BACKGROUND Malaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming. Plant derived synthetic pharmaceutical compounds are found to be a foremost research to obtain diverse range of potent leads. Amongst them, the chalcone scaffold is a functional template for drug discovery. The present study involves synthesis of ten chalcones with various substitution pattern in rings A and B and assessment of their anti-malarial efficacy against chloroquine sensitive and chloroquine resistant strains as well as of their cytotoxicity and effect on haemozoin production. METHODS The chalcones were synthesized by Claisen-Schmidt condensation between equimolar quantities of substituted acetophenones and aryl benzaldehydes (or indole-3-carboxaldehyde) and were screened for anti-malarial activity by WHO Mark III schizont maturation inhibition assay. The cytotoxicity profile of a HeLa cell line was evaluated through MTT viability assay and the selectivity index (SI) was calculated. Haemozoin inhibition assay was performed to illustrate mode of action on a Plasmodium falciparum strain. RESULTS The IC50 values of all compounds were in the range 0.10-0.40 μg/mL for MRC-2 (a chloroquine sensitive strain) and 0.14-0.55 μg/mL for RKL-9 (a chloroquine resistant strain) of P. falciparum. All the chalcones showed low cellular toxicity with minimal haemolysis. The statistically significant reduction (p < 0.05) in the haemozoin production suggests a similar mechanism than that of chloroquine. CONCLUSIONS Out of ten chalcones, number 7 was found to be a lead compound with the highest potency (IC50 = 0.11 µg/mL), as compared to licochalcone (IC50 = 1.43 µg/mL) and with high selectivity index of 85.05.

中文翻译：

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查耳酮的体外抗疟药功效：细胞毒性概况，作用机理及其对红细胞的影响。

背景技术疟疾在流行地区广泛地导致死亡率和发病率，并且耐药性寄生虫的出现令人震惊。发现植物衍生的合成药物化合物是获得各种各样有效的潜在先导的首要研究。其中，查耳酮支架是药物发现的功能模板。本研究涉及在环A和环B中合成十个具有不同取代方式的查耳酮，并评估其对氯喹敏感和耐氯喹菌株的抗疟疾功效，以及它们的细胞毒性和对血红素生成的影响。方法通过等摩尔量的取代的苯乙酮和芳基苯甲醛（或吲哚-3-羧甲醛）之间的Claisen-Schmidt缩合反应合成查耳酮，并通过WHO Mark III裂殖子成熟抑制试验筛选其抗疟活性。通过MTT活力测定法评估HeLa细胞系的细胞毒性谱，并计算选择性指数（SI）。进行了血红素抑制试验以说明对恶性疟原虫菌株的作用方式。结果所有化合物的IC50值对于恶性疟原虫MRC-2（对氯喹敏感的菌株）的IC50值在0.10-0.40μg/ mL范围内，而对RKL-9（对氯喹耐药的菌株）的RKL-9的IC50值在0.14-0.55μg/ mL范围内。所有查耳酮均显示出低细胞毒性，溶血作用极小。具有统计意义的减少幅度（p <0。05）血红蛋白的产生暗示了与氯喹相似的机理。结论在十个查耳酮中，第7号是铅化合物，其效价最高（IC50 = 0.11 µg / mL），而相比之下，利索康宁（IC50 = 1.43 µg / mL）且选择性指数高达85.05。