Potent selective thienoxazinone inhibitors of herpes proteases

Jarvest, Richard L.; Connor, Susan C.; Gorniak, Joselina G.; Jennings, L. J.; Serafinowska, Halina T.; West, Andrew B.

doi:10.1016/s0960-894x(97)00300-4

Cited by 56 publications

(22 citation statements)

References 12 publications

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“…They possess various biological activities such as antimicrobial [3], hypolipidacmic [4], antidiabetic [5], anti-inflammatory [6], antimycobacterial [7], antithrombotic [8], antagonism to progesterone receptor [9], antitumor [10], antiviral [11], leucocyte clastase [12] and scrotonin reuptakes [13]. The ground state equilibration of organic compounds was established using spectroscopic data [14].…”

Section: Intrductionmentioning

confidence: 99%

Hammett Spectral Correlations in some Aryl 1,3-Oxazine-4-Thione Derivatives

Thirunarayanan

Sekar

2014

ILCPA

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A series of some aryl 1,3-oxazine-4-thione derivatives have been synthesized by 1-methyl imidazole catalyzed three component one pot synthetic method in room temperature. The purities of these thiones were studied by their physical constants and spectroscopic data. The infrared and 13 C NMR spectral data of CN and CS were correlated with Hammett substituent constants, F and R parameters using single and multi-linear regression analysis. From the results of statistical analysis, the effect of substituent on the spectral data was studied.Keywords: 1,3-oxazine-4-thiones; IR spectra; 13 C NMR spectra; Hammett correlation INTRDUCTIONAryl 1,3-oxazine-4-thiones are pharmaceutical important heterocycles [1,2] [21]. The spatial arrangement of protons such as cis and trans of organic stereo chemical compounds [22] were studied using NMR spectra. Currently chemists and spectroscopic researchers [23][24][25][26][27][28][29] have paid much more interest for correlation of spectral data with Hammett substituent constants. Thirunarayanan and Ravi [30] have studied the effect of substituents of some pyrazoline-1-ethanones. Substituent effects on the spectral group frequencies of 9H-fluorenayl bromides were studied by Thirunarayanan [31]. Sakthinathan et al., have investigated the effect of substituents on naphthyl based pyrazoline derivatives [32]. Sasikala et al.,[22] have evaluated the effect of substituents and antimicrobial activities of some 5-bromo-2-thienyl based pyrazolines. The spectral correlation of infrared and nuclear magnetic resonance spectra of E-imines have been predicted by Sakthinathan et. al. and Suresh et al.,[33,34]. Thirunarayanan and Sekar have investigated the substituent effects on the IR and NMR spectral frequencies of some 3-(3,4-

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Section: Intrductionmentioning

confidence: 99%

Hammett Spectral Correlations in some Aryl 1,3-Oxazine-4-Thione Derivatives

Thirunarayanan

Sekar

2014

ILCPA

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“…These reactive amino acids provide the opportunity to identify inhibitors that bind covalently to the active site by reacting with the serine hydroxyl group or disulphide bonding with cysteine. Several unique classes of compounds such as thieno [2,3-d]ioxazinones and spirocyclopropyl oxazolones ( Figure 5) have been described as inhibiting the HCMV protease by acylation of the active site serine [69][70][71][72][73]. Benzimidazole sulphoxides ( Figure 5) that inhibit the HCMV protease by reacting with the active site cysteine have also been described [74].…”

Section: Hcmv Protease Inhibitorsmentioning

confidence: 99%

Non‐nucleoside inhibitors of herpesviruses

Wathen¹

2002

Reviews in Medical Virology

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While the treatment of herpes simplex virus with acyclovir and similar nucleoside analogues was one of the first success stories in antiviral chemotherapy, substantial unmet medical needs remain for herpesvirus diseases. In particular, the increasing numbers of immunosuppressed people due to AIDS, transplantation, cancer and aging has driven the need for improved antivirals to treat diseases caused by human cytomegalovirus (HCMV). Currently available drugs for the treatment of HCMV diseases are less than ideal agents due to issues of toxicity, modest efficacy and poor oral bioavailability. High throughput screening of large compound collections for inhibitors of specific viral enzymes or inhibition of viral growth in cell culture have identified a number of new HCMV inhibitors at several pharmaceutical companies. These compounds act by inhibition of novel molecular targets such as the viral protein kinase, viral protease and viral proteins involved in DNA cleavage/packaging. In addition, novel non-nucleoside inhibitors of the herpesvirus DNA polymerase have recently been described. This review will summarise some of these research efforts and will focus on non-nucleoside compounds that directly inhibit a viral process.

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“…Further chemical structure optimization led to the thiophene oxazinones (68,69), depicted in Figure 6, which are potent and selective mechanism based inhibitors of the HCMV protease with enhanced stability relative to benzoxazinones. 112 A parallel synthesis approach was utilized to prepare a range of N-acyl analogs 113 (70,71) and further studies revealed that these potent and selective inhibitors of HCMV act by not only acylating the catalytic serine 132 (opening of the oxazine ring of the inhibitor) but also by alkylating cysteine 161 of the protease (Michael addition to an enedione side chain). 114 Incorporation of moieties with H-bonding potential in an attempt to increase potency vs. the enzyme, led to the thienoxazinone derived nitroso and hydroxylamine compounds (72,73) which are some of the most potent, non-peptide inhibitors of HCMV protease prepared to date.…”

Section: Hcmv Protease Inhibitorsmentioning

confidence: 99%

Recent strategies in the development of new human cytomegalovirus inhibitors

Martı́nez¹,

Castro²,

Gil³

et al. 2001

Medicinal Research Reviews

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Human cytomegalovirus (HCMV) is one of the most common opportunistic infections in immunucompromised individuals, such as AIDS patients and organ transplant recipients, and is the most frequent congenital viral infection in humans. Despite a reduction of the incidence of AIDS‐related opportunistic infections in patients under highly active antiretroviral treatment, attention should be paid to the HCMV risk factor in these individuals. Furthermore, HCMV may have an important role in atherosclerosis. Existing antiviral treatments for the HCMV infection suffer from poor bioavailability, toxicity, and limited effectiveness, mainly due to the development of drug resistance. Fortunately there are novel and potentially very effective new compounds undergoing pre‐clinical and clinical evaluation. This review provides an overview in the last five years of new HCMV inhibitors (chemical structures, SAR, and new mechanisms of action) with the aim to provide new clues for the development of future drugs against this opportunistic virus. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 227–244, 2001

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Potent selective thienoxazinone inhibitors of herpes proteases

Cited by 56 publications

References 12 publications

Hammett Spectral Correlations in some Aryl 1,3-Oxazine-4-Thione Derivatives

Hammett Spectral Correlations in some Aryl 1,3-Oxazine-4-Thione Derivatives

Non‐nucleoside inhibitors of herpesviruses

Recent strategies in the development of new human cytomegalovirus inhibitors

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