Wube Abraham, Hüfner Antje, Seebacher Werner, Kaiser Marcel, Brun Reto, Bauer Rudolf, Bucar Franz
Department of Pharmacognosy, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 4/1, A-8010 Graz, Austria.
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 1, A-8010 Graz, Austria.
Molecules. 2014 Sep 10;19(9):14204-20. doi: 10.3390/molecules190914204.
A diverse array of 4-(1H)-quinolone derivatives bearing substituents at positions 1 and 2 were synthesized and evaluated for antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense, and cytotoxicity against L-6 cells in vitro. Furthermore, selectivity indices were also determined for both parasites. All compounds tested showed antimalarial activity at low micromolar concentrations, with varied degrees of selectivity against L-6 cells. Compound 5a was found to be the most active against P. falciparum, with an IC50 value of 90 nM and good selectivity for the malarial parasite compared to the L-6 cells. Compound 10a, on the other hand, showed a strong antitrypanosomal effect with an IC50 value of 1.25 µM. In this study side chain diversity was explored by varying the side chain length and substitution pattern on the aliphatic group at position-2 and a structure-antiprotozoal activity study revealed that the aromatic ring introduced at C-2 contributed significantly to the antiprotozoal activities.
合成了一系列在1位和2位带有取代基的4-(1H)-喹诺酮衍生物，并对其抗恶性疟原虫和布氏罗得西亚锥虫的抗原虫活性以及对L-6细胞的体外细胞毒性进行了评估。此外，还测定了两种寄生虫的选择性指数。所有测试化合物在低微摩尔浓度下均显示出抗疟活性，对L-6细胞具有不同程度的选择性。发现化合物5a对恶性疟原虫活性最高，IC50值为90 nM，与L-6细胞相比，对疟原虫具有良好的选择性。另一方面，化合物10a显示出强烈的抗锥虫作用，IC50值为1.25 μM。在本研究中，通过改变2位脂肪族基团的侧链长度和取代模式来探索侧链多样性，结构-抗原虫活性研究表明，在C-2处引入的芳环对抗原虫活性有显著贡献。
