Viana Gil Mendes, Cunha-Junior Edézio Ferreira da, Assumpção Paloma Wetler Meireles Carreiros, Rezende Marianne Grilo, Emiliano Yago Sousa Dos Santos, Soares Laiza Maria da Silva, Pereira Gabriel Rodrigues Coutinho, Rodrigues Carlos Rangel, Cabral Lucio Mendes, Torres-Santos Eduardo Caio
Laboratório de Tecnologia Industrial Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil.
Laboratório de Imunoparasitologia, Unidade Integrada de Pesquisa em Produtos Bioativos e Biociências, Centro Multidisciplinar UFRJ-Macaé, Universidade Federal do Rio de Janeiro, Macaé 27970-000, Brazil.
Pharmaceuticals (Basel). 2024 Nov 23;17(12):1573. doi: 10.3390/ph17121573.
Leishmaniasis, caused by protozoa and transmitted by vectors, presents varied clinical manifestations based on parasite species and host immunity. The lack of effective vaccines or treatments has prompted research into new therapies, including thiourea derivatives, which have demonstrated antiprotozoal activities. We synthesized two series of ,'-disubstituted thiourea derivatives through the reaction of isothiocyanates with amines. These compounds were evaluated in vitro against promastigote and amastigote forms of , alongside cytotoxicity assessments on macrophages. In silico studies were conducted to analyze structure-activity relationships (SARs) and drug-likeness. A total of fifty thiourea derivatives were synthesized and tested. Compound from the first generation exhibited significant anti-leishmanial activity with an IC of 4.9 ± 1.2 µM and over 80-fold selectivity compared to that of miltefosine (IC = 7.5 ± 1.2 µM). The introduction of a piperazine ring in the second-generation thioureas enhanced potency and selectivity, with compound achieving an IC of 1.8 ± 0.5 µM and a selectivity index of approximately 70. Pharmacokinetic predictions indicated favorable profiles for the active compounds. SAR and ADMET analyses identified compound as the most promising candidate for further preclinical evaluation, suggesting that piperazine thiourea derivatives represent a novel class of anti-leishmanial agents.
利什曼病由原生动物引起并通过媒介传播，根据寄生虫种类和宿主免疫力呈现出多样的临床表现。由于缺乏有效的疫苗或治疗方法，促使人们对新疗法进行研究，包括硫脲衍生物，这些衍生物已显示出抗原生动物活性。我们通过异硫氰酸酯与胺的反应合成了两个系列的N,N'-二取代硫脲衍生物。这些化合物在体外针对杜氏利什曼原虫的前鞭毛体和无鞭毛体形式进行了评估，并对巨噬细胞进行了细胞毒性评估。进行了计算机模拟研究以分析构效关系（SARs）和药物相似性。总共合成并测试了五十种硫脲衍生物。第一代化合物表现出显著的抗利什曼活性，IC50为4.9±1.2μM，与米替福新（IC50 = 7.5±1.2μM）相比具有超过80倍的选择性。在第二代硫脲中引入哌嗪环提高了效力和选择性，化合物实现了1.8±0.5μM的IC50和约70的选择性指数。药代动力学预测表明活性化合物具有良好的特性。构效关系和药物代谢动力学/药物毒性预测分析确定化合物为进一步临床前评估最有前景的候选物，表明哌嗪硫脲衍生物代表了一类新型的抗利什曼病药物。
