Slafer Brian W, Dessoy Marco A, de Oliveira Ramon G, Mollo Maria C, Lee Eun, Matheeussen An, Maes Louis, Caljon Guy, Ferreira Leonardo L G, Krogh Renata, Andricopulo Adriano D, Cruz Luiza R, Mowbray Charles E, Kratz Jadel M, Dias Luiz C
Institute of Chemistry, State University of Campinas, Campinas 13083-970, São Paulo, Brazil.
Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Antwerp 2000, Belgium.
ACS Omega. 2024 May 13;9(20):22360-22370. doi: 10.1021/acsomega.4c01919. eCollection 2024 May 21.
Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular , hits and were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds displayed good potency (EC amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC MRC-5 = 32-64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.
恰加斯病（CD）是一种由原生动物引起的被忽视的热带寄生虫病（NTD），全球有600万人受其影响，在流行地区常常导致经济负担、发病和死亡。鉴于缺乏高效且安全的治疗方法，迫切需要用于恰加斯病的新型、可负担且适用的药物。在这项工作中，我们展示了针对新型氰基吡啶类似物作为抗恰加斯病药物的从苗头化合物到先导化合物的研究。在针对细胞内[具体寄生虫名称未给出]的表型筛选中，确定了苗头化合物[化合物名称未给出]，它们显示出有前景的效力并兼具平衡的物理化学性质。作为拉丁美洲先导优化联盟的一部分，设计、合成了一组40种化合物，并针对细胞内无鞭毛体和相关人类细胞系进行了测试。结构修饰集中在三个位置：氰基吡啶核心、连接基和右侧。评估了所选化合物的吸收、分布、代谢和排泄（ADME）性质、亲脂性、动力学溶解度、渗透性和肝微粒体稳定性。化合物[具体化合物名称未给出]显示出良好的效力（无鞭毛体的半数有效浓度（EC）<1 μM）），并且大多数化合物没有表现出显著的细胞毒性（人胚肺成纤维细胞（CC MRC - 5）= 32 - 64 μM）。尽管效力和选择性之间平衡良好，但该系列化合物的抗寄生虫活性似乎由亲脂性驱动，由于不良的ADME性质和潜在的非特异性问题，使得该系列化合物的研发不可行。
