2. Academic Validation
  3. 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

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

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.

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