ₅₀  = 8.0μM上PMM和CC ₅₀  = 32.0μM上MCR-5）。在计算机上进行了分子对接研究和ADME-Tox特性预测，以验证与预期靶标相互作用的假设并评估这些衍生物的药物相似性。