Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC 50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC 50 = 2.2−2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2− 6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by Xray crystallography.

Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Improved Anti-Resistance Efficacy

“…19,20 Hydrolysis of 6a−g with 1 mol/L aq. NaOH solution in a mixed THF/MeOH (6:1) for 12 h at room temperature afforded the corresponding diarylpyrimidinecarboxylic acids 7a−g in 60− 77% yields, which were then subjected to amidation of appropriate amines in the presence of HOBt and EDCI in dry DMF at room temperature for 13 h, delivering the target products 8a−v in 50−85% yields, all of which were fully identified by spectroscopy ( 1 H NMR and 13 C NMR) and highresolution mass spectrometry (HRMS).…”

“…The DAPY family has always been at the forefront of research on NNRTIs in the development of new anti-HIV drugs. − Our previous investigations for non-NRTIs expanded the DAPY family and multiple series of DAPY derivatives were discovered . Introducing a planar conjugated naphthyl fragment to replace the left wing of ETR was proposed by us to enhance the π–π stacking interactions with the surrounding aromatic residues in the hydrophobic pocket, composed of residues Y181, Y188, F227, and W229, leading to the identification of naphthyl-DAPY series (Figure ).…”

Recent Advances in the Synthesis and Applications of m-Aryloxy Phenols

“…The compound resulting from the synthesis by Frączk and his group in 2018 was an intermediate in creating novel diaryl ethers, which are NNRTIs with improved solubility. These inhibitors showed promising results with IC 50 values at low micromolar to sub-micromolar concentrations [ 38 , 39 , 40 ].…”