Molecular docking, synthesis and in vitro antimalarial evaluation of certain novel curcumin analogues

ABSTRACT The receptor protein PfATP6 has been identified as the common target of artemisinin and curcumin. The work was initiated to assess the antimalarial activity of six curcumin derivatives based on their binding affinities and correlating the in silico docking outcome with in vitro antimalarial screening results. A ligand library of thirty two Knoevenagel condensates of curcumin were designed and docked against PfATP6 protein and six compounds with the best binding scores were synthesized and screened for their antimalarial activity against the sensitive 3D7 strain of Plasmodium falciparum. ADME/Tox, pharmacokinetic and pharmacodynamic profiles of the designed compounds were analyzed and reported. 4-FB was found to have similar binding energy to the standard artemisinin (-6.75 and -6.73 respectively) while 4-MB, 3-HB, 2-HB, B, 4-NB displayed better binding energy than curcumin (-5.95, -5.89, -5.68, -5.35, -5.29 and -5.25 respectively). At a dose of 50 µg/mL all the six compounds showed 100% schizont inhibition while at 5µg/ml, five showed more than 75% inhibition and better results than curcumin. 4-FB showed the best activity with 97.8% schizonticidal activity. The in vitro results superimpose the results obtained from the in silico study thereby encouraging development of promising curcumin leads in the battle against malaria.

摘要 受体蛋白PfATP6已被确定为青蒿素与姜黄素的共同作用靶点。本研究旨在基于结合亲和力评估六种姜黄素衍生物的抗疟活性，并将虚拟对接结果与体外抗疟筛选结果进行关联分析。本研究设计了包含32种姜黄素克诺文格尔缩合物的配体库，并针对PfATP6蛋白开展分子对接；随后选取结合评分最优的6种化合物进行合成，并针对恶性疟原虫敏感株3D7开展抗疟活性筛选。对所设计化合物的ADME/Tox（吸收-分布-代谢-排泄/毒性）、药代动力学及药效动力学特征进行了分析与报道。研究发现4-FB的结合能与标准青蒿素相近（分别为-6.75和-6.73）；而4-MB、3-HB、2-HB、B、4-NB的结合能均优于姜黄素（分别为-5.95、-5.89、-5.68、-5.35、-5.29和-5.25）。在50 μg/mL的给药浓度下，6种化合物均展现出100%的裂殖体抑制率；而在5 μg/mL浓度下，其中5种化合物的裂殖体抑制率超过75%，活性优于姜黄素。其中4-FB的抗疟活性最优，裂殖体杀灭率达97.8%。体外实验结果与虚拟模拟研究结果高度吻合，这为抗疟研究中开发极具潜力的姜黄素先导化合物提供了有力支撑。