Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria.
Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria.
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DOI：
10.3390/molecules28186471
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发表时间：
2023-09-06
期刊：
影响因子：
--
通讯作者：
Nirmalan NJ
中科院分区：
文献类型：
--
作者：
Magwaza RN;Abubaker M;Hussain B;Haley M;Couper K;Freeman S;Nirmalan NJ
对一线抗疟药物的耐药性的出现要求开发针对耐药疟疾的新疗法。喹啉类抗疟药物的疗效促进了新型喹啉类药物的开发。4-氨基喹啉肼类似物对多重耐药恶性疟原虫K1菌株的IC50值为0.60 ~ 49 μM， 72 h的IC50值为0.026 ~ 0.219 μM。结果表明，诱导物对HepG2细胞的IC50值为0.87 ~ 11.1 μM，对MDBK细胞的IC50值为1.66 ~ 11.7 μM，对HepG2细胞的IC50值为0.87 ~ 11.1 μM。筛选的先导化合物对恶性疟原虫72 h具有较高的选择性指数。阶段特异性分析表明，寄生虫生命周期的环期受影响最大。基于抗疟效果和体外安全性，先导化合物4-（2-苄基肼基）-6-甲氧基-2-甲基喹啉2进入联用研究，检测协同作用，与蒿甲醚联用的IC90组合指数为0.599，表明具有协同抗疟活性。化合物2在不同的恶性疟原虫（3D7, Dd2）上进行了筛选，结果显示化合物2与K1的活性相近，表明多药耐药与敏感疟原虫之间无交叉耐药。体内分析显示，约氏P. yoelii NL（非致死）处理小鼠（20 mg/kg和5 mg/kg）对寄生虫血症有抑制作用。
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 Plasmodium falciparum: IC50 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 IC50 values of 0.87–11.1 μM, whereas in MDBK cells, IC50 values ranged from 1.66 to 11.7 μM. High selectivity indices were observed for the lead compounds screened at 72 h on P. falciparum. 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 2 was progressed to drug combination studies for the detection of synergism, with a combinatory index of 0.599 at IC90 for the combination with artemether, indicating a synergistic antimalarial activity. Compound 2 was screened on different strains of P. falciparum (3D7, Dd2), which maintained similar activity to K1, suggesting no cross-resistance between multidrug resistance and sensitive parasite strains. In vivo analysis with 2 showed the suppression of parasitaemia with P. yoelii NL (non-lethal)-treated mice (20 mg/kg and 5 mg/kg).
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