Toxicity and poor adherence to treatment that favors the generation of resistance in the Leishmania parasites highlight the need to develop better alternatives. Here, we evaluated the in vitro effectiveness of hydrazone derived from chromanes 2-(2,3-dihydro-4H-1-benzothiopyran-4-ylidene) hydrazide (TC1) and 2-(2,3-dihydro-4H-1-benzopyran-4-ylidene) hydrazide (TC2) and the mixture of triterpene saponin hederagenin-3-O-(3,4-O-diacetyl-ß-D-xylopyranosyl-(1à3)-a-L- rhamnopyranosyl-(1à2)-a-L-arabinofuranoside, hederagenin-3-O-(3,4-O-diacetyl-a-L- arabinopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside and, hederagenin-3-O-(4-O-acetyl-ß-D-xylopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside from Sapindus saponaria (SS) on L. braziliensis and L. pifanoi. Mixtures of TC1 or TC2 with saponin were formulated for topical application and the therapeutic effectiveness was evaluated in the model for cutaneous leishmaniasis (CL) in golden hamster. The mode of action of these compounds was tested on various parasite processes and ultrastructural parasite modifications. TC1, TC2 and SS showed moderate cytotoxicity when tested independently but toxicity was improved when tested in combination. The compounds were more active against intracellular Leishmania amastigotes. In vivo studies showed that combinations of TC1 or TC2 with SS in 1:1 ratio (w/w) cured 100% of hamsters with no signs associated with toxicity. The compounds did cause changes in the mitochondrial activity of the parasite with a decrease in ATP levels and depolarization of membrane potential and overproduction of reactive oxygen species; nevertheless, these effects were not related to alterations in membrane permeability. The phagolysosome ultrastructure was also affected impacting the survival of Leishmania but the function of the lysosome nor the pH inside the phagolysosome did not change. Lastly, there was a protease inhibition which was directly related to the decrease in the ability of Leishmania to infect and multiply inside the macrophage. The results suggest that the combination of TC1 and TC2 with SS in a 1:1 ratio is capable of curing CL in hamsters. This effect may be due to the ability of these compounds to affect parasite survival and the ability to infect new cells.

毒性和对治疗的依从性差，有利于利什曼原虫寄生虫产生抗药性，这表明需要开发更好的替代品。在这里，我们评估了在体外从色满-2-腙衍生的有效性（2,3-二氢-4H-1-苯并噻喃-4-亚基）肼（TC1）和2-（2,3-二氢-4H-1-苯并吡喃-4-亚烷基）酰肼（TC2）和三萜皂苷hederagenin-3-O-（3,4-O-diacetyl-ß-D-吡喃吡喃糖基-（1à3）-aL-鼠李糖吡喃糖基-（1à2）-aL的混合物-阿拉伯呋喃糖苷，二十碳皂苷元-3-O-（3,4-O-二乙酰基-aL-阿拉伯吡喃糖基-（1à3）-aL-鼠李糖吡喃糖基-（1à2）-aL-阿拉伯呋喃糖苷和二十多金属蛋白酶-3-O-（4-O-乙酰基β-d-xylopyranosyl-（1A3）-Al-鼠李糖（1A2）从-Al阿拉伯呋喃糖苷无患肥皂草（SS）上L. braziliensis和L. pifanoi。配制TC1或TC2与皂苷的混合物用于局部应用，并在金色仓鼠皮肤利什曼病（CL）模型中评估治疗效果。这些化合物的作用方式已在各种寄生虫过程和超微结构寄生虫修饰中进行了测试。单独测试时，TC1，TC2和SS表现出中等的细胞毒性，但联合测试时毒性提高。该化合物对细胞内利什曼原虫amastigotes具有更高的活性。体内研究表明，TC1或TC2与SS的比例为1：1（w / w）的组合可治愈100％的仓鼠，而无毒性迹象。这些化合物的确引起了寄生虫线粒体活性的变化，ATP水平下降，膜电位去极化，活性氧过高。但是，这些作用与膜通透性的改变无关。吞噬酶体的超微结构也受到影响，影响了利什曼原虫的存活，但溶酶体的功能或吞噬体内部的pH均未改变。最后，蛋白酶抑制与利什曼原虫能力下降直接相关。在巨噬细胞内部感染并繁殖。结果表明，TC1和TC2与SS的比例为1：1的组合能够固化仓鼠中的CL。这种作用可能是由于这些化合物影响寄生虫存活的能力以及感染新细胞的能力所致。