Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles

  • J Med Chem. 2016 Sep 8;59(17):7991-8007. doi: 10.1021/acs.jmedchem.6b00738.
Dongwei Kang  1 ,  Zengjun Fang  1  2 ,  Zhenyu Li  1 ,  Boshi Huang  1 ,  Heng Zhang  1 ,  Xueyi Lu  1 ,  Haoran Xu  1 ,  Zhongxia Zhou  1 ,  Xiao Ding  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, Jinan 250012, Shandong P.R. China.
  • 2. The Second Hospital, Shandong University , No. 247 Beiyuan Avenue, Jinan 250033, China.
  • 3. Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
PMID: 27541578 DOI: 10.1021/acs.jmedchem.6b00738
Abstract

We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its Antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.