Alves Marina A, de Queiroz Aline C, Leite Anderson Brandão, Martins Felipe T, Doriguetto Antonio C, Barreiro Eliezer J, Alexandre-Moreira Magna S, Lima Lídia M
Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio, ®), Universidade Federal do Rio de Janeiro (UFRJ), CCS PO Box 68023, Cidade Universitária 21941-902 Rio de Janeiro RJ Brazil http://www.inct-inofar.ccs.ufrj.br http://www.lassbio.icb.ufrj.br.
Programa de Pós-graduação em Química, Instituto de Química, UFRJ 21941-909 Rio de Janeiro RJ Brazil.
RSC Adv. 2020 Mar 26;10(21):12384-12394. doi: 10.1039/d0ra00287a. eCollection 2020 Mar 24.
Leishmaniasis is a neglected parasitic disease, and current treatment includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. Therefore, new leishmanicidal drugs are still an unquestionable medical need. In this paper we described the design conception of a new framework, the carbamoyl--aryl-imine-urea, to obtain putative leishmanicidal drug-candidates. Compounds 9a-e and 10a-e were designed and synthesized and their leishmanicidal activity was studied in comparison to pentamidine, miltefosine and meglumine antimoniate. The conformational profile of the new carbamoyl--aryl-imine-urea framework was investigated by X-ray diffraction studies, using compound 9a as a model. The plasma stability of this putative peptide mimetic subunit was studied for compound 10e (LASSBio-1736). Among the congeneric series, LASSBio-1736 was identified as a new antileishmanial drug-candidate, displaying plasma stability, cytotoxicity against amastigote forms of and , and leishmanicidal activity in a cutaneous leishmaniasis murine model, without preliminary evidence of hepatic or renal toxicity.
利什曼病是一种被忽视的寄生虫病，目前的治疗方法存在毒性限制、疗效不一、成本高昂以及剂量和治疗方案不便等问题。因此，新型杀利什曼原虫药物仍然是毋庸置疑的医学需求。在本文中，我们描述了一种新框架——氨基甲酰基 - 芳基 - 亚胺 - 脲的设计理念，以获得潜在的杀利什曼原虫候选药物。设计并合成了化合物9a - e和10a - e，并将它们的杀利什曼原虫活性与喷他脒、米替福新和葡甲胺锑酸盐进行了比较研究。以化合物9a为模型，通过X射线衍射研究对新型氨基甲酰基 - 芳基 - 亚胺 - 脲框架的构象特征进行了研究。对化合物10e（LASSBio - 1736）研究了这种潜在肽模拟亚基的血浆稳定性。在同系物系列中，LASSBio - 1736被鉴定为一种新型抗利什曼原虫候选药物，具有血浆稳定性、对无鞭毛体形式的[具体寄生虫名称缺失]和[具体寄生虫名称缺失]的细胞毒性，以及在皮肤利什曼病小鼠模型中的杀利什曼原虫活性，且没有肝毒性或肾毒性的初步证据。
