Thieno[3,2-c]quinoline-4-yl-amines - synthesis and investigation of activity against malaria pH-Dependant reduction of the methyl 2-(2-nitrophenyl)thiophene-3-carboxylate 3, formed by Suzuki coupling of methyl 2-iodothiophene-3-carboxylate (2) with 2-nitrophenylboronic acid, yielded the cyclic hydroxamic acid 4 and the lactam 5, respectively. The 4-chlorothieno[3,2-c]quinoline 6 was formed from the lactam 5 by heating with POCI3/PCI5s. Melting of 6 with the novaldiamine base in phenol gave the chloroquine analogue 7, whereas the amodiaquine and the pyronaridine analogues 8 and 9 were obtained using phenol Mannich bases. The reaction of 6 with putrescine and N,N'-bis(3-aminopropyl)piperazine as spacer formed the bisquinoline derivatives 10 and 11 as well as the monosubstituted quinoline 12. In the same manner the isomeric 4-chlorothieno[2,3-c]quinoline 13 reacted to yield the quinoline-4-yl-amines 14-16. The compounds 7-12 and 14-16 were tested for in vitro growth inhibition of the malaria parasite Plasmodium falciparum. As most active compound the pyronaridine derivative 9 displayed an IC50 value of 210 nM with the chloroquine sensitive P. falciparum strain 3D7 and 750 nM with the chloroquine resistant P. falciparum strain Dd2. The N,N'-bis(3-aminopropyl)piperazine derivative 11 displayed in vivo activity in Plasmodium vinckei infected mice with an ED50 value of 30 mg/kg after i.p. administration.

中文翻译：

---

[噻吩并[3,2-c]喹啉-4-基-胺类药物的合成和抗疟活性研究]。

Thieno [3,2-c] quinoline-4-yl-amines-疟疾pH依赖性还原的合成和研究，pH依赖的是由Suzuki偶联形成的甲基2-（2-硝基苯基）噻吩-3-羧酸3还原用2-硝基苯基硼酸的2-碘噻吩-3-羧酸酯（2）分别得到环状异羟肟酸4和内酰胺5。通过与POCI3 / PCI5s加热，由内酰胺5形成4-氯噻吩并[3，2-c]喹啉6。用酚醛清漆胺碱将6与苯酚熔融，得到氯喹类似物7，而氨苯二醌和吡咯烷类似物8和9是使用苯酚曼尼希碱获得的。6与腐胺和N，N'-双（3-氨基丙基）哌嗪作为间隔基的反应形成双喹啉衍生物10和11以及单取代的喹啉12。同样，异构体4-氯噻吩并[2，3-c]喹啉13反应产生喹啉-4-基胺14-16。测试了化合物7-12和14-16对疟原虫恶性疟原虫的体外生长抑制。作为最具活性的化合物，吡咯烷衍生物9在对氯喹敏感的恶性疟原虫菌株3D7中显示的IC50值为210 nM，对于对氯喹具有抗性的恶性疟原虫菌株Dd2显示的IC50值为750 nM。N，N'-双（3-氨基丙基）哌嗪衍生物11在ipck施用后在温氏疟原虫感染的小鼠中表现出体内活性，ED50值为30 mg / kg。作为最具活性的化合物，吡咯烷衍生物9对氯喹敏感的恶性疟原虫菌株3D7的IC50值为210 nM，对耐氯喹的恶性疟原虫Dd2的IC50值为750 nM。N，N'-双（3-氨基丙基）哌嗪衍生物11在ipck施用后在温氏疟原虫感染的小鼠中表现出体内活性，ED50值为30 mg / kg。作为最具活性的化合物，吡咯烷衍生物9在对氯喹敏感的恶性疟原虫菌株3D7中显示的IC50值为210 nM，对于对氯喹具有抗性的恶性疟原虫菌株Dd2显示的IC50值为750 nM。N，N'-双（3-氨基丙基）哌嗪衍生物11在ipck给药后在温氏疟原虫感染的小鼠中表现出体内活性，ED50值为30 mg / kg。