OBJECTIVES Drugs for Neglected Diseases initiative (DNDi) has identified three chemical lead series, the nitroimidazoles, benzoxaboroles and aminopyrazoles, as innovative treatments for visceral leishmaniasis. The leads discovered using phenotypic screening, were optimised following disease- and compound-specific criteria. Several leads of each series were progressed and preclinical drug candidates have been nominated. Here we evaluate the efficacy of the lead compounds of each of these three chemical classes in in vitro and in vivo models of cutaneous leishmaniasis. METHODS The in vitro activity of fifty-five compounds was evaluated against the intracellular amastigotes of L. major, L. aethiopica, L. amazonensis, L. panamensis, L. mexicana and L. tropica. The drugs demonstrating potent activity (EC50 < 5 μM) against at least 4 of 6 species were subsequently evaluated in vivo in different L. major - BALB/c mouse models using a 5 or 10-day treatment with either the oral or topical formulations. Efficacy was expressed as lesion size (measured daily using callipers), parasite load (by quantitative PCR - DNA) and bioluminescence signal reduction relative to the untreated controls. RESULTS The selected drug compounds (3 nitroimidazoles, 1 benzoxaborole and 3 aminopyrazoles) showed consistent and potent activity across a range of Leishmania species that are known to cause CL with EC50 values ranging from 0.29 to 18.3 μM. In all cases, this potent in vitro antileishmanial activity translated into high levels of efficacy with a linear dose-response against murine CL. When administered at 50 mg/kg/day, DNDI-0690 (nitroimidazole), DNDI-1047 (aminopyrazole) and DNDI-6148 (benzoxaborole) all resulted in a significant lesion size reduction (no visible nodule) and an approximate 2-log-fold reduction of the parasite load as measured by qPCR compared to the untreated control. CONCLUSIONS The lead compounds DNDI-0690, DNDI-1047 and DNDI-6148 showed excellent activity across a range of Leishmania species in vitro and against L. major in mice. These compounds offer novel potential drugs for the treatment of CL.

中文翻译：

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新型苯并恶唑，硝基咪唑和氨基吡唑类具有对抗实验性皮肤利什曼病的活性。

目标药物被忽视疾病计划（DNDi）已确定了三个化学铅系列，即硝基咪唑，苯并x硼烷和氨基吡唑类，作为内脏利什曼病的创新疗法。使用表型筛选发现的线索根据疾病和化合物特异性标准进行了优化。每个系列的几条线索均已取得进展，临床前候选药物已被提名。在这里，我们评估皮肤利什曼病的体外和体内模型中这三种化学类别中每一种的先导化合物的功效。方法评估了55种化合物的体外活性，它们对大麦芽孢杆菌，埃塞俄比亚苦瓜，亚马逊落叶松，巴拿马巴拿马草，墨西哥梅毒和热带L. 表现出有效活性的药物（EC50 < 随后使用不同的口服或局部制剂治疗5或10天，在不同的主要L. BALB / c小鼠模型中针对6种物种中的至少4种对5μM）进行了体内评估。相对于未经处理的对照组，功效表示为病变大小（每天使用卡尺测量），寄生虫负荷（通过定量PCR-DNA）和生物发光信号减少。结果所选的药物化合物（3种硝基咪唑，1种苯并恶唑和3种氨基吡唑）在一系列利什曼原虫种类中表现出一致而有效的活性，这些物质已知会导致CL，其EC50值为0.29至18.3μM。在所有情况下，这种有效的体外抗疟疾活性转化为高水平的功效，并具有针对鼠类CL的线性剂量反应。当以每天50 mg / kg的剂量服用DNDI-0690（硝基咪唑）时，DNDI-1047（氨基吡唑）和DNDI-6148（苯并三硼环）与未处理的对照组相比，均导致病灶大小明显减少（无可见结节），并且通过qPCR测得的寄生虫载量减少了约2对数倍。结论头号化合物DNDI-0690，DNDI-1047和DNDI-6148在体外的多种利什曼原虫物种以及对小鼠的L.major L.表现出优异的活性。这些化合物为治疗CL提供了新的潜在药物。主要在小鼠。这些化合物为治疗CL提供了新的潜在药物。主要在小鼠。这些化合物为治疗CL提供了新的潜在药物。