2. Academic Validation
  3. Development of Novel Dihydrofuro[3,4- d]pyrimidine Derivatives as HIV-1 NNRTIs to Overcome the Highly Resistant Mutant Strains F227L/V106A and K103N/Y181C

Development of Novel Dihydrofuro[3,4- d]pyrimidine Derivatives as HIV-1 NNRTIs to Overcome the Highly Resistant Mutant Strains F227L/V106A and K103N/Y181C

  • J Med Chem. 2022 Feb 10;65(3):2458-2470. doi: 10.1021/acs.jmedchem.1c01885.
Dongwei Kang 1,  Yanying Sun 1,  Da Feng 1,  Shenghua Gao 1,  Zhao Wang 1,  Lanlan Jing 1,  Tao Zhang 1,  Xiangyi Jiang 1,  Hao Lin 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Peng Zhan 1 3,  Xinyong Liu 1 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 2 Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
  • 3 China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
PMID: 35061384 DOI: 10.1021/acs.jmedchem.1c01885
Abstract

Here, we report the design, synthesis, structure-activity relationship studies, Antiviral activity, Enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-d]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs). Compounds 14b (EC50 = 5.79-28.3 nM) and 16c (EC50 = 2.85-18.0 nM) exhibited superior potency against a panel of HIV-1-resistant strains. Especially, for the changeling mutations F227L/V106A and K103N/Y181C, both compounds exhibited remarkably improved activity compared to those of etravirine and rilpivirine. Moreover, 14b and 16c showed moderate RT Enzyme inhibition (IC50 = 0.14-0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, 14b and 16c exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.

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