Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS |
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| Authors: | Zhi‐Yuan Wu Na Liu Dr Bingjie Qin Dr Li Huang Dr Fei Yu Dr Keduo Qian Dr Susan L Morris‐Natschke Prof Shibo Jiang Prof Chin Ho Chen Prof Kuo‐Hsiung Lee Prof Lan Xie |
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| Affiliation: | 1. Beijing Institute of Pharmacology & Toxicology, 27 Tai‐Ping Road, Beijing, 100850 (China);2. Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC 27710 (USA);3. Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065 (USA);4. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 (USA);5. Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai 200032 (China);6. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung (Taiwan) |
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| Abstract: | Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C‐ring were synthesized and evaluated for anti‐HIV activity and certain drug‐like properties. Ten compounds showed high anti‐HIV activity (EC50<10 nM ). In particular, (E)‐6‐(2′′‐bromo‐4′′‐cyanovinyl‐6′′‐methoxy)phenoxy‐N2‐(4′‐cyanophenyl)pyridin‐2,3‐diamine ( 8 c ) displayed low‐nanomolar antiviral potency (3–7 nM ) against wild‐type and drug‐resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine ( 1 b ). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1–2.1) than 1 b (RFC: 11.8–13.0). Compound 8 c also exhibited better metabolic stability (in vitro half‐life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug‐like properties, 8 c merits further development as an anti‐HIV drug candidate. |
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| Keywords: | anti‐HIV activity antiviral agents diarylpyridinamines drug‐like properties lipophilicity |
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