Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-08-18 , DOI: 10.1016/j.bmcl.2020.127502 Scott Eagon 1 , Jared T Hammill 2 , Jordan Bach 1 , Nikalet Everson 3 , Tyler A Sisley 4 , Michael J Walls 5 , Sierra Durham 6 , Dylan R Pillai 7 , Mofolusho O Falade 2 , Amy L Rice 2 , Joshua J Kimball 3 , Horacio Lazaro 3 , Celine DiBernardo 1 , R Kiplin Guy 2
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A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.
中文翻译：
靶向恶性疟原虫热休克90蛋白ATP结合口袋的四氢-β-咔啉的抗疟活性。
合成了一系列已知针对恶性疟原虫热激90蛋白的铅化合物的四氢-β-咔啉衍生物，并测定了其对寄生虫的效力和对人细胞系的毒性。使用基于合理结构的设计策略，发现了一种新的铅化合物，其效力比原始铅化合物大两个数量级。这种新的先导化合物的其他模型表明，有多种途径可进一步提高针对该靶标的效力，从而可能为治疗药物铺平道路，该药物的作用方式与目前的任何临床治疗方法均不同。
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