Otero Elver, García Elisa, Palacios Genesis, Yepes Lina M, Carda Miguel, Agut Raúl, Vélez Iván D, Cardona Wilson I, Robledo Sara M
Chemistry of Colombian Plants, Institute of Chemistry, Exact and Natural Sciences School, Universidad de Antioquia-UdeA, Calle 70, No. 52-21, A.A 1226, Medellín, Colombia.
PECET-Medical Research Institute, School of Medicine, Universidad de Antioquia-UdeA, Calle 70, No. 52-21, A.A 1226 Medellín, Colombia.
Eur J Med Chem. 2017 Dec 1;141:73-83. doi: 10.1016/j.ejmech.2017.09.064. Epub 2017 Sep 29.
The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. (V) panamensis (18-23, 26 and 30) and eight of them against T. cruzi (19-22, 24 and 28-30) with EC values lower than 40 μM. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 μM and 8.25 and 8.69 μM, respectively. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Most of the compounds showed antiprotozoal activity and with exception of 18, 26 and 28, the remaining compounds were toxic for mammalian cells, yet they have potential to be considered as candidates for anti-trypanosomal and anti-leishmanial drug development. The activity is dependent on the length of the alkyl linker with compound 19, bearing a four-carbon alkyl chain, the most performing hybrid. In general, hydroxyl groups increase both activity and cytotoxicity and the presence of the double bond in the side chain is not decisive for cytotoxicity and anti-protozoal activity.
本文描述了十二种三氯生 - 咖啡酸杂化物的合成、细胞毒性、抗利什曼原虫和抗锥虫活性。通过光谱分析相结合的方法阐明了合成产物的结构。对合成的化合物针对哥伦比亚最常见的利什曼原虫物种巴拿马利什曼原虫（L. (V) panamensis）的无鞭毛体形式以及对人类致病物种克氏锥虫（Trypanosoma cruzi）进行了评估。针对人U - 937巨噬细胞评估了细胞毒性。八种化合物对巴拿马利什曼原虫（18 - 23、26和30）有活性，其中八种对克氏锥虫（19 - 22、24和28 - 30）有活性，其半数效应浓度（EC）值低于40μM。化合物19 - 22、24和28 - 30显示出比苯硝唑（BNZ）更高的活性。酯类化合物19和21对巴拿马利什曼原虫和克氏锥虫都是活性最高的化合物，其EC值分别为3.82和11.65μM以及8.25和8.69μM。化合物19 - 22、24和28 - 30显示出比苯硝唑（BNZ）更高的活性。大多数化合物显示出抗原虫活性，除了18、26和28外，其余化合物对哺乳动物细胞有毒性，但它们有潜力被视为抗锥虫和抗利什曼原虫药物开发的候选物。活性取决于烷基连接链的长度，带有四碳烷基链的化合物19是表现最佳的杂化物。一般来说，羟基会增加活性和细胞毒性，并且侧链中双键的存在对细胞毒性和抗原虫活性不是决定性的。
