Arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea, acting as a key enzyme in the biosynthesis of polyamines. Leishmania growth and survival is dependent on polyamine biosynthesis; therefore, inhibition of Leishmania arginase may be a promising therapeutic strategy. Here, we evaluated a series of thirty-six chalcone derivatives as potential inhibitors of Leishmania infantum arginase (LiARG). In addition, the activity of selected inhibitors against L. infantum parasites was assessed in vitro. Seven compounds exhibited LiARG inhibition above 50% at 100 μM. Among them, compounds LC41, LC39, and LC32 displayed the greatest inhibition values (72.3 ± 0.3%, 71.9 ± 11.6%, and 69.5 ± 7.9%, respectively). Molecular docking studies predicted hydrogen bonds and hydrophobic interactions between the most active chalcones (LC32, LC39, and LC41) and specific residues from LiARG's active site, such as His140, Asn153, His155, and Ala193. Compound LC32 showed the highest activity against L. infantum promastigotes (IC₅₀ of 74.1 ± 10.0 μM), whereas compounds LC39 and LC41 displayed the best results against intracellular amastigotes (IC₅₀ of 55.2 ± 3.8 and 70.4 ± 9.6 μM, respectively). Moreover, compound LC39 showed more selectivity against parasites than host cells (macrophages), with a selectivity index (SI) of 107.1, even greater than that of the reference drug Fungizone®. Computational pharmacokinetic and toxicological evaluations showed high oral bioavailability and low toxicity for the most active compounds. The results presented here support the use of substituted chalcone skeletons as promising LiARG inhibitors and antileishmanial drug candidates.

精氨酸酶催化水解 升-精氨酸成 升-鸟氨酸和尿素，在多胺的生物合成中起关键作用。 利什曼原虫生长和存活取决于多胺的生物合成；因此，抑制利什曼原虫精氨酸酶可能是一种有前途的治疗策略。在这里，我们评估了一系列三十六种查尔酮衍生物作为潜在的抑制剂婴儿利什曼原虫精氨酸酶（LiARG）。此外，所选抑制剂的抗婴儿乳杆菌 评估了寄生虫 体外。七种化合物在100μM下表现出超过50％的LiARG抑制作用。其中，化合物LC41，LC39和LC32表现出最大的抑制值（分别为72.3±0.3％，71.9±11.6％和69.5±7.9％）。分子对接研究预测了活性最高的查耳酮（LC32，LC39和LC41）与LiARG活性位点的特定残基（如His140，Asn153，His155和Ala193）之间的氢键和疏水相互作用。化合物LC32对婴儿乳杆菌前鞭毛体（IC ₅₀为74.1±10.0μM），而化合物LC39和LC41对细胞内变形虫表现出最好的结果（IC _50分别为55.2±3.8和70.4± 9.6μM ）。此外，化合物LC39对寄生虫的选择性比宿主细胞（巨噬细胞）高，选择性指数（SI）为107.1，甚至比参考药物Fungizone®高。计算的药代动力学和毒理学评估显示，对于最具活性的化合物，口服生物利用度高，毒性低。此处提出的结果支持使用取代的查耳酮骨架作为有前途的LiARG抑制剂和抗衰老药物候选物。