Functionalized Naphthalimide-4-aminoquinoline Conjugates as Promising Antiplasmodials, with Mechanistic Insights.,ACS Medicinal Chemistry Letters

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Functionalized Naphthalimide-4-aminoquinoline Conjugates as Promising Antiplasmodials, with Mechanistic Insights.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-01-08 , DOI: 10.1021/acsmedchemlett.9b00521
Shalini ₁ , Jenny Legac ₂ , Adebayo A Adeniyi ₃ , Prishani Kisten ₄ , Philip J Rosenthal ₂ , Parvesh Singh ₄ , Vipan Kumar ₁

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A series of 25 conjugates has been synthesized to evaluate their antiplasmodial potency and cytotoxicity against the chloroquine resistant (CQR) W2 strain of P. falciparum and Vero kidney cell lines, respectively. Most of the compounds showed IC50 values in the lower nM range and proved to be many fold more active than chloroquine (CQ). The studies were extended to decipher modes of action using techniques including UV-vis absorption, NMR titrations, and mass spectrometry, and conclusions were strengthened by docking and density functional theory (DFT) simulations. The most active compound, with IC50 15 nM and selectivity index >4000, proved to be an interesting template for antimalarial drug discovery. To the best of our knowledge this is the first report of a potent naphthalimide based antiplasmodial conjugate.

中文翻译：

功能化的萘二甲酰亚胺-4-氨基喹啉缀合为有前途的抗疟原虫，并具有机械学见解。

已经合成了一系列25种共轭物，分别评估了它们对恶性疟原虫和Vero肾细胞系的氯喹抗性（CQR）W2菌株的抗血浆效力和细胞毒性。大多数化合物在较低的nM范围内显示出IC50值，并证明其活性比氯喹（CQ）高出许多倍。使用紫外线可见吸收，NMR滴定和质谱等技术将研究扩展到破译作用模式，并且通过对接和密度泛函理论（DFT）模拟来加强结论。最具活性的化合物，IC50为15 nM，选择性指数> 4000，被证明是发现抗疟药物的有趣模板。据我们所知，这是一种有效的基于萘二甲酰亚胺的抗血浆共轭物的报道。

更新日期：2020-01-10

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