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J Med Chem. 2019 Feb 14;62(3):1484-1501. doi: 10.1021/acs.jmedchem.8b01656. Epub 2019 Jan 18.

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.

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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.
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.
Department of Molecular Biophysics and Biochemistry , Yale University , New Haven , Connecticut 06520-8114 , United States.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research , KU Leuven , Herestraat 49 Postbus 1043 (09.A097) , B-3000 Leuven , Belgium.
Surgical Oncology Research Facility , Duke University Medical Center , Box 2926, Durham , North Carolina 27710 , United States.
Natural Products Research Laboratories, Eshelman School of Pharmacy , University of North Carolina , Chapel Hill , North Carolina 27599 , United States.
Chinese Medicine Research and Development Center , China Medical University and Hospital , Taichung 40402 , Taiwan.
Department of Theoretical Chemistry and Biology, Royal Institute of Technology (KTH) , AlbaNova University Center , S-106 91 Stockholm , Sweden.


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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