All currently used first-line and second-line drugs for the treatment of leishmaniasis exhibit several drawbacks including toxicity, high costs and route of administration. Furthermore, some drugs are associated with the emergence of drug resistance. Thus, the development of new treatments for leishmaniasis is a priority in the field of neglected tropical diseases. The present work highlights the use of natural derived products, i.e. chalcones, as potential source of antileishmanial agents. Thirty-one novel chalcone compounds have been synthesized and their activity has been evaluated against promastigotes of Leishmania donovani; 16 compounds resulted active against L. donovani in a range from 3.0 to 21.5 μM, showing low toxicity against mammalian cells. Among these molecules, 6 and 16 showed good inhibitory activity on both promastigotes and intracellular amastigotes, coupled with an high selectivity index. Furthermore, compounds 6 and 16 inhibited the promastigote growth of other leishmanial species, including L. tropica, L. major and L. infantum. Finally, 6 and 16 interacted with high affinity with trypanothione reductase (TR), an essential enzyme for the leishmanial parasite and compound 6 inhibited TR with sub-micromolar potency. Thus, the effective inhibitory activity against Leishmania, the lack of toxicity on mammalian cells and the ability to block a crucial parasite's enzyme, highlight the potential for compound 6 to be optimized as novel drug candidate against leishmaniasis.

当前所有用于治疗利什曼病的一线和二线药物均表现出若干缺点，包括毒性，高成本和给药途径。此外，一些药物与耐药性的出现有关。因此，开发用于治疗利什曼病的新疗法是被忽视的热带病领域的优先事项。本工作着重介绍了使用天然来源的产品（即查耳酮）作为抗衰老剂的潜在来源。已经合成了三十一种新的查尔酮化合物，并且已经评价了它们对利什曼原虫的前鞭毛体的活性。16种化合物在3.0至21.5μM范围内具有对抗多诺氏乳杆菌的活性，对哺乳动物细胞显示出低毒性。在这些分子中，图6和图16显示了对前鞭毛体和胞内变形虫的良好抑制活性，并具有高选择性指数。此外，化合物6和16抑制了其他利什曼原虫种类的前鞭毛体生长，包括利斯特乳杆菌，大乳杆菌和婴儿乳杆菌。最后，6和16与Trypanothione还原酶（TR）高度亲和力相互作用，TR是利什曼原虫的必需酶，化合物6以亚微摩尔浓度抑制TR。因此，对利什曼原虫的有效抑制活性缺乏对哺乳动物细胞的毒性以及阻止重要的寄生虫酶的能力，突出了化合物6被优化为抗利什曼病的新型候选药物的潜力。