Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR

Lu, Huan-Huan; Xue, Ping; Zhu, Yuan‐Yuan; Ju, Xin; Zheng, Xuezhe; Zhang, Xun; Xiao, Ting; Pannecouque, Christophe; Li, Tingting; Gu, Shuang‐Xi

doi:10.1016/j.bmc.2017.03.009

Cited by 28 publications

(8 citation statements)

References 37 publications

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“…As shown in Figure 7 a,b, the backbone of Lys 101 forms two hydrogen bonds with the nitrogen atoms of the pyrimidine and -NH linker of compound 43 , respectively. This result is in agreement with our previous report that the residue Lys101 might interact with DAPYs and CAPYs through hydrogen bonds [ 8 ]. The same interactions were also observed in the binding mode of compound 46 .…”

Section: Resultssupporting

confidence: 94%

“…Fifty-two DAPY and CAPY compounds belonging to the HIV-1 NNRTI class were obtained from our previous studies and used to set up the 3D-QSAR models [ 5 , 8 , 11 ]. All the compounds were randomly divided into two sets, including 40 compounds as a training set to generate the model and 12 compounds as a test set to validate the model.…”

Section: Methodsmentioning

confidence: 99%

“…Until now, a large amount of NNRTIs with diverse chemical structures have been reported, such as dihydroalkoxybenzyloxopyrimidines, benzophenones, diaryl ethers, diaryltriazines, and diarylpyrimidines (DAPYs). Among these series of NNRTIs, DAPYs are considered to be one of the most successful anti-HIV families [ 8 ]. Etravirine (TMC125) and rilpivirine (TMC278) ( Figure 1 ), two representative members of DAPYs, have been approved by the U.S. Food and Drug Administration in 2008 and 2011, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Because of the fact that the right wing of the DAPY structure has been confirmed as a key pharmacophore for anti-HIV-1 activity [ 11 ], the structural modifications were mainly carried on the left wing, the central pyrimidine ring, and their linker (L–C bridge) ( Figure 1 ). Recently, we synthesized a series of DAPYs ( Figure 1 ) by modifying the left wing as well as the linker, and most of them exhibited potent anti-HIV-1 activity [ 5 , 8 ]. However, when modifying the left wing, the modifications were often confined to different substituted aromatic groups without considering cycloalkyl groups.…”

Section: Introductionmentioning

confidence: 99%

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Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Liu

Wang

Wan

et al. 2018

IJMS

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Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure–activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q2 = 0.679, R2 = 0.983, and rpred2 = 0.884) and comparative molecular similarity indices analysis (CoMSIA, q2 = 0.734, R2 = 0.985, and rpred2 = 0.891), exhibited good predictive abilities and significant statistical reliability. The docking results demonstrated that the phenyl ring at the C4-position of the pyrimidine ring was better than the cycloalkanes for the activity, as the phenyl group was able to participate in π–π stacking interactions with the aromatic residues of the binding site, whereas the cycloalkanes were not. The pharmacophore model and 3D-QSAR contour maps provided significant insights into the key structural features of DAPYs that were responsible for the activity. On the basis of the obtained information, a series of novel DAPY analogues of HIV-1 NNRTIs with potentially higher predicted activity was designed. This work might provide useful information for guiding the rational design of potential HIV-1 NNRTI DAPYs.

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Section: Resultssupporting

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Liu

Wang

Wan

et al. 2018

IJMS

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“…In 2017, 30 analogues of X‐CH 2 ‐DAPYs (X = NH, O, S) were synthesized. In this series, the most potent compound 22 with a combination of an o ‐F‐Ph moiety and O‐CH 2 ‐DAPYs (Figure7) displayed anti‐WT HIV activity with an EC 50 value of 5.8 nM and an SI of 26,034 36 . Moreover, this compound revealed good activity against HIV‐1 mutant strains (E138K, EC 50 = 0.30 μM).…”

Section: Improvement On Pharmacodynamicsmentioning

confidence: 93%

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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Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

2018

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Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) have always been an important part of the anti‐HIV‐1 combination therapy known as combination antiretroviral therapy (cART) since 1996. The use of NNRTIs for about 22 years has led to some mutations in the residues that compose the reverse transcriptase active site, resulting in the emergence of drug‐resistant viruses. Thus, the search for new potent NNRTIs with an improved safety profile and activity against drug‐resistant HIV strains is indispensable, and many hit and lead NNRTIs have been discovered in the last decade. This review provides an overview of the development in this field from 2013 to August 2018.

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Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR

Cited by 28 publications

References 37 publications

Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

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

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

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