Design, economical synthesis and antiplasmodial evaluation of vanillin derived allylated chalcones and their marked synergism with artemisinin against chloroquine resistant strains of Plasmodium falciparum
Design, economical synthesis and antiplasmodial evaluation of vanillin derived allylated chalcones and their marked synergism with artemisinin against chloroquine resistant strains of Plasmodium falciparum
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DOI：
10.1016/j.ejmech.2014.03.079
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发表时间：
2014-05-22
影响因子：
6.7
通讯作者：
Sahal, Dinkar
中科院分区：
文献类型：
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作者：
Sharma, Nandini;Mohanakrishnan, Dinesh;Sahal, Dinkar
采用SYBR绿色I法研究了一系列以甘草查尔酮A为先导分子的烯丙基化查尔酮化合物对氯喹（CQ）敏感的Pf 3D 7和抗CQ的PfINDO恶性疟原虫株的体外血液期抗疟原虫活性。在测试的42种查耳酮中，8种显示IC 50 < 5 μ M。结构-活性关系（SAR）研究显示9 {1-（4-氯苯基）-3-[3-甲氧基-4-（丙-2-烯-1-基氧基）苯基]-丙-2-烯-1-酮}对Pf 3D 7最有效（IC 50：2.5 μ M），对PfDd 2和PfINDO菌株的抗性指数分别为1.2和6.6。随后，研究了与标准抗疟药法替米星（ART）和氯喹（CQ）的协同效应9，以便为选择最佳伙伴药物提供依据。9与ART的体外组合显示出对PfINDO的强协同作用（Sigma FIC 50：0.31-0.72），但对Pf 3D 7的轻微拮抗作用（Sigma FIC 50：1.97-2.64）是累加的。ART+9组合的Sigma FIC 50 0.31分别对应于9和ART的IC 50降低320倍和3倍。9与CQ的类似组合显示出针对两种菌株的协同作用至加和作用至轻度拮抗作用{Sigma FIC 50：0.668-2269（PfINDO）; 1.45-2.83（Pf 3D 7）}。药物暴露后停药表明，在IC 100单独服用9杀死恶性疟原虫的环，滋养体和寄生虫。ART和9（1X Sigma FIC 100）的组合选择性地抑制环的生长，而其2X Sigma FIC 100组合导致环的杀死而不影响滋养体和寄生虫。相比之下，CQ和9的1x组合（Sigma FIC 100：0.5）杀死环和滋养体。9种处理的恶性疟原虫培养物中的DNA片段化和线粒体膜电位（Delta Psi m）损失表明疟疾寄生虫发生了细胞凋亡死亡。ADME性质的预测表明，大多数分子没有违反Lipinski的参数，并具有低的TPSA值，表明良好的吸收。结果表明9对CQ抗性Pf具有有希望的药物样性质，并且具有与经典抗疟药物协同作用的倾向，以及容易和经济的合成。(C)2014年Elsevier Masson SAS。All rights reserved.
The in vitro blood stage antiplasmodial activity of a series of allylated chalcones based on the licochalcone A as lead molecule was investigated against chloroquine (CQ) sensitive Pf3D7 and CQ resistant PfINDO strains of Plasmodium falciparum using SYBR Green I assay. Of the forty two chalcones tested, eight showed IC50 < 5 mu M. Structure-activity relationship (SAR) studies revealed 9 {1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]-prop-2-en-1-one} as the most potent (IC50: 2.5 mu M) against Pf3D7 with resistance indices of 1.2 and 6.6 against PfDd2 and PfINDO strains, respectively. Later on, the synergistic effects 9 with standard antimalarials fartemisinin (ART) and chloroquine (CQ)} were studied in order to provide the basis for the selection of the best partner drug. In vitro combinations of 9 with ART showed strong synergy against PfINDO (Sigma FIC50: 0.31-0.72) but additive to slight antagonistic effects (Sigma FIC50: 1.97-2.64) against Pf3D7. Sigma FIC50 0.31 of ART+9 combination corresponded to a 320 fold and 3 fold reduction in IC50 of 9 and ART, respectively. Similar combinations of 9 with CQ showed synergy to additivity to mild antagonism against the two strains {Sigma FIC50: 0.668-2269 (PfINDO); 1.45-2.83 (Pf3D7)}. Drug exposure followed by drug withdrawal indicated that 9 taken alone at IC100 killed rings, trophozoites and schizonts of P. falciparum. The combination of ART and 9 (1X Sigma FIC100) selectively inhibited the growth of rings while the 2X Sigma FIC100 combination of the same caused killing of rings without affecting trophozoites and schizonts. In contrast, the 1x combination of CQ and 9 (Sigma FIC100: 0.5) killed rings and trophozoites. DNA fragmentation and loss of mitochondrial membrane potential (Delta Psi m) in the 9 treated P. falciparum culture indicated apoptotic death in malaria parasites. Prediction of ADME properties revealed that most of the molecules did not violate Lipinski's parameters and have low TPSA value suggesting good absorption. The results suggest the promising drug-like properties of 9 against CQ resistant Pf and propensity for synergy with classical antimalarial drugs together with easy and economical synthesis. (C) 2014 Elsevier Masson SAS. All rights reserved.