Odcase inhibitors as Anti-virals and antibiotics

a technology of odcase inhibitors and antibiotics, which is applied in the direction of biocide, sugar derivatives, plant growth regulators, etc., can solve the problems of limited or non-existent structure-activity relationship investigation and inhibitor design, and the odcase inhibitor has not gained much traction in the 1980s and 1990s as a drug targ

Inactive Publication Date: 2010-04-08
KOTRA LAKSHMI P +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028]Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Problems solved by technology

2).xii,xiii,xiv However, the development of inhibitor candidates has been limited due to their toxicities and lack of specificity.xii There is also very limited or non-existent structure-activity relationship investigations and inhibitor design against ODCase.
Thus, ODCase has not gained much traction in 1980s and 1990s as a drug target.
The market size for antimicrobial agents is more than US$25 billion per year and the emergence of bacterial resistance worldwide is a limiting factor to current drugs.

Method used

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  • Odcase inhibitors as Anti-virals and antibiotics
  • Odcase inhibitors as Anti-virals and antibiotics
  • Odcase inhibitors as Anti-virals and antibiotics

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 6-iodo uridine (Ia) and 6-iodo-uridine-5′-O-monophosphate (Ib)

[0144]

[0145]Compounds Ia and Ib were synthesized from uridine. Introduction of the iodo moiety at the C-6 position of protected uridine was achieved using lithium diisopropylamide followed by treatment with iodine.xxxiv Deprotection with TFA followed gave compound Ia, and the subsequent phosphorylation with phosphorus oxychloride afforded the mononucleotide Ijbxxxv,xxxvi,xxxvii Then, the compound Ib was transformed into its ammonium salt by neutralization with 0.5 M NH4OH solution at 0° C. and freeze-dried to get the ammonium salt as a powder.

[0146](a) 5′-O-(t-Butyldimethylsilyl)-2′,3′-O-isopropylidene uridine. A stirred suspension of uridine (1 g, 4.1 mmol) in anhydrous acetone (50 mL) was treated with H2SO4 (0.5 mL) drop wise at room temperature and the resulting mixture was stirred for an additional hour. The reaction was then neutralized with Et3N and was concentrated. The crude mixture was purified by co...

example 2

Synthesis of compounds Ic and Id

[0151]

[0152]Introduction of the iodo moiety at the C-6 position of fully protected uridine was achieved through LDA and iodine, and further substitution of the iodo by the azido group produced the 6-azido derivative shown in the above scheme.xxxviii Deprotection of the isopropylidene and t-butyldimethylsilyl groups using trifluoroacetic acid yielded 6-azido-uridine Ic. Monophosphorylation of Id with phosphorus oxychloride to afford its mononucleotide followed by the reduction of the azido group with Pd / C gave the compound 6-amino-uridine-5′-O-monophosphate Ic in good yield.xxxix,xl,xli

[0153](a) 6-Azido-5′-O-(t-butyldimethylsilyl)-2′,3′-O-isopropylidene uridine. 5′-O-(t-Butyldimethylsilyl)-2′,3′-O-isopropylidene-6-iodo uridine (0.25 g, 0.48 mmol) was dissolved in dry DMF (3 mL) and NaN3 (0.034 g, 0.53 mmol) was added. The reaction mixture was stirred at room temperature for 1 hr in the dark. Organic solvent was evaporated under vacuum and the crude wa...

example 3

Anti-Viral Activity

[0156]Molecules containing the core structure, formula I, with specific substitutions at C-6 position (R1) of the pyrimidine moiety are either noncovalent or covalent inhibitors of orotidine monophosphate decarboxylase (ODCase). The molecular structures listed above also include, but are not limited to, all chemically-reasonable tautomeric forms of the above structures as well as the prodrugs forms that release the above mentioned compounds and their tautomers. These molecules, described above, exhibit antiviral activities and protect the cells from viral infections. Such molecules can be used in the treatment of viral infections either alone or in combination with other methods of treatment.

[0157]Selected compounds of Formula I were incubated with MDCK cells (for influenza virus A / WSN / 33) and L2 cells (for MHV-1 infection—a mouse SARS like corona virus representing a model for human SARS-like corona virus) for 5 hrs with 100 μM compounds. These compound-treated c...

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Abstract

The present invention includes the utility of anti-viral and / or antibacterial effective amounts of 6-substituted nucleoside derivatives of formula (I) (e.g. 6-iodouridine and 6-iodouridine monophosphate) in the treatment or prevention of viral infections (e.g. Flavivridae, Bunyaviridae, or Togaviridae, or viral infections of hepatitis C, hepatitis B, herpes, influenza, HIV, polio, Coxsackie A / B, rhino, small pox, Ebola, West Nile, or corona virus) and / or bacterial infections (e.g. H. pylori, S. Aureus, B. anthracis, Mycobacterial tuberculosis, M. leprae, M. avium, P. aueruginosa, Streptococcal species, and Pneumocystis carinii).

Description

FIELD OF THE INVENTION[0001]The present invention relates to methods of using certain 6-substituted uridine compounds for the treatment and prevention of viral and bacterial infections.BACKGROUND OF THE INVENTION[0002]ODCase (EC 4.1.1.23) plays a central role in the de novo synthesis of uridine-5′-O-monophosphate (UMP). UMP is a building block, synthesized de novo from aspartic acid, for the synthesis of other pyrimidine nucleotides such as uridine-5′-O-triphosphate (UTP), cytidine-5′-O-triphosphate (CTP), thymidine-5′-O-triphosphate (TMP) and 2′-deoxy-cytidine-5′-O-triphosphate (dCTP) (FIG. 1). Pyrimidine nucleotides are the building blocks for the synthesis of RNA and DNA, the essential molecules for cell replication and survival. Due to its important role in the cell's de novo nucleic acid synthesis, ODCase is present in bacteria, archea, parasites and in humans, i.e. almost every species except in viruses. This enzyme catalyzes the decarboxylation of orotidine monophosphate (OMP...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7072A61K31/513A61P31/14A61P31/18A61P31/16A61P31/06A61P31/04
CPCC07H19/073C07H19/067A61P31/04A61P31/06A61P31/12A61P31/14A61P31/16A61P31/18A61P33/02A61P33/06Y02A50/30
Inventor KOTRA, LAKSHMI P.PAI, EMIL F.
Owner KOTRA LAKSHMI P
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