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
posted on 2022-01-21, 21:34authored byDongwei Kang, Yanying Sun, Da Feng, Shenghua Gao, Zhao Wang, Lanlan Jing, Tao Zhang, Xiangyi Jiang, Hao Lin, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
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.