De D, Krogstad F M, Byers L D, Krogstad D J
Department of Tropical Medicine and the Center for Infectious Diseases, Tulane School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112, USA.
J Med Chem. 1998 Dec 3;41(25):4918-26. doi: 10.1021/jm980146x.
Aminoquinolines (AQs) with diaminoalkane side chains (-HNRNEt2) shorter or longer than the isopentyl side chain [-HNCHMe(CH2)3NEt2] of chloroquine are active against both chloroquine-susceptible and -resistant Plasmodium falciparum. (De, D.; et al. Am. J. Trop. Med. Hyg. 1996, 55, 579-583). In the studies reported here, we examined structure-activity relationships (SARs) among AQs with different N, N-diethyldiaminoalkane side chains and different substituents at the 7-position occupied by Cl in chloroquine. 7-Iodo- and 7-bromo-AQs with diaminoalkane side chains [-HN(CH2)2NEt2, -HN(CH2)3NEt2, or -HNCHMeCH2NEt2] were as active as the corresponding 7-chloro-AQs against both chloroquine-susceptible and -resistant P. falciparum (IC50s of 3-12 nM). In contrast, with one exception, 7-fluoro-AQs and 7-trifluoromethyl-AQs were less active against chloroquine-susceptible P. falciparum (IC50s of 15-50 nM) and substantially less active against chloroquine-resistant P. falciparum (IC50s of 18-500 nM). Furthermore, most 7-OMe-AQs were inactive against both chloroquine-susceptible (IC50s of 17-150 nM) and -resistant P. falciparum (IC50s of 90-3000 nM).
带有比氯喹的异戊基侧链[-HNCHMe(CH2)3NEt2]短或长的二氨基烷烃侧链(-HNRNEt2)的氨基喹啉(AQs)对氯喹敏感和耐药的恶性疟原虫均有活性。(De, D.等人，《美国热带医学与卫生杂志》，1996年，55卷，579 - 583页)。在本文报道的研究中，我们研究了具有不同N,N -二乙基二氨基烷烃侧链以及氯喹中被氯占据的7位带有不同取代基的AQs之间的构效关系(SARs)。带有二氨基烷烃侧链[-HN(CH2)2NEt2、-HN(CH2)3NEt2或-HNCHMeCH2NEt2]的7 -碘代和7 -溴代AQs对氯喹敏感和耐药的恶性疟原虫的活性与相应的7 -氯代AQs相当(IC50为3 - 12 nM)。相比之下，除了一个例外，7 -氟代AQs和7 -三氟甲基AQs对氯喹敏感的恶性疟原虫活性较低(IC50为15 - 50 nM)，对氯喹耐药的恶性疟原虫活性则显著较低(IC50为18 - 500 nM)。此外，大多数7 - OMe - AQs对氯喹敏感(IC50为17 - 150 nM)和耐药的恶性疟原虫(IC50为90 - 3000 nM)均无活性。
