Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs

Acta Pharmaceutica Sinica B

Xinyong Liu¹  Jinmi Zou²  Da Feng²  Fenju Wei²  Boshi Huang²  Yanying Sun²  Dongwei Kang²  Tong Zhao²  Samuel Desta²  Peng Zhan²  Tiziana Ginex³  Christophe Pannecouque⁴  Erik De Clercq⁴ 

[1] Corresponding authors. Tel./fax: [phone].;Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China;Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy, Campus Torribera, Institute of Biomedicine and Institute of Theoretical and Computational Chemistry, University of Barcelona, Santa Coloma de Gramenet 08921, Spain;Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven B-3000, Belgium;

关键词: HIV-1;    NNRTIs;    NNIBP;    Thiophene[3,2-d]pyrimidine;    Hydrophobic channel;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown