Leão Luiz P M O, de B Vieira Nátalie, Oliveira Paula P S, Chagas-Paula Daniela A, Soares Marisi G, Souza Thiago B, Baldim João L, Costa-Silva Thais A, Tempone Andre G, Dias Danielle F, Lago João Henrique G
Institute of Chemistry, Federal University of Alfenas, Minas Gerais 37130-001, Brazil.
Pharmacy School, Federal University of Ouro Preto, Minas Gerais 35400-000, Brazil.
Bioorg Med Chem Lett. 2023 Mar 1;83:129190. doi: 10.1016/j.bmcl.2023.129190. Epub 2023 Feb 19.
Gibbilimbol B and analogues were isolated from the Brazilian plant Piper malacophyllum and displayed activity against trypomastigote forms of Trypanosoma cruzi as well as reduced toxicity against NCTC cells. These results stimulated the preparation of a series of 24 chemically related analogues to study the potential of these compounds against T. cruzi trypomastigotes and explore structure-activity relationships. Initially, 12 compounds were planned, maintaining the same extension of the linear side chain of gibbilimbol B and unsaturation on the C-4 position but changing the functional groups - ester and amide - and variating the substituent at the p-position in the aromatic ring. Other 12 compounds were prepared using a branched side chain containing an ethyl group at the C-2 position. Overall, these structurally-related analogues demonstrated promising activity against trypomastigote forms (EC < 20 μM) and no mammalian cytotoxicity to fibroblasts (CC > 200 μM). Using multivariate statistics and machine learning analysis, aspects associated with structure/activity were related to their three-dimensional structure and, mainly, to the substituents on the aromatic ring. Obtained results suggested that the presence of t-butyl or nitro groups at p-position with appropriate side chains causes an alteration in the electron topological state, Van der Waals volumes, surface areas, and polarizabilities of tested compounds which seem to be essential for biological activity against T. cruzi parasites.
吉比利姆博尔B及其类似物是从巴西植物软叶胡椒中分离出来的，对克氏锥虫的锥鞭毛体形式具有活性，并且对NCTC细胞的毒性降低。这些结果促使人们制备了一系列24种化学相关的类似物，以研究这些化合物对克氏锥虫锥鞭毛体的潜力，并探索构效关系。最初，计划合成12种化合物，保持吉比利姆博尔B的线性侧链长度和C-4位的不饱和度不变，但改变官能团——酯基和酰胺基——并改变芳环对位的取代基。另外12种化合物是使用在C-2位含有乙基的支链侧链制备的。总体而言，这些结构相关的类似物对锥鞭毛体形式表现出有前景的活性（EC<20μM），并且对成纤维细胞没有哺乳动物细胞毒性（CC>200μM）。使用多变量统计和机器学习分析，与结构/活性相关的方面与其三维结构有关，主要与芳环上的取代基有关。获得的结果表明，对位存在叔丁基或硝基并带有适当的侧链会导致受试化合物的电子拓扑状态、范德华体积、表面积和极化率发生改变，这似乎是对克氏锥虫寄生虫具有生物活性所必需的。
