Weis Robert, Schlapper Christian, Brun Reto, Kaiser Marcel, Seebacher Werner
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, Universitätsplatz 1, A-8010 Graz, Austria.
Eur J Pharm Sci. 2006 Aug;28(5):361-8. doi: 10.1016/j.ejps.2006.04.003. Epub 2006 Apr 18.
Only three drugs are available for the treatment of East African trypanosomiasis. Patients suffer from painful application, severe side effects and increasing resistance against these drugs. Malaria tropica kills more than 2 million people every year mainly due to growing drug resistance. 4-Dialkylaminobicyclo[2.2.2]octan-2-ols and some of their esters have shown activity against both the causative organisms, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Ethers and new esters with markedly higher lipophilicity were prepared in three-step procedures from acyclic synthons. The new compounds were screened for their antiprotozoal activities against T. b. rhodesiense (STIB 900) and P. falciparum K1 (resistant to chloroquine and pyrimethamine), and for their cytotoxicity with L-6 cells by means of in vitro microplate assays. The results were compared to those of the parent compounds indicating that higher lipophilicity increases the antiprotozoal activities. The pivalate 10a showed the highest antitrypanosomal activity. The 4-chlorobenzoate 9b exhibited good antiplasmodial activity and low cytotoxicity. The most active antiplasmodial agent was the benzhydryl ether 13c which was nearly as active as chloroquine against sensitive strains.
仅有三种药物可用于治疗东非锥虫病。患者在用药时会感到疼痛，且会出现严重的副作用，同时对这些药物的耐药性也在增加。热带疟疾每年导致超过200万人死亡，主要原因是耐药性不断增强。4-二烷基氨基双环[2.2.2]辛烷-2-醇及其一些酯类对致病生物罗德西亚布氏锥虫和恶性疟原虫均显示出活性。从无环合成子通过三步法制备了具有明显更高亲脂性的醚类和新型酯类。通过体外微孔板试验，对新化合物针对罗德西亚布氏锥虫（STIB 900）和恶性疟原虫K1（对氯喹和乙胺嘧啶耐药）的抗原生动物活性以及对L-6细胞的细胞毒性进行了筛选。将结果与母体化合物的结果进行比较，表明更高的亲脂性会增加抗原生动物活性。新戊酸酯10a显示出最高的抗锥虫活性。4-氯苯甲酸酯9b表现出良好的抗疟活性和低细胞毒性。活性最高的抗疟剂是二苯甲基醚13c，其对敏感菌株的活性几乎与氯喹相当。
