Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitors

Yu, Shenghui; Sanchez, Tino W.; Liu, Yang; Yin, Yanzhen; Neamati, Nouri; Zhao, Guisen

doi:10.1016/j.bmcl.2013.09.018

Cited by 10 publications

(3 citation statements)

References 25 publications

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“…The X‐ray structure of prototypic foamy virus integrase (PFV‐IN) with DNA and two Mg 2+ ions (PDB: 3OYA) was selected for the docking study since it has been demonstrated that PFV IN is a good model for the development of HIV‐1 IN inhibitors . Moreover, the secondary structures of the HIV‐1 IN catalytic core domain and PFV IN have a high similarity with calculated root‐mean square deviations . Raltegravir was also re‐docked into the X‐ray structure of 3OYA in order to validate the docking protocol, and the docking results are shown in Figs.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Evaluation and Molecular Docking of Calix[4]arene‐Based β‐Diketo Derivatives as HIV‐1 Integrase Inhibitors

Luo

Zhao

et al. 2015

Archiv der Pharmazie

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In this publication, we design and report the synthesis of calix[4]arene-based β-diketo derivatives as novel HIV-1 integrase (IN) inhibitors. The target compounds were obtained using Claisen condensation, and their structures were characterized by NMR and ESI-MS. Preliminary bioassays showed that calix[4]arene-based β-diketo derivatives inhibit strand transfer (ST) with IC50 values between 5.9 and 21.2 µM. Docking studies revealed the predominant binding modes that were distinct from the binding modes of raltegravir, which suggests a novel binding region in the IN active site. Moreover, these compounds are predicted not to interact with some of the key amino acids (GLN148 and ASN155) implicated in viral resistance. Therefore, this series of compounds can further be investigated for a possible chemotype to circumvent resistance to clinical HIV-1 IN inhibitors.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Evaluation and Molecular Docking of Calix[4]arene‐Based β‐Diketo Derivatives as HIV‐1 Integrase Inhibitors

Luo

Zhao

et al. 2015

Archiv der Pharmazie

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“…For docking studies, we utilized the PFV-IN structure in a complex with two magnesium ions (Mg 2+ ), raltegravir, and a double-stranded DNA (DS) (PDB code: 3OYA). It has been previously reported that the PFV-integrase and HIV integrase secondary structures have a high degree of homology with an RMSD of 1.04 (39). The co-crystallized ligand, raltegravir, was redocked to verify the method.…”

Section: Molecular Docking Studymentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 8-methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazides as Potential Anti-HIV Agents

et al. 2022

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Background: The development of a highly safe and potent scaffold is a significant challenge in anti-HIV drug discovery. Objectives: This study aimed at developing a novel series of anti-HIV agents based on HIV integrase inhibitor pharmacophores. Methods: A novel series of 8-methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives featuring various substituted benzoyl and N-phenyl carboxamide and carbothioamide moieties were designed and synthesized. Results: According to the biological evaluation, all the developed compounds were effective against HIV at concentrations lower than 150 µM, associated with no significant cytotoxicity (CC50 > 500 µM). Conclusions: Compound 8b, possessing a 4-fluorobenzoyl group, was the most potent compound, with an EC50 of 75 µM. Docking studies revealed that the binding modes of designed compounds are similar to the known HIV integrase inhibitors.

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“…Dolutegravir is the only second generation strand transfer integrase inhibitor to be approved by FDA in August 2013 for a broad population of HIV-infected patients and is also expected to treat HIV-2 infection [16,17]. Thus, with an aim to design a novel HIV-1 integrase inhibitor which can overcome these resistance issues of existing drugs, we performed 3D-QSAR (CoMFA and CoMSIA) studies on 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide derivatives reported by Yu et al [18] and Zhang et al [19] as HIV-1 integrase inhibitors. This model was generated to study the relationship of molecular properties with biological activity (in this study HIV-1 integrase inhibitory activity).…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR studies on 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4- carboxamide derivatives as HIV-1 integrase inhibitors

Patel

Bhatt

2016

Journal of the Taiwan Institute of Chemical Engineers

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Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitors

Cited by 10 publications

References 25 publications

Synthesis, Biological Evaluation and Molecular Docking of Calix[4]arene‐Based β‐Diketo Derivatives as HIV‐1 Integrase Inhibitors

Synthesis, Biological Evaluation and Molecular Docking of Calix[4]arene‐Based β‐Diketo Derivatives as HIV‐1 Integrase Inhibitors

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 8-methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazides as Potential Anti-HIV Agents

3D-QSAR studies on 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4- carboxamide derivatives as HIV-1 integrase inhibitors

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