Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 5; p. 1050
• Main Authors: Lei, Yuan, Han, Sheng, Yang, Yang, Pannecouque, Christophe, De Clercq, Erik, Zhuang, Chunlin, Chen, Fen-Er
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.02.2020; MDPI
• Subjects: Acquired immune deficiency syndrome; AIDS; Antiretroviral drugs; Biphenyl; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; cyanomethyl linker; Cytotoxicity; diarylpyrimidine; Drug development; Drug resistance; HIV; hiv-1; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus; Humans; Hybridization; Models, Molecular; molecular hybridization; Molecular modelling; Mutants; Mutation - genetics; Nevirapine; nonnucleoside reverse transcriptase inhibitor (nnrti); Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Regression Analysis; Resistant mutant; reverse transcriptase; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; Selectivity; Strains (organisms); Substitutes; Toxicity; Viruses; United States > US; HIV-1; biphenyl; diarylpyrimidine; molecular hybridization; reverse transcriptase; nonnucleoside reverse transcriptase inhibitor (NNRTI); cyanomethyl linker
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25051050

The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound exhibited the best activity against wild-type HIV-1 with an EC (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC (50% cytotoxic concentration value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC : E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure-activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.