Tahghighi Azar, Parhizgar Arezoo Rafie, Karimi Safoura, Irani Mahboubeh
Malaria and Vector Research Group, Biotechnology Research Center; Medicinal Chemistry Laboratory, Department of Clinical Research, Pasteur Institute of Iran, Tehran, Iran.
Malaria and Vector Research Group, Biotechnology Research Center, Pasteur Institute of Iran; Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.
J Vector Borne Dis. 2019 Jul-Sep;56(3):221-230. doi: 10.4103/0972-9062.289395.
BACKGROUND & OBJECTIVES: Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity.
A new series of quinoline derivatives containing N-alkyl (piperazin-1-yl)methyl benzamidine moiety was synthesized by reacting 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzonitrile with appropriate primary amines. The synthesized compounds were investigated for inhibitory activity by inhibition test of heme detoxification (ITHD). Their antiplasmodial activity was then evaluated using the classical 4-day suppressive test (Peter's test) against Plasmodium berghei-infected mice (ANKA strain).
The results showed that the percentage of heme detoxification inhibition in the active compounds was 90%. The most promising analogs, N-butyl-4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzamidine (compound 1e), and 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)]-N-(4-methylpentan-2-yl)benzamidine (compound 1f) displayed 97.65 and 99.18% suppressions at the doses of 75 and 50 mg/kg/day, respectively. Further, the mean survival time of the mice treated with these compounds was higher than that of the negative control group.
INTERPRETATION & CONCLUSION: The newly synthesized amodiaquine analogs presented sufficient antiplasmodial activity with excellent suppressions and high in vitro heme detoxification inhibition. Higher mean survival time of the mice treated with synthetic compounds further confirmed the in vivo antimalarial activity of these new AQ analogs. Therefore, these compounds have the potential to replace common drugs from 4-aminoquinoline class. However, further investigations such as pharmacokinetic evaluations, cytotoxicity, toxicity, and formulation seem to be necessary.
由于疟原虫耐药性迅速增加，迫切需要开发新的抗疟药物。本研究合成了新型阿莫地喹（AQ）类似物，并对其抗疟活性进行了评估。
通过使4-[(4-(7-氯喹啉-4-基)哌嗪-1-基)甲基]苄腈与适当的伯胺反应，合成了一系列含有N-烷基（哌嗪-1-基）甲基苯甲脒部分的新型喹啉衍生物。通过血红素解毒抑制试验（ITHD）研究合成化合物的抑制活性。然后使用经典的4天抑制试验（彼得试验）对感染伯氏疟原虫（ANKA株）的小鼠评估其抗疟活性。
结果表明，活性化合物的血红素解毒抑制率为90%。最有前景的类似物，N-丁基-4-[(4-(7-氯喹啉-4-基)哌嗪-1-基)甲基]苯甲脒（化合物1e）和4-[(4-(7-氯喹啉-4-基)哌嗪-1-基)甲基]-N-(4-甲基戊-2-基)苯甲脒（化合物1f）在剂量分别为75和50mg/kg/天时，抑制率分别为97.65%和99.18%。此外，用这些化合物处理的小鼠的平均存活时间高于阴性对照组。
新合成的阿莫地喹类似物具有足够的抗疟活性，具有优异的抑制作用和高体外血红素解毒抑制率。用合成化合物处理的小鼠较高的平均存活时间进一步证实了这些新型AQ类似物的体内抗疟活性。因此，这些化合物有可能取代4-氨基喹啉类的常用药物。然而，进一步的研究，如药代动力学评估、细胞毒性、毒性和制剂研究似乎是必要的。
