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Discovery of Novel Diarylpyrimidine Derivatives as Potent HIV‑1 NNRTIs Targeting the “NNRTI Adjacent” Binding Site

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journal contribution
posted on 27.02.2018, 00:00 by Zhipeng Huo, Heng Zhang, Dongwei Kang, Zhongxia Zhou, Gaochan Wu, Samuel Desta, Xiaofang Zuo, Zhao Wang, Lanlan Jing, Xiao Ding, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
A novel series of diarylpyrimidine derivatives, which could simultaneously occupy the classical NNRTIs binding pocket (NNIBP) and the newly reported “NNRTI Adjacent” binding site, were designed, synthesized, and evaluated for their antiviral activities in MT-4 cell cultures. The results demonstrated that six compounds (20, 27 and 3134) showed excellent activities against wild-type (WT) HIV-1 strain (EC50 = 2.4–3.8 nM), which were more potent than that of ETV (EC50 = 4.0 nM). Furthermore, 20, 27, 33, and 34 showed more potent or equipotent activity against single mutant HIV-1 strains compared to that of ETV. Especially, 20 showed marked antiviral activity, which was 1.5-fold greater against WT and 1.5- to 3-fold greater against L100I, K103N, Y181C, Y188L, and E138K when compared with ETV. In addition, all compounds showed lower toxicity (CC50 = 5.1–149.2 μM) than ETV (CC50 = 2.2 μM). The HIV-1 RT inhibitory assay was further conducted to confirm their binding target. Preliminary structure–activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed comprehensively.