Discovery of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the Tolerant Region I of NNIBP

作者：Kang, Dongwei; Ding, Xiao; Wu, Gaochan; Huo, Zhipeng; Zhou, Zhongxia; Zhao, Tong; Feng, Da; Wang, Zhao; Tian, Ye; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng^*; Liu, Xingyong^*

来源：ACS Medicinal Chemistry Letters, 2017, 8(11): 1188-1193.

DOI：10.1021/acsmedchemlett.7b00361

• HIV-1
• NNRTIs
• thiophene(3,2-d]pyrimidine
• tolerant region I
• drug design

Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991-8007; J. Med. Chem. 2017, 60, 4424-4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains. All the derivatives exhibited moderate to excellent potency against wild-type (WT) HIV-1 in MT-4 cells. Among them, sulfonamide compounds 9b and 9d were single-figure-nanomolar inhibitors with EC50 values of 9.2 and 7.1 nM, respectively. Indeed, 9a and 9d were effective against the whole viral panel except RES056. Notably, both compounds showed potent antiviral activity against K103N (EC50 = 0.032 and 0.070 mu M) and E138K (EC50 = 0.035 and 0.045 mu M, respectively). Furthermore, 9a and 9d exhibited high affinity for WT HIV-1 RT (IC50 = 1.041 and 1.138 mu M, respectively) and acted as classical NNRT inhibitors (NNRTIs). These results are expected to be helpful in the design of thiophenepyrimidine-based NNRTIs with more potent activity against HIV strains with RT mutations.

• 出版日期2017-11
• 单位河北医科大学; 山东大学