Magwaza Rachael N, Abubaker Muna, Hussain Buthaina, Haley Michael, Couper Kevin, Freeman Sally, Nirmalan Niroshini J
Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester M13 9PT, UK.
School of Science, Engineering and Environment, University of Salford, Manchester M5 4WT, UK.
Molecules. 2023 Sep 6;28(18):6471. doi: 10.3390/molecules28186471.
The emergence of resistance to first-line antimalarial drugs calls for the development of new therapies for drug-resistant malaria. The efficacy of quinoline-based antimalarial drugs has prompted the development of novel quinolines. A panel of 4-aminoquinoline hydrazone analogues were tested on the multidrug-resistant K1 strain of : IC values after a 48 h cycle ranged from 0.60 to 49 µM, while the 72 h cycle ranged from 0.026 to 0.219 μM. Time-course assays were carried out to define the activity of the lead compounds, which inhibited over 50% growth in 24 h and 90% growth in 72 h. Cytotoxicity assays with HepG2 cells showed IC values of 0.87-11.1 μM, whereas in MDBK cells, IC values ranged from 1.66 to 11.7 μM. High selectivity indices were observed for the lead compounds screened at 72 h on . Analyses of stage specificity revealed that the ring stages of the parasite life cycle were most affected. Based on antimalarial efficacy and in vitro safety profiles, lead compound 4-(2-benzylidenehydrazinyl)-6-methoxy-2-methylquinoline was progressed to drug combination studies for the detection of synergism, with a combinatory index of 0.599 at IC for the combination with artemether, indicating a synergistic antimalarial activity. Compound was screened on different strains of (3D7, Dd2), which maintained similar activity to K1, suggesting no cross-resistance between multidrug resistance and sensitive parasite strains. In vivo analysis with showed the suppression of parasitaemia with NL (non-lethal)-treated mice (20 mg/kg and 5 mg/kg).
对一线抗疟药物产生耐药性，这就需要研发针对耐药疟疾的新疗法。喹啉类抗疟药物的疗效促使新型喹啉的开发。对一组4-氨基喹啉腙类似物在多药耐药的K1疟原虫株上进行了测试：48小时周期后的IC值范围为0.60至49μM，而72小时周期的IC值范围为0.026至0.219μM。进行了时间进程分析以确定先导化合物的活性，这些化合物在24小时内抑制超过50%的生长，在72小时内抑制90%的生长。用HepG2细胞进行的细胞毒性试验显示IC值为0.87 - 11.1μM，而在MDBK细胞中，IC值范围为1.66至11.7μM。在72小时筛选的先导化合物对疟原虫显示出高选择性指数。阶段特异性分析表明，寄生虫生命周期的环状阶段受影响最大。基于抗疟疗效和体外安全性概况，先导化合物4-(2-苄叉肼基)-6-甲氧基-2-甲基喹啉进入药物联合研究以检测协同作用，与蒿甲醚联合时在IC下的联合指数为0.599，表明具有协同抗疟活性。化合物在不同的疟原虫株（3D7、Dd2）上进行了筛选，其活性与K1株相似，表明多药耐药株和敏感寄生虫株之间没有交叉耐药性。对疟原虫的体内分析显示，用NL（非致死性）处理的小鼠（20mg/kg和5mg/kg）的疟原虫血症受到抑制。
