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Spectinomycinamide as an anti-tuberculosis agent

A halogen, compound technology, applied in the field of spectinomycin amide as an anti-tuberculosis agent, can solve the problems of patient non-compliance, increased number, limited treatment options, etc.

Active Publication Date: 2016-06-01
UNIV OF TENNESSEE RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This long and cumbersome regimen leads to patient non-compliance
This in turn has led to an increase in the number of multidrug resistant (MDR) and extensively drug resistant (XDR) strains found in the clinic, for which effective treatment options are extremely limited

Method used

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  • Spectinomycinamide as an anti-tuberculosis agent
  • Spectinomycinamide as an anti-tuberculosis agent
  • Spectinomycinamide as an anti-tuberculosis agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0792] Synthesis of Spectinomycin Analogs

[0793] General Methods: The 3'-deoxy3'-acylamino and 3'-deoxy3'(R)-alkylamino spectinomycins disclosed in the present invention were synthesized according to methods similar to those previously described. see Woitun et al. J. Antibiot (Tokyo), 34(1), 22-27(1981); and Maier et al. , J. Antibiot (Tokyo), 34(1), 16-21 (1981). 1,3-Dibenzyloxycarbonyl-3′(R)-aminospectinomycin from spectinomycin dihydrochloride pentahydrate as figure 1 The synthesis shown is in two steps. First, apply benzyl chloroformate and NaHCO in water 3 , the methyl secondary amine in ring A was protected as benzyl carbamate with carboxybenzyl (CBz). The protected intermediate was then reductively aminated with ammonium nitrate and sodium cyanoborohydride in methanol to afford the 3'-deoxy-3'-amino derivative.

[0794] The amines were then used in the synthesis of the target 3'-acylaminospectinomycin derivatives by coupling them to various acids by using H...

Embodiment 2

[0870] General in vitro and in vivo methods

[0871] MIC determination: application according to Clinical Laboratory Standards Institute (ClinicalLaboratoryStandardsInstitute) (CLSI; National, C.F.C.L.S., Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Seventh Edition: Approved Standard M7-A7, CLSI, Wayne, Pennsylvania, U.S.A., 2008) was used to measure the MIC by a microbroth dilution method, and the reading was checked visually. 2-fold serial dilutions of antibiotics in 100 μL of appropriate broth medium were first prepared in 96-well round bottom microtiter plates (NalgeNunc International, Rochester, New York, USA). Add an equal volume (100 μL) of about 10 5 Bacterial broth inoculum in cfu / mL of bacteria to give a final drug concentration starting at 200 μg / mL and the plates were incubated aerobically at 37°C. M. tuberculosis and M. bovis BCG microtiter plates were incubated for 7 days, while the other strains were incubated o...

Embodiment 3

[0883] Antituberculous activity

[0884] The anti-tuberculosis activity of spectinomycin analogs against Mycobacterium tuberculosis H37Rv was determined in Middlebrook 7H9 supplemented with 10% ADC medium by dilution in drug microbroth in 96-well plates. Plates were incubated at 37°C for 7 days and then read visually for growth inhibition according to a previously described method. See for example Hurdle et al. , J. Antimicrob. Chemother, 62(5), 1037-1045 (2008). The results are shown in Table 1 and Table 2.

[0885] Table 1.3'-deoxy3'(R)-acylamino spectinomycin anti-tuberculosis activity

[0886]

[0887]

[0888]

[0889]

[0890] Table 2.3'-Deoxy 3'(R)-Alkylamino Spectinomycin Anti-tuberculosis Activity

[0891]

[0892] Multiple compounds showed good anti-tuberculosis MIC values, many of which had better anti-tuberculosis activity compared to spectinomycin. The structure-activity relationship of this series is very tight in terms of structural change...

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Abstract

The present application describes novel 3'-deoxy-3'-acylamino spectinomycin compounds. Also described are methods of using 3'-deoxy-3-acylamino spectinomycin and other spectinomycin analogs for the treatment of tuberculosis and for the treatment of microbial infections.

Description

[0001] Cross References to Related Applications [0002] The presently disclosed subject matter claims the benefit of US Provisional Patent Application 61 / 228,266, filed July 24, 2009, the disclosure of which is hereby incorporated by reference in its entirety. [0003] Government interests [0004] The subject matter disclosed herein was made with United States Government support under Grant No. R01AI062415 awarded by the National Institutes of Health. Accordingly, the United States Government has certain rights in the subject matter disclosed herein. technical field [0005] The presently disclosed subject matter provides a new class of spectinomycin analogs and describes their use in the treatment of tuberculosis and other microbial infections. [0006] abbreviation [0007] ℃ = degrees Celsius [0008] μg=microgram [0009] μL=microliter [0010] μM = micromolar [0011] ATCC = American Type Culture Collection [0012] CBz = carboxybenzyl [0013] cfu = colony for...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/00A61K31/335
CPCA61K31/133A61K31/357A61K31/423A61K31/427A61K31/4409A61K31/4433A61K31/496A61K31/497A61K31/501A61K31/506A61P31/04A61P31/06A61P43/00C07D493/04
Inventor R·E·李J·齐J·G·胡德勒B·迈博姆P·K·瓦戴迪拉凯什J·刘
Owner UNIV OF TENNESSEE RES FOUND
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