Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

Wu, Zhe; Liu, Na; Qin, Bingjie; Huang, Li; Yu, Fei; Qian, Keduo; Morris‐Natschke, Susan L.; Jiang, Shibo; Chen, Chin Ho; Lee, Kuo Hsiung̀; Xie, Linghai

doi:10.1002/cmdc.201400075

Cited by 13 publications

(12 citation statements)

References 24 publications

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“…This comes in accordance with the previous studies reporting that iodo-derivatives exhibited the most potent activity as helicase inhibitors against replication of coronaviruses (24). In addition, it was reported that the aromatic substituent influences dramatically te anti-corona viruses activity (25). The current study reveals that orientation of halogen affected the activity, so that para--substituted compounds within the series 9-16 were showed higher helicase inhibitory activity compared to the ortho-ones.…”

Section: Structure-activity Relationship (Sar)mentioning

confidence: 57%

Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors

2020

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AbstractMiddle East respiratory syndrome coronavirus (MERS-CoV) had emerged and spread because of the worldwide travel and inefficient healthcare provided for the infected patients in several countries. Herein we investigated the anti-MERS-CoV activity of newly synthesized sixteen halogenated triazole compounds through the inhibition of helicase activity using the FRET assay. All new compounds underwent justification for their target structures via microanalytical and spectral data. SAR studies were performed. Biological results revealed that the most potent compounds were 4-(cyclopent-1-en-3-ylamino)-5-(2-(4-iodophenyl)hydrazinyl)-4H-1,2,4-triazole-3-thiol (16) and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol (12). In silico molecular docking of the most potent compounds was performed to the active binding site of MERS-CoV helicase nsp13. Molecular docking results are in agreement with experimental findings.

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Section: Structure-activity Relationship (Sar)mentioning

confidence: 57%

Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors

2020

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“…Preserving these known necessary pharmacophore elements, compound 34 was synthesized by modification of Y and R 2 substituents located on the phenoxy ring (A ring). This compound demonstrated excellent anti‐HIV‐1 potency against both wild‐type and resistant virus strains with mutation on E138K or K101E positions . It also showed favorable physiochemical properties and a good equilibrium between potency and lipophilicity.…”

Section: Modification Of Existing Nnrti Scaffoldsmentioning

confidence: 99%

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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“…Subsequently, multiple structural modifications were introduced to identify structure-activity relationship (SAR) and structure-property relationship (SPR) correlations for DAANs and DAPAs as new HIV-1 NNRTI agents. The subsequent leads 2b 13 (DAAN) and 3b 14 (DAPA) exhibited not only extremely high potency against both wild-type (EC 50 values of 0.39 and 3.25 nM, respectively) and drug-resistant (EC 50 values of 1.8–3.4 and 3.5–6.9 nM, respectively) viral replication but also improved druglike properties. Lead 2b had a desirable log P value of 3.68 and a high water solubility of 90 µg/mL at pH 2.0, but its higher metabolism and instability in various solvents prompted continued structural optimization.…”

Section: Introductionmentioning

confidence: 99%

Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus

Liu¹,

Wei²,

Huang

et al. 2016

J. Med. Chem.

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Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R1 group might provide greater efficacy against the E138K mutant.

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Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

Cited by 13 publications

References 24 publications

Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors

Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors

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

Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus

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