5-tert-Butyl-N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide Derivatives as Novel Potent Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase: Initiating a Quest for New Antitubercular Drugs

Velaparthi, Subash; Brunsteiner, Michael; Uddin, Reaz; Wan, Baojie; Franzblau, Scott G.; Petukhov, Pavel A.

doi:10.1021/jm701372r

Cited by 104 publications

(63 citation statements)

References 26 publications

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“…Genetically stable rBCG vaccines expressing Gag, BCG-Gag and BCGpan-Gag were generated using the Pasteur strain of BCG and a pantothenate auxotroph of Pasteur (BCGΔ panCD ). Pantothenate is a key precursor of coenzyme A and the acyl carrier protein and is essential for many intracellular processes including fatty acid metabolism, cell signalling and synthesis of polyketides and non-ribosomal peptides [26]. A M. tuberculosis pantothenate, auxotroph as well a BCG pantothenate auxotroph, have been studied in mice and guinea pigs.…”

Section: Introductionmentioning

confidence: 99%

Priming with a Recombinant Pantothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ T Cells

et al. 2012

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A safe and effective HIV vaccine is required to significantly reduce the number of people becoming infected with HIV each year. In this study wild type Mycobacterium bovis BCG Pasteur and an attenuated pantothenate auxotroph strain (BCGΔpanCD) that is safe in SCID mice, have been compared as vaccine vectors for HIV-1 subtype C Gag. Genetically stable vaccines BCG[pHS400] (BCG-Gag) and BCGΔpanCD[pHS400] (BCGpan-Gag) were generated using the Pasteur strain of BCG, and a panothenate auxotroph of Pasteur respectively. Stability was achieved by the use of a codon optimised gag gene and deletion of the hsp60-lysA promoter-gene cassette from the episomal vector pCB119. In this vector expression of gag is driven by the mtrA promoter and the Gag protein is fused to the Mycobacterium tuberculosis 19 kDa signal sequence. Both BCG-Gag and BCGpan-Gag primed the immune system of BALB/c mice for a boost with a recombinant modified vaccinia virus Ankara expressing Gag (MVA-Gag). After the boost high frequencies of predominantly Gag-specific CD8+ T cells were detected when BCGpan-Gag was the prime in contrast to induction of predominantly Gag-specific CD4+ T cells when priming with BCG-Gag. The differing Gag-specific T-cell phenotype elicited by the prime-boost regimens may be related to the reduced inflammation observed with the pantothenate auxotroph strain compared to the parent strain. These features make BCGpan-Gag a more desirable HIV vaccine candidate than BCG-Gag. Although no Gag-specific cells could be detected after vaccination of BALB/c mice with either recombinant BCG vaccine alone, BCGpan-Gag protected mice against a surrogate vaccinia virus challenge.

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Section: Introductionmentioning

confidence: 99%

Priming with a Recombinant Pantothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ T Cells

et al. 2012

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“…The enzyme performs the condensation of pantoate and β-alanine, by using ATP as cofactor, to form the vitamin pantothenate (25)(26)(27)(28). Several approaches have been used to develop inhibitors, including high-throughput screening (29,30), mimicking the reaction intermediate (31,32), and more recently, we have demonstrated the application of dynamic combinatorial chemistry (33) as well as fragment growing and fragment linking (34,35). These further justify the choice of Pts as a model system to benchmark our biophysical fragment screening strategy.…”

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confidence: 99%

Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery

Silvestre

Blundell

Abell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

100

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In fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have benchmarked an integrated biophysical approach for fragment screening and validation against Mycobacterium tuberculosis pantothenate synthetase. A primary screen of 1,250 fragments library was performed by thermal shift, followed by secondary screen using one-dimensional NMR spectroscopy (water ligand observed gradient spectroscopy and saturation transfer difference binding experiments) and ultimate hit validation by isothermal titration calorimetry and X-ray crystallography. Our multibiophysical approach identified three distinct binding sites for fragments and laid a solid foundation for successful structure-based elaboration into potent inhibitors.drug design | hot spots | protein-ligand interactions

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“…The reaction of 15b with substituted- [1,3,4]thiadiazol-2-ylamine 23 and substituted benzothiazol-2-ylamine 25 in triethylamine/chloroform, yielded the corresponding thiadiazoles 24 and benzothiazoles 26 (Scheme 7) [32].…”

Section: Reactions Oxidationmentioning

confidence: 99%

“…Pyrazoles are valuable moieties of bioactive compounds showing antimicrobial [1], anticancer [2], anti-inflammatory [3], and selective enzyme inhibitory activities [4]. Moreover, a series of pyrazole derivatives is used as insecticides [5], fungicides [6,7], and herbicides [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

5-Chloropyrazole-4-carboxaldehydes as synthon in heterocyclic synthesis

et al. 2015

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5-tert-Butyl-N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide Derivatives as Novel Potent Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase: Initiating a Quest for New Antitubercular Drugs

Cited by 104 publications

References 26 publications

Priming with a Recombinant Pantothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ T Cells

Priming with a Recombinant Pantothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ T Cells

Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery

5-Chloropyrazole-4-carboxaldehydes as synthon in heterocyclic synthesis

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