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首页> 外文期刊>Journal of Young Pharmacists >Evaluation of novel 1-(4-(substituted)piperazin-1-yl)-2-(phenylamino)ethanone derivatives as Falcipain-2 inhibitors
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Evaluation of novel 1-(4-(substituted)piperazin-1-yl)-2-(phenylamino)ethanone derivatives as Falcipain-2 inhibitors

机译：新型1-（4-（取代）哌嗪-1-基）-2-（苯氨基）乙酮衍生物作为Falcipain-2抑制剂的评价

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Background: Malaria, an infectious disease transmitted by mosquitoes, has affected the world since the beginning of recorded human history and it remains an ensconced global health challenge even today. Among the various proteases, expressed in the life cycle of parasite, cysteine protease falcipain-2 plays a pivotal role in parasite food assimilation and inhibition of this protease cause deleterious effects on the growth of parasite. Methods: Employing a ligand-based approach, 1-(4-(substituted)piperazin-1-yl)-2-(phenylamino)ethanone derivatives were designed and synthesized from the starting material piperazine in a sequence of reactions. Structural assignments are based on spectral data (1H NMR, mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Furthermore, molecular docking studies were performed using Glide 5.9 software to incur a precise picture of the active ligand at the atomic level which will be helpful in the discovery of new antimalarial drugs. Results: Among the screening results of seventeen novel entities, three compounds (6h, 6n and 6o) have showed good inhibitory activity and eleven compounds were showed weak to moderate inhibitor activity. Docking studies for these active analogues revealed that the amino acids Trp 206, Ile 85, Leu 84, Val 152 most commonly involved in hydrophobic interactions and Asn 173, Cys 42, Gln 36, amino acids involved in hydrogen bonding. Conclusion: The preliminary structure-activity relationships indicated that compound 6h, is the most potent compound from this series, and it can be used as a potential lead compound in the designing of new candidates to optimize the inhibitory potencies of this class of compounds, and potentially with potent antimalarial activity.
机译：背景：疟疾是一种由蚊子传播的传染病，自人类历史记录以来一直影响着世界，即使在今天，它仍然是全球人类健康面临的挑战。在寄生虫的生命周期中表达的各种蛋白酶中，半胱氨酸蛋白酶falcipain-2在寄生虫食物同化中起关键作用，抑制这种蛋白酶对寄生虫的生长造成有害影响。方法：采用基于配体的方法，从原料哌嗪经一系列反应设计并合成了1-（4-（取代）哌嗪-1-基）-2-（苯氨基）乙酮衍生物。结构分配基于光谱数据（ 1 1 H NMR，质量）和元素分析。最终化合物的纯度通过HPLC确认。测试了化合物对重组falcipain-2酶的体外falcipain-2抑制剂活性。此外，使用Glide 5.9软件进行了分子对接研究，以在原子水平上获得活性配体的精确图片，这将有助于发现新的抗疟药。结果：在十七种新实体的筛选结果中，三种化合物（6h，6n和6o）表现出良好的抑制活性，而十一种化合物表现出弱至中等的抑制活性。这些活性类似物的对接研究表明，氨基酸Trp 206，Ile 85，Leu 84，Val 152最常参与疏水性相互作用，而Asn 173，Cys 42，Gln 36最常参与氢键结合的氨基酸。结论：初步的结构-活性关系表明，化合物6h是该系列中最有效的化合物，可以用作潜在的潜在化合物，设计新的候选物以优化此类化合物的抑制能力，并且可能具有强大的抗疟疾活性。

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