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

Dongwei Kang; Yanying Sun; Da Feng; Shenghua Gao; Zhao Wang; Lanlan Jing; Tao Zhang; Xiangyi Jiang; Hao Lin; De Clercq Erik; Christophe Pannecouque; Peng Zhan; Xinyong Liu

doi:10.1021/acs.jmedchem.1c01885

Abstract

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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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