Bifunctional antibiotics for targeting rRNA and resistance-causing enzymes and for inhibition of anthrax lethal factor

Inactive Publication Date: 2005-07-07
TECHNION RES & DEV FOUND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] The present invention overcomes the deficiencies of the prior art by providing a novel group of aminoglycosides which share some structural features of currently available aminoglycosides with regard to the backbone, while also having significant structural differenc

Problems solved by technology

Indeed, microbiologists today warn of a “medical disaster” which could lead back to the era before penicillin, when even seemingly small infections were potentially lethal.
However, this approach is both time-consuming and financially prohibitive, yet remains indispensable if an acceptable level of care is to be provided in the immediate future.
Unfortunately, prolonged clinical use of currently available aminoglycosides has resulted in effective selection of resistance to this family of antibacterial agents (9).
Presently, resistance to these agents is widespread among pathogens worldwide which severely limits their usefulness.
Through

Method used

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  • Bifunctional antibiotics for targeting rRNA and resistance-causing enzymes and for inhibition of anthrax lethal factor
  • Bifunctional antibiotics for targeting rRNA and resistance-causing enzymes and for inhibition of anthrax lethal factor
  • Bifunctional antibiotics for targeting rRNA and resistance-causing enzymes and for inhibition of anthrax lethal factor

Examples

Experimental program
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Effect test

example i

General Synthesis of the Compounds of the Present Invention and Syntheses of Specific Exemplary Intermediates

[0130] The strategy for the construction of all three sets of compounds in FIG. 3 featured the use of a common acceptor for each set (acceptors 1-3 in FIG. 4), to which the monosaccharide donors were connected, followed by a two-step deprotection to yield the target C5″-branched derivatives. The protecting groups used in this study served admirably in terms of ease of attachment and removal and survivability under the reaction conditions, whereas the thioglycoside-NIS (31) and trichloroacetimidate-BF3 (32) glycosidation methods proved to be both rapid and efficient.

[0131] This Example describes the overall synthetic procedure with optional variations; the following Examples include specific non-limiting examples of the synthetic process as it was performed for the present invention.

[0132] The neomycin acceptor 1 is readily accessible from the commercial neomycin B (49). Th...

example 2

Selection of Structures for Compounds of the Present Invention

[0168] The previous Example related to a general scheme which may optionally be used for any compound according to the present invention, as well as optionally for generating a library of compounds according to the present invention. This Example describes the selection of some non-limiting, illustrative structures for compounds according to the present invention.

[0169] One important aspect of the present invention is the use of functional aminoglycosides to solve the problem of cytotoxicity. Without wishing to be limited by a single hypothesis, these structures were selected to ameliorate this problem. One of the major drawbacks of aminoglycosides is their relatively high toxicity. Neomycin B is the most toxic of aminoglycosides, yet it is primarily used for topical infections. It is highly nephrotoxic and ototoxic and is by far the most potent in the area of neuromuscular blockage. Aminoglycosides are nephrotoxic beca...

example 3

Specific Synthesis of Selected Compounds of the Present Invention

[0174] Example 1 included a general synthetic scheme which may optionally be used for any compound according to the present invention, as well as optionally for generating a library of compounds according to the present invention. This Example provides an illustrative, non-limiting synthetic process that was performed for selected compounds according to the present invention.

[0175] As shown in FIGS. 10-12, a compound was prepared according to a synthetic scheme which started with neomycin B being converted to a general acceptor, as described with regard to Example 1. FIGS. 10 and 11 show the syntheses of the monosaccharide donors. Neomycin B (Compound I) is shown in FIG. 12 after being converted to an acceptor 1 to which the monosaccharide donors of FIG. 7 can be coupled.

[0176] The protecting groups used in this study served admirably in terms of the ease of attachment and removal and survivability under the reactio...

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Abstract

A novel group of aminoglycosides which share some structural features of currently available aminoglycosides with regard to the backbone, while also having significant structural differences, is disclosed. The similarity enables these aminoglycosides to be highly potent and effective antibiotics, while the significant differences enable these aminoglycosides to reduce or even block antibiotic resistance. The aminoglycosides of the present invention are suitable for inhibition of antrax lethal factor, hence are suitable for use as a cure for anthrax.

Description

[0001] This application is a continuation-in-part of PCT Patent Application No. PCT / IL2004 / 000490, filed Jun. 9, 2004, which claims priority from U.S. Pat. application Ser. No. 10 / 829,976, filed Apr. 23, 2004, and U.S. Provisional Patent Applications Nos. 60 / 540,359, filed Feb. 2, 2004, and 60 / 484,293, filed Jul. 3, 2003. This application also claims the benefit of priority from U.S. Provisional Patent Application No. 60 / 608,372, filed Sep. 10, 2004. The teachings of the above applications are hereby incorporated by reference as if fully set forth herein.FIELD OF THE INVENTION [0002] The present invention relates to bi-functional antibiotics, and in particular to aminoglycosides which are capable of reducing the efficacy of and / or blocking antibiotic resistance. The aminoglycosides of the present invention are suitable for inhibition of anthrax lethal factor, hence are suitable for use as a cure for anthrax. BACKGROUND OF THE INVENTION [0003] The rapid spread of antibiotic resistanc...

Claims

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Application Information

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IPC IPC(8): C07H15/00
CPCC07H15/232C07H15/00
Inventor BAASOV, TIMORFRIDMAN, MICHABELAKHOV, VALERYYARON, SIMA
Owner TECHNION RES & DEV FOUND LTD
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