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

Yuan Lei,Fen-Er Chen,Yang Yang,Erik De Clercq,Sheng Han,Chunlin Zhuang,Christophe Pannecouque

doi:10.3390/molecules25051050

Abstract

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 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 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.

Highlights

Acquired immune deficiency syndrome (AIDS) is a serious public health problem worldwide caused by the human immunodeficiency virus (HIV) [1,2]
The synthesis of target molecules is depicted in Scheme 1, leading to a mixture of enantiomers
The arylboronic acids 3a–n with different substituted 2-(4-bromophenyl)acetonitriles 4a–c via Suzuki–Miyaura cross-coupling reaction catalyzed by PdCl2 provided the key intermediate biphenyl acetonitriles 5a–p in a mixed solvent of PEG400 and water at room temperature [30]

Summary

Introduction

Acquired immune deficiency syndrome (AIDS) is a serious public health problem worldwide caused by the human immunodeficiency virus (HIV) [1,2]. For AIDS treatment, targeting different steps of the HIV life cycle [4,5]. The nonnucleoside reverse transcriptase inhibitor (NNRTI), as the vital component of the HAART regimen, inhibits the transformation of the single-stranded viral RNA to double-stranded DNA (dsDNA). It binds to an allosteric hydrophobic pocket, named the NNRTI-binding pocket (NNIBP), located 10 Å from the DNA catalytic active site of reverse transcriptase (RT). With the efforts of the past decades, six NNRTIs were approved by the FDA (Figure 1) [8]. Nevirapine (NVP), delavirdine (DLV), and efavirenz (EFV), the first-generation NNRTIs, bind to NNIBP in a rigid “butterfly-like”

Methods

Results

Conclusion