具有改善类药性质的强效抗疟2-吡唑基喹诺酮（Q）抑制剂
Potent Antimalarial 2-Pyrazolyl Quinolone (Q) Inhibitors with Improved Drug-like Properties.
作者信息
David Hong W, Leung Suet C, Amporndanai Kangsa, Davies Jill, Priestley Richard S, Nixon Gemma L, Berry Neil G, Samar Hasnain S, Antonyuk Svetlana, Ward Stephen A, Biagini Giancarlo A, O'Neill Paul M
机构信息
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K.
Research Centre for Drugs & Diagnostics, Parasitology Department, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, U.K.
出版信息
ACS Med Chem Lett. 2018 Oct 19;9(12):1205-1210. doi: 10.1021/acsmedchemlett.8b00371. eCollection 2018 Dec 13.
Abstract
A series of 2-pyrazolyl quinolones has been designed and synthesized in 5-7 steps to optimize for both antimalarial potency and various drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC (concentration of drug required to achieve half maximal growth suppression) values in the range of 15-33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q site of the parasite complex, which is supported by crystallographic studies of bovine cytochrome complex.
摘要
已设计并通过5至7步合成了一系列2-吡唑基喹诺酮类化合物，以优化其抗疟效力以及各种药物代谢和药代动力学（DMPK）特性。与药物敏感菌株（3D7）相比，最有效的化合物对多药耐药寄生虫菌株（W2）无交叉耐药性，其IC（达到最大生长抑制一半所需的药物浓度）值在15-33 nM范围内。此外，该系列成员对阿托伐醌耐药寄生虫分离株（TM90C2B）保持中等活性。所述的2-吡唑基系列显示出改善的DMPK特性，包括与先前报道的喹诺酮系列相比提高的水溶性，以及通过细胞毒性评估获得的可接受的安全范围。据信，2-吡唑基喹诺酮类化合物与寄生虫复合物的泛醌还原Q位点结合，这得到了牛细胞色素复合物晶体学研究的支持。
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