A Copper(I)-Catalyzed 1,2,3-Triazole Azide−Alkyne Click Compound Is a Potent Inhibitor of a Multidrug-Resistant HIV-1 Protease Variant

Giffin, Michael J.; Heaslet, H.; Brik, Ashraf; Lin, Ying‐Chuan; Cauvi, Gabrielle; Wong, Chi‐Huey; McRee, Duncan E.; Elder, John H.; Stout, C.D.; Torbett, Bruce E.

doi:10.1021/jm800149m

Cited by 230 publications

(98 citation statements)

References 48 publications

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“…In addition, they have shown a broad spectrum of biological properties such as anti-bacterial 2 anti-allergic 3 , anti-HIV activity 4 and also serve as potential chemotherapeutic agents for various diseases 5 . On the other hand, substituted pyrimidine nuclei are found antiviral 6 , anti-tubercular, antineoplastic, anti-inflammatory, diuretic, antimalarial and cardiovascular 7 .…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure and DFT Studies of 4-(1-Benzyl-5-Methyl-1h-1,2,3-Triazol-4-Yl)-6-(3- Methoxyphenyl)pyrimidin-2-Amine

Murugavel¹,

Vijayakumar²,

Nagarajan³

et al. 2014

J. Chil. Chem. Soc.

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The title compound 1, 4-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine (C 21 H 20 N 6 O), was synthesized and structurally characterized by elemental analysis, 1 H NMR, 13 C NMR and single crystal X-ray diffraction. The molecular conformation is stabilized by an intramolecular C-H…N hydrogen bond, which generates an S(6) ring motif. In the crystal, molecules are linked by two pairs of inversion-related amine N-H N and C-H N hydrogen bonds, each generating alternate R 2 2 (8) ring motifs in a zigzag supramolecular chain that runs along c-axis. These chains stack along a-axis via amine N-H…O hydrogen bonds forming a two-dimensional supramolecular network. Density functional theory calculations of the structure, Mulliken population analyses on atomic charges and thermodynamic functions of the title compound were performed by using (DFT/B3LYP) method with the 6-311G(d,p) basis set level. The charge energy distribution and site of chemical reactivity of molecules were obtained by mapping electron density isosurface with electrostatic potential surfaces. The thermo dynamical properties of the title compound at different temperature have been calculated and corresponding relations between the properties and temperature have also been obtained.

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Section: Introductionmentioning

confidence: 99%

Crystal Structure and DFT Studies of 4-(1-Benzyl-5-Methyl-1h-1,2,3-Triazol-4-Yl)-6-(3- Methoxyphenyl)pyrimidin-2-Amine

Murugavel¹,

Vijayakumar²,

Nagarajan³

et al. 2014

J. Chil. Chem. Soc.

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“…Similar approaches comparing the structures of FIV and drug-resistant HIV-1 PRs to that of WT HIV-1 PR have led to the development of additional PR-inhibiting compounds with broadened efficacy (8,9,19,29,41,42). Our approach in studying substrate and inhibitor specificities has been to exchange amino acid residues in and around the active site of FIV PR with structurally equivalent residues of HIV-1 PR.…”

mentioning

confidence: 99%

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

Lin¹,

Torbett

Elder³

2010

J Virol

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Feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1) proteases (PRs)share only 23% amino acid identity and exhibit distinct specificities yet have very similar 3-dimensional structures. Chimeric PRs in which HIV residues were substituted in structurally equivalent positions in FIV PR were prepared in order to study the molecular basis of PR specificity. Previous in vitro analyses showed that such substitutions dramatically altered the inhibitor specificity of mutant PRs but changed the rate and specificity of Gag cleavage so that chimeric FIVs were not infectious. Chimeric PRs encoding combinations of the I37V, N55M, M56I, V59I, L97T, I98P, Q99V, and P100N mutations were cloned into FIV Gag-Pol, and those constructs that best approximated the temporal cleavage pattern generated by wild-type FIV PR, while maintaining HIV-like inhibitor specificity, were selected. Two mutations, M56I and L97T, were intolerant to change and caused inefficient cleavage at NC-p2. However, a mutant PR with six substitutions (I37V, N55M, V59I, I98P, Q99V, and P100N) was selected and placed in the context of full-length FIV-34TF10. This virus, termed YCL6, had low-level infectivity ex vivo, and after passage, progeny that exhibited a higher growth rate emerged. The residue at the position of one of the six mutations, I98P, further mutated on passage to either P98H or P98S. Both PRs were sensitive to the HIV-1 PR inhibitors lopinavir (LPV) and darunavir (DRV), as well as to the broad-based inhibitor TL-3, with 50% inhibitory concentrations (IC 50 ) of 30 to 40 nM, consistent with ex vivo results obtained using mutant FIVs. The chimeras offer an infectivity system with which to screen compounds for potential as broad-based PR inhibitors, define structural parameters that dictate specificity, and investigate pathways for drug resistance development.

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“…The 1,3-DC of 5 modified starters 11 and 12 will also allow the evaluation of whether such changes improved the antiviral performance against newly appearing multidrug-resistant viruses. 24 The employment of the catalysed 1, 3 strains of HIV-1 in a peripheral blood mononuclear cell-based assay and inhibits syncytium formation in the AA-2 cell line. Worldwide extended influenza viruses caused seasonal epidemic.…”

mentioning

confidence: 99%

1,3-Dipolar cycloadditions: applications to the synthesis of antiviral agents

2009

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A Copper(I)-Catalyzed 1,2,3-Triazole Azide−Alkyne Click Compound Is a Potent Inhibitor of a Multidrug-Resistant HIV-1 Protease Variant

Cited by 230 publications

References 48 publications

Crystal Structure and DFT Studies of 4-(1-Benzyl-5-Methyl-1h-1,2,3-Triazol-4-Yl)-6-(3- Methoxyphenyl)pyrimidin-2-Amine

Crystal Structure and DFT Studies of 4-(1-Benzyl-5-Methyl-1h-1,2,3-Triazol-4-Yl)-6-(3- Methoxyphenyl)pyrimidin-2-Amine

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

1,3-Dipolar cycloadditions: applications to the synthesis of antiviral agents

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