Inhibition of human cytomegalovirus protease by benzoxazinones and evidence of antiviral activity in cell culture

Abood, Norman; Schretzman, Lori; Flynn, Daniel L.; Houseman, Kathrine A.; Wittwer, Arthur J.; Dilworth, Vickie M.; Hippenmeyer, Paul J.; Holwerda, Barry C.

doi:10.1016/s0960-894x(97)00368-5

Cited by 46 publications

(27 citation statements)

References 19 publications

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“…The structures of compounds 4a-g were confirmed by elemental analysis as well as spectroscopically (IR, 1 H and 13 C NMR and MS electrospray mass spectrometry). The signal at around 177-179 ppm in 13 C NMR denoted the presence of the carbamate thiocarbonyl group C=S. The signals at around 158-159 and 164-165 ppm were attributed to the quaternary carbon of junction and carbonyl of pyrazolic nucleus respectively.…”

Section: Chemistrymentioning

confidence: 99%

“…1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were recorded on a Bruker Avance II spectrometer using tetramethylsilane as an internal standard,.Mass spectra were obtained by electrospray ionisation technique (ESI) on a Perkin Elmer SCIEX API 300 spectrometer.…”

Section: Generalmentioning

confidence: 99%

“…Several benzo-oxazinones and related fused heterocycles are of interest as potential bioactive molecules. [10][11][12][13][14][15][16][17][18][19] On the other hand, pyrazole and their derivatives are associated with various pharmaceutical activities. 20,21 We reported previously the synthesis and biological activity evaluation of a new series of Nsubstituted pyrazolo-oxazin-2-one compounds on the basis of PASS prediction results.…”

Section: Introductionmentioning

confidence: 99%

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N-substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones

Geronikaki¹,

Bennamane²,

Nedjar-Kolli³

et al. 2010

Arkivoc

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Targeting to the synthesis of potent dual acting COX/LOX inhibitors as future anti-inflammatory drugs, we attempted a modification of the compounds based on docking analysis results. A substitution of the oxygen of the oxo-group of the oxazin-2-one ring by sulphur resulted in a four to over ten fold improvement of COX and LOX inhibitory action. N-phenyl derivatives exhibited the best biological properties with the 4-methoxy-phenyl derivative showing the best COX-1 and LOX inhibitory action and the 4-Br-phenyl derivative exhibiting the best COX-2 inhibitory action combined with good COX-1 and LOX inhibitory capacity.

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Section: Chemistrymentioning

confidence: 99%

Section: Generalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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N-substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones

Geronikaki¹,

Bennamane²,

Nedjar-Kolli³

et al. 2010

Arkivoc

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“…Several investigations to seek herpesvirus protease inhibitors have recently reported various low molecular weight inhibitors [24][25][26][27][28][29][30][31][32][33] and peptidomimetic inhibitors. 21,34,35) While a low molecular weight inhibitor with in vitro antiviral activity and stability in human plasma has been found, 29) there are likely to be problems involved with the peptidomimetic inhibitors, which display poor cell penetration and are easily subjected to degradation in cell culture.…”

Section: Effects Of 14-dihydroxynaphthalene and Naphthoquinones On Mmentioning

confidence: 99%

“…21,34,35) While a low molecular weight inhibitor with in vitro antiviral activity and stability in human plasma has been found, 29) there are likely to be problems involved with the peptidomimetic inhibitors, which display poor cell penetration and are easily subjected to degradation in cell culture. 21,35) These facts suggest that the low molecular weight inhibitors, compounds 1-4 are more suitable than the peptidomimetic inhibitors as antiherpesvirus agents.…”

Section: Effects Of 14-dihydroxynaphthalene and Naphthoquinones On Mmentioning

confidence: 99%

Selective Nonpeptidic Inhibitors of Herpes Simplex Virus Type 1 and Human Cytomegalovirus Proteases.

Matsumoto

Misawa

Chiba

et al. 2001

Biological & Pharmaceutical Bulletin

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Herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV) belong to the family Herpesviridae and cause severe opportunistic infections in immunocompromised individuals, including organ transplant recipients and AIDS patients. [1][2][3] Present clinical therapies commonly use viral DNA polymerase inhibitors such as acyclovir and ganciclovir, but this approach has been accompanied by the emergence of resistant mutants and various toxicities. 1)Therefore, treatment clinics need new antiviral drugs for combating herpesvirus infections.Herpesviruses, including HSV-1 and HCMV, encode a protease that is essential for the production of infectious virus particles. 4,5) The proofs obtained by site-directed mutagenesis 6,7) and chemical modification with diisopropyl-fluorophosphate [8][9][10] indicate that this protease is a serine protease. Recent results for the crystal structures of the HCMV, [11][12][13][14] varicella-zoster virus, 15) HSV-1 16) and HSV-2 16) proteases have shown that these proteases exhibit a novel fold and possess a unique catalytic triad in which the third member of the triad has a histidine substituted for an aspartic acid residue. Since their discovery, herpesvirus proteases have become a novel target of antiviral drugs. In this paper, we report the characterization of several potent inhibitors of HSV-1 and HCMV proteases obtained by random screening of a chemical compound library with the reverse-phase high-performance liquid chromatography (HPLC) assay system. MATERIALS AND METHODS Construction of HSV-1 Protease Expression VectorThe plasmid pRB4057 17) possessing the UL26 gene of HSV-1 was used as the template for polymerase chain reaction (PCR) amplification of the coding sequence for the protease catalytic domain (amino acids 1-247). Oligonucleotide primers were synthesized based on the published UL26 open reading frame.18) PCR was performed using Pwo DNA polymerase (Boehringer Mannheim) for 30 cycles of 2 min at 95°C, 2 min at 68°C and 2 min at 72°C. The resulting amplification product was digested with EcoRI and SmaI before ligation into corresponding sites of the pGEX-4T-1 (Pharmacia Biotech) plasmid. The resulting plasmid pGSTThHP was introduced into Escherichia coli BL21(DE3) pLysS to express HSV-1 protease fused in frame to glutathione S-transferase.Expression and Purification of HSV-1 Protease The bacterial cells harboring pGSTThHP were cultured in 1 l of 2ϫYT medium (1.6% Bacto tryptone, 1% Bacto yeast extract, 0.5% NaCl) containing 100 mg/ml ampicillin at 30°C to an OD 660 of 4, at which time isopropyl-1-thio-b-D-galactopyranoside was added to a final concentration of 0.1 mM, then growth was continued for 14 h. We then resuspended 11 g (wet weight) of the bacterial cell pellet in 55 ml of 50 mM Tris-HCl, pH 8.0, 150 mM NaCl, and 1 mM EDTA, lysed the cells by sonication, and ultracentrifuged them at 180000ϫg for 30 min at 4°C. This supernatant was loaded on a glutathione Sepharose 4B column (Pharmacia Biotech), which was equilibrated with 50 mM Tris-HCl, pH 8.0, 150 mM NaCl,...

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Copper‐Catalyzed N‐Alkyl Formamide Activation: Tandem Oxidative Coupling Approach for the Construction of C−N and C−O Bonds to Synthesize 3‐Alkyl‐1,3‐Benzoxazine‐2,4‐Dione and 4‐Methylene‐3‐Alkyl‐1,3‐Benzoxazine‐2‐One Derivatives

et al. 2022

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Inhibition of human cytomegalovirus protease by benzoxazinones and evidence of antiviral activity in cell culture

Cited by 46 publications

References 19 publications

N-substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones

N-substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones

Selective Nonpeptidic Inhibitors of Herpes Simplex Virus Type 1 and Human Cytomegalovirus Proteases.

Copper‐Catalyzed N‐Alkyl Formamide Activation: Tandem Oxidative Coupling Approach for the Construction of C−N and C−O Bonds to Synthesize 3‐Alkyl‐1,3‐Benzoxazine‐2,4‐Dione and 4‐Methylene‐3‐Alkyl‐1,3‐Benzoxazine‐2‐One Derivatives

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