Potent antimalarial 2-Pyrazolyl Quinolone bc 1 (Qi) inhibitors with improved drug-like properties
| Autor: | Richard S. Priestley, Giancarlo A. Biagini, Paul M. O'Neill, Kangsa Amporndanai, Jill Davies, W. David Hong, Gemma L. Nixon, Svetlana V. Antonyuk, Stephen A. Ward, Suet C. Leung, S. Samar Hasnain, Neil G. Berry |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Drug Chemistry medicine.drug_class media_common.quotation_subject Organic Chemistry Drug resistance Pharmacology Quinolone Biochemistry Multiple drug resistance 03 medical and health sciences 030104 developmental biology Pharmacokinetics Drug Discovery medicine Potency IC50 Drug metabolism media_common |
| Zdroj: | ACS Medicinal Chemistry Letters |
| Popis: | [Image: see text] A series of 2-pyrazolyl quinolones has been designed and synthesized in 5–7 steps to optimize for both in vitro antimalarial potency and various in vitro 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(50) (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 in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q(i) site of the parasite bc(1) complex, which is supported by crystallographic studies of bovine cytochrome bc(1) complex. |
| Databáze: | OpenAIRE |
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