Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors

Yan, Zihong; Wu, Huawei; Chen, Wenxue; Wu, Yan; Piao, Hu‐Ri; He, Qiuqin; Chen, Fen‐Er; Clercq, Erik De; Pannecouque, Christophe

doi:10.1016/j.bmc.2014.03.020

Cited by 17 publications

(3 citation statements)

References 16 publications

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“…In this study, we have taken 10 DAPYs that displayed the most potent anti-HIV-1 activity, with excellent selectivity for infected over uninfected cells. DAPYs, 1 [12] , 2 [13] , 3 [14] 4 [15] , 5 [16] , 6-7 [17] , 8 [18] , 9 [19] and 10 [20] studied in silico for their potential anti-HIV activity along with their physicochemical and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties. The relative Structure-Activity Relationship (SAR) discussions were also investigated together with the comparative docking analysis.…”

Section: Molecular Docking Structure-activity Relationship Admet Eval...mentioning

confidence: 99%

Molecular Docking Structure-Activity Relationship, ADMET Evaluation and Pharmacokinetics Studies of Anti-HIV Agents and Methyl-Diarylpyrimidines Non-Nucleoside Reverse Transcriptase Inhibitors

Li¹,

Yan²,

Zheng³

et al. 2022

IJPS

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In this study, the interaction between human immunodeficiency virus reverse transcriptase and methyldiarylpyrimidines containing a hydroxyimino, hydrazine, hydroxyl, cyclopropylamino, cyano or chloro etc. substituent was studied by molecular docking simulation, molecular docking was accomplished with AutoDock4.2 and absorption, distribution, metabolism, excretion and toxicity-structure-activity relationship and Swiss absorption, distribution, metabolism and excretion servers were used to predict the pharmacokinetics and absorption, distribution, metabolism, excretion and toxicity properties of all compounds. As a result, molecular docking analysis revealed that there are extensive interactions between the diarylpyrimidine derivatives and Lys101, Tyr188, Val179, Lys103, Glu138, Leu234, Phe227 and Trp229 residues in the active site of human immunodeficiency virus-1 reverse transcriptase. The formation of hydrogen bonds between diarylpyrimidines and the residues Lys101 and Glu138 play important roles in inhibiting the activity of human immunodeficiency virus. All compounds respect the conditions mentioned in Lipinski's rule and have acceptable absorption, distribution, metabolism, excretion and toxicity properties. The preliminary structure-activity relationship was also investigated. A preliminary structureactivity relationship analysis of these target molecules highlighted a preference for the smaller or more flexible group's substitution in the linker between the left ring and the pyrimidine skeleton for enhancing the anti-human immunodeficiency virus-1 activity. The acrylonitrile C 4 -substituent substantially improved the potency against wild-type human immunodeficiency virus-1 and several mutant strains, and the 2 nd position is the most preferred position to improve antiviral activity. This information might be helpful for further diarylpyrimidine optimizations.

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Section: Molecular Docking Structure-activity Relationship Admet Eval...mentioning

confidence: 99%

Molecular Docking Structure-Activity Relationship, ADMET Evaluation and Pharmacokinetics Studies of Anti-HIV Agents and Methyl-Diarylpyrimidines Non-Nucleoside Reverse Transcriptase Inhibitors

Li¹,

Yan²,

Zheng³

et al. 2022

IJPS

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“…Moreover, 17 was with a higher SI value of 106,367 24,25 . The cyano and chloro groups were introduced at the linker position in compounds 18 – 20 , 22,33,34 displaying the superior inhibitory activity toward WT HIV‐1 (EC 50 = 2 nM) and the double mutant strains (RES059, EC 50 = 41 nM) (Figure 6). The SAR and molecular docking studies suggested that CH–CN group was considered to be well positioned into the hydrophobic cavity that was formed by Y181/Y188 and V179 residues.…”

Section: Improvement On Pharmacodynamicsmentioning

confidence: 99%

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

Zhuang

Chen

2021

Medicinal Research Reviews

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Drug discovery of human immunodeficiency virus (HIV) is a hot field in medicinal chemistry community for many years. The diarylpyrimidines (DAPYs) are the second‐generation non‐nucleoside reverse transcriptase inhibitors (NNRTIs) targeting reverse transcriptase, playing a great irreplaceable role in HIV transcriptional therapy. However, fast‐growing drug‐resistant mutations as nonnegligible challenge are still unpredictably appeared in the clinical practice, leading to deactivate or reduce the existing drugs. In the last 20 years, more and more novel DAPY derivatives have developed with the purpose to counter the mutants. Nevertheless, most of them have dissatisfactory pharmacokinetics (PK) or poor antiviral activity toward resistant mutant strains. In this article, we will analyze the NNRTI derivatives with promising druggability, and summarize a series of druggability modification strategies to improve the antiviral activity, reduce toxicity and improve the PK properties in recent years. The prospects of DAPYs and the directions for future efforts will be discussed.

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“…Schiff bases with amines provided, after reduction of the imino double bond, (cyclopropylamino)methylenes 19 or (alkylamino)methylenes. 20 Further types of carbon-based linkers include halomethylene, 21 cyanomethylene, 22 and hydroxymethylene 23 linkers. Additionally, hydroxy(alkyl)methylene analogues were prepared by reacting alkylmagnesium compounds with the carbonyl group.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anti-human immunodeficiency virus activity of substituted (o,o-difluorophenyl)-linked-pyrimidines as potent non‐nucleoside reverse transcriptase inhibitors

Čechová

Dejmek

Baszczyňski

et al. 2019

Antivir Chem Chemother

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With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o,o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o,o-difluoro-p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.

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Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors

Cited by 17 publications

References 16 publications

Molecular Docking Structure-Activity Relationship, ADMET Evaluation and Pharmacokinetics Studies of Anti-HIV Agents and Methyl-Diarylpyrimidines Non-Nucleoside Reverse Transcriptase Inhibitors

Molecular Docking Structure-Activity Relationship, ADMET Evaluation and Pharmacokinetics Studies of Anti-HIV Agents and Methyl-Diarylpyrimidines Non-Nucleoside Reverse Transcriptase Inhibitors

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

Synthesis and anti-human immunodeficiency virus activity of substituted (o,o-difluorophenyl)-linked-pyrimidines as potent non‐nucleoside reverse transcriptase inhibitors

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