Structure-Based Optimization of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants

  • J Med Chem. 2017 May 25;60(10):4424-4443. doi: 10.1021/acs.jmedchem.7b00332.
Dongwei Kang  1 ,  Zengjun Fang  1  2 ,  Boshi Huang  1 ,  Xueyi Lu  1 ,  Heng Zhang  1 ,  Haoran Xu  1 ,  Zhipeng Huo  1 ,  Zhongxia Zhou  1 ,  Zhao Yu  1 ,  Qing Meng  1 ,  Gaochan Wu  1 ,  Xiao Ding  1 ,  Ye Tian  1 ,  Dirk Daelemans  3 ,  Erik De Clercq  3 ,  Christophe Pannecouque  3 ,  Peng Zhan  1 ,  Xinyong Liu  1
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, 250012 Jinan, Shandong P.R. China.
  • 2. The Second Hospital of Shandong University , no. 247 Beiyuan Avenue, Jinan 250033, China.
  • 3. Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
PMID: 28481112 DOI: 10.1021/acs.jmedchem.7b00332
Abstract

This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016 , 59 , 7991 - 8007 ). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro Antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure-activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 Infection.