Zhongxia Zhou

Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles

We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.

Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays

Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.

Structure-Based Optimization of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants

This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016 , 59 , 7991 - 8007 ). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure-activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 infection.

First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific anti-vaccinia and adenovirus agents via ‘privileged scaffold’ refining approach

Abstract A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) method. The biological significance of the novel synthesized quinazolines was highlighted by evaluating them in vitro for antiviral activity, wherein several compounds exhibited excellent activity specifically against vaccinia and adenovirus. Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with an EC50 value of 1.7μM, which was 15 fold than that of the reference drug Cidofovir (EC50 =25μM). 24b13 was the most potent compound against adenovirus-2 with an EC50 value of 6.2μM, which proved lower than all the reference drugs. Preliminary structure–activity relationships were also discussed. To the best of our knowledge, no data are present in the literature on antiviral activity of 3-hydroxy-quinazoline-2,4(1H,3H)-diones against DNA-viruses. Thus, these findings warrant further investigations (library expansion and compound refinement) on this novel class of antiviral agents.

Novel diaryltriazines with a picolinonitrile moiety as potent HIV-1 RT inhibitors: a patent evaluation of WO2016059647(A2)

ABSTRACT Diaryltriazine derivatives, which are structurally related to diarylpyrimidines, are a representative class of HIV-1 reverse transcriptase inhibitors with remarkable antiviral activities against wild-type and several mutant strains of HIV-1. A series of novel diaryltriazines with a picolinonitrile moiety was reported as potent HIV-1 RT inhibitors in the patent WO2016059647(A2). Two representative compounds 5e (hydrochloride) and 6e (hydrochloride) exhibited outstanding activities against various HIV-1 strains in cell-based assays, which were superior to those of AZT. Moreover, modeling simulation study is performed and discussed in details, providing deep insights and valuable information to explain the excellent antiviral potency of 6e. Finally, several cases to improve anti-drug-resistance profiles by targeting highly conserved residues in HIV-1 RT are herein preliminarily summarized.

Discovery of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the Tolerant Region I of NNIBP

Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991-8007; J. Med. Chem. 2017, 60, 4424-4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains. All the derivatives exhibited moderate to excellent potency against wild-type (WT) HIV-1 in MT-4 cells. Among them, sulfonamide compounds 9b and 9d were single-figure-nanomolar inhibitors with EC50 values of 9.2 and 7.1 nM, respectively. Indeed, 9a and 9d were effective against the whole viral panel except RES056. Notably, both compounds showed potent antiviral activity against K103N (EC50 = 0.032 and 0.070 μM) and E138K (EC50 = 0.035 and 0.045 μM, respectively). Furthermore, 9a and 9d exhibited high affinity for WT HIV-1 RT (IC50 = 1.041 and 1.138 μM, respectively) and acted as classical NNRT inhibitors (NNRTIs). These results are expected to be helpful in the design of thiophenepyrimidine-based NNRTIs with more potent activity against HIV strains with RT mutations.

Arylazolyl(azinyl)thioacetanilides: Part 19: Discovery of Novel Substituted Imidazo[4,5-b]pyridin-2-ylthioacetanilides as Potent HIV NNRTIs Via a Structure-based Bioisosterism Approach.

With the continuation of our unremitting efforts toward the discovery of potent HIV‐1 NNRTIs, a series of novel imidazo[4,5‐b]pyridin‐2‐ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure‐based drug design. Almost all of the title compounds displayed moderate to good activities against wild‐type (wt) HIV‐1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell‐based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 and 0.073 μm against wt HIV‐1, respectively, which was much more effective than the control drug nevirapine (EC50 = 0.26 μm) and comparable to delavirdine (EC50 = 0.038 μm). In addition, one selected compound showed a remarkable reverse transcriptase inhibitory activity compared to nevirapine and etravirine. In the end of this manuscript, preliminary structure–activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization.

Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery

Based on the detailed analysis of the binding mode of diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries of novel NNRTIs, with the aim to probe biologically relevant chemical space of solvent-exposed tolerant regions in NNRTIs binding pocket (NNIBP). The most potent compound 21a exhibited significant activity against the whole viral panel, being about 1.5-2.6-fold (WT, EC50 = 2.44 nM; L100I, EC50 = 4.24 nM; Y181C, EC50 = 4.80 nM; F227L + V106A, EC50 = 17.8 nM) and 4-5-fold (K103N, EC50 = 1.03 nM; Y188L, EC50 = 7.16 nM; E138K, EC50 = 3.95 nM) more potent than the reference drug ETV. Furthermore, molecular simulation was conducted to understand the binding mode of interactions of these novel NNRTIs and to provide insights for the next optimization studies.

Influenza A virus polymerase: an attractive target for next-generation anti-influenza therapeutics

The influenza RNA-dependent RNA polymerase (RdRP) is conserved among different types of influenza virus, playing an important part in transcription and replication. In this regard, influenza RdRP is an attractive target for novel anti-influenza drug discovery. Herein, we will introduce the structural and functional information of influenza polymerase; and an overview of inhibitors targeting the PA endonuclease and PB2 cap-binding site is provided, along with the approaches utilized for identification of these inhibitors. The protein-protein interactions (PPIs) of the three polymerase subunits: PA, PB1 and PB2, are described based on the published crystal structures, and inhibitors targeting the PA-PB1 interaction are introduced briefly.

1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries

A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.