期刊
ACTA PHARMACEUTICA SINICA B
卷 10, 期 5, 页码 878-894出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2019.08.013
关键词
HIV-1; NNRTIs; NNIBP; Thiophene[3,2-d] pyrimidine; Hydrophobic channel
资金
- Key Project of NSFC for International Cooperation (China) [81420108027]
- National Natural Science Foundation of China (NSFC) [81273354, 81573347, 81903453]
- Young Scholars Program of Shandong University (YSPSDU, China) [2016WLJH32]
- Shandong Provincial Natural Science Foundation (China) [ZR2019BH011]
- China Postdoctoral Science Foundation [2018M640641, 2019T120596]
- Key research and development project of Shandong Province (China) [2017CXGC1401]
- KU Leuven (Belgium) [GOA 10/014]
- Spanish Government (MINECO Project) [SAF2017-881074-R]
- Generalitat de Catalunya (Spain) [2017SGR1746]
In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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