Sharma Nandini, Mohanakrishnan Dinesh, Sharma Upendra Kumar, Kumar Rajesh, Sinha Arun Kumar, Sahal Dinkar
Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, HP, India.
Malaria Research Laboratory, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
Eur J Med Chem. 2014 May 22;79:350-68. doi: 10.1016/j.ejmech.2014.03.079. Epub 2014 Apr 1.
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 μM. 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 μM) 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 {artemisinin (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 (ΣFIC50: 0.31-0.72) but additive to slight antagonistic effects (ΣFIC50: 1.97-2.64) against Pf3D7. ΣFIC50 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 {ΣFIC50: 0.668-2.269 (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 ΣFIC100) selectively inhibited the growth of rings while the 2X ΣFIC100 combination of the same caused killing of rings without affecting trophozoites and schizonts. In contrast, the 1X combination of CQ and 9 (ΣFIC100: 0.5) killed rings and trophozoites. DNA fragmentation and loss of mitochondrial membrane potential (ΔΨm) 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.
以甘草查耳酮A为先导分子，研究了一系列烯丙基化查耳酮对恶性疟原虫氯喹（CQ）敏感株Pf3D7和CQ耐药株PfINDO的体外血液期抗疟活性，采用SYBR Green I检测法。在测试的42种查耳酮中，有8种的IC50≤5μM。构效关系（SAR）研究表明，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Pf3D7的活性最强（IC50：2.5μM），对PfDd2和PfINDO菌株的耐药指数分别为1.2和6.6。随后，研究了9与标准抗疟药{青蒿素（ART）和氯喹（CQ）}的协同作用，以便为选择最佳联合用药提供依据。9与ART的体外联合对PfINDO显示出强协同作用（ΣFIC50：0.31 - 0.72），但对Pf3D7有相加至轻微拮抗作用（ΣFIC50：1.97 - 2.64）。ART + 9组合的ΣFIC50为0.31，分别对应9和ART的IC50降低320倍和3倍。9与CQ的类似组合对这两种菌株显示出协同至相加至轻度拮抗作用{ΣFIC50：0.668 - 2.269（PfINDO）；1.45 - 2.83（Pf3D7）}。药物暴露后停药表明，单独使用9在IC100时可杀死恶性疟原虫的环状体、滋养体和裂殖体。ART和9的组合（1X ΣFIC100）选择性抑制环状体的生长，而相同组合的2X ΣFIC100可杀死环状体，而不影响滋养体和裂殖体。相比之下，CQ和9的1X组合（ΣFIC100：0.5）可杀死环状体和滋养体。9处理的恶性疟原虫培养物中的DNA片段化和线粒体膜电位（ΔΨm）丧失表明疟原虫发生凋亡死亡。ADME性质预测表明，大多数分子未违反Lipinski参数，且TPSA值较低，表明吸收良好。结果表明，9具有针对CQ耐药Pf的良好类药性质，与经典抗疟药具有协同倾向，且合成简便经济。
