Identification of Dihydrofuro[3,4- d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties

  • J Med Chem. 2019 Feb 14;62(3):1484-1501. doi: 10.1021/acs.jmedchem.8b01656.
Dongwei Kang  1 ,  Heng Zhang  1 ,  Zhao Wang  1 ,  Tong Zhao  1 ,  Tiziana Ginex  2 ,  Francisco Javier Luque  2 ,  Yang Yang  3 ,  Gaochan Wu  1 ,  Da Feng  1 ,  Fenju Wei  1 ,  Jian Zhang  1 ,  Erik De Clercq  4 ,  Christophe Pannecouque  4 ,  Chin Ho Chen  5 ,  Kuo-Hsiung Lee  6  7 ,  N Arul Murugan  8 ,  Thomas A Steitz  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. Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy, Campus Torribera, Institute of Biomedicine (IBUB) and Institute of Theoretical and Computational Chemistry (IQTCUB) , University of Barcelona , 08921 Santa Coloma de Gramenet , Spain.
  • 3. Department of Molecular Biophysics and Biochemistry , Yale University , New Haven , Connecticut 06520-8114 , United States.
  • 4. Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research , KU Leuven , Herestraat 49 Postbus 1043 (09.A097) , B-3000 Leuven , Belgium.
  • 5. Surgical Oncology Research Facility , Duke University Medical Center , Box 2926, Durham , North Carolina 27710 , United States.
  • 6. Natural Products Research Laboratories, Eshelman School of Pharmacy , University of North Carolina , Chapel Hill , North Carolina 27599 , United States.
  • 7. Chinese Medicine Research and Development Center , China Medical University and Hospital , Taichung 40402 , Taiwan.
  • 8. Department of Theoretical Chemistry and Biology, Royal Institute of Technology (KTH) , AlbaNova University Center , S-106 91 Stockholm , Sweden.
PMID: 30624934 DOI: 10.1021/acs.jmedchem.8b01656
Abstract

To address drug resistance to HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4- d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC50 = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.