N(2)-Substituted D,L-Cycloserine Derivatives: Synthesis and Evaluation as Alanine Racemase Inhibitors.

Kim, Myoung Goo; Strych, Ulrich; Krause, Kurt L.; Benedik, Michael J.; Kohn, Harold

doi:10.7164/antibiotics.56.160

Cited by 23 publications

(14 citation statements)

References 18 publications

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“…Kim et al 46 investigated the importance of N(2)-structural site in cyloserine for bioactivity. Eighteen derivatives of N(2)substituted D,L-cycloserine 6 ( Figure 5) were synthesised from D,L-cycloserine.…”

Section: Inhibitors Of Alanine Racemasementioning

confidence: 99%

Inhibitors of alanine racemase enzyme: a review

Azam

Jayaram

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Alanine racemase is a fold type III PLP-dependent amino acid racemase enzyme catalysing the conversion of l-alanine to d-alanine utilised by bacterial cell wall for peptidoglycan synthesis. As there are no known homologs in humans, it is considered as an excellent antibacterial drug target. The standard inhibitors of this enzyme include O-carbamyl-d-serine, d-cycloserine, chlorovinyl glycine, alaphosphin, etc. d-Cycloserine is indicated for pulmonary and extra pulmonary tuberculosis but therapeutic use of drug is limited due to its severe toxic effects. Toxic effects due to off-target affinities of cycloserine and other substrate analogs have prompted new research efforts to identify alanine racemase inhibitors that are not substrate analogs. In this review, an updated status of known inhibitors of alanine racemase enzyme has been provided which will serve as a rich source of structural information and will be helpful in generating selective and potent inhibitor of alanine racemase.

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Section: Inhibitors Of Alanine Racemasementioning

confidence: 99%

Inhibitors of alanine racemase enzyme: a review

Azam

Jayaram

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…A series of N(2)-substituted derivatives of compound 16 (Kim et al, 2003b) (Fig. 20) and five-and six-membered heterocycles (Kim et al, 2003a) were prepared and evaluated for inhibitory activities against Alr from various bacterial species, as well as in growth inhibition assays.…”

Section: Formation Of D-ala -D-alamentioning

confidence: 99%

Cytoplasmic steps of peptidoglycan biosynthesis

et al. 2008

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The biosynthesis of bacterial cell wall peptidoglycan is a complex process that involves enzyme reactions that take place in the cytoplasm (synthesis of the nucleotide precursors) and on the inner side (synthesis of lipid-linked intermediates) and outer side (polymerization reactions) of the cytoplasmic membrane. This review deals with the cytoplasmic steps of peptidoglycan biosynthesis, which can be divided into four sets of reactions that lead to the syntheses of (1) UDP-N-acetylglucosamine from fructose 6-phosphate, (2) UDP-N-acetylmuramic acid from UDP-N-acetylglucosamine, (3) UDP-N-acetylmuramyl-pentapeptide from UDP-N-acetylmuramic acid and (4) D-glutamic acid and dipeptide D-alanyl-D-alanine. Recent data concerning the different enzymes involved are presented. Moreover, special attention is given to (1) the chemical and enzymatic synthesis of the nucleotide precursor substrates that are not commercially available and (2) the search for specific inhibitors that could act as antibacterial compounds.

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“…1 Several older drugs are being explored for analogs using TB-specific assays. An NCDDG group has been exploring D-cycloserine whose molecular target is alanine racemase [47][48][49]. The molecular structure of hinge area over the active site in M. tuberculosis differs from that of other bacteria and to date no new inhibitors have been identified.…”

Section: Explorations Of Existing Drugsmentioning

confidence: 98%

New Tuberculosis Drugs in Development

Laughon¹

2007

CTMC

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Over the past 50 years, no new drug classes have been introduced to treat tuberculosis. Tuberculosis (TB) kills nearly two million people a year mainly in the poorest communities in the developing world. It afflicts millions more. About one third of the world's population is silently infected with TB that may erupt into disease with increased age or suppression of the immune system. Nearly nine million new active cases develop every year. The World Health Organization (WHO) declared the disease a global emergency as long ago as 1993. Although huge efforts in public health control have reduced the disease burden within most established market economies, in Africa and Asia the epidemic continues to accelerate, particularly fueled by the HIV epidemic. Furthermore, resistance to the standard drugs isoniazid and rifampicin is increasing worldwide. Since the 1990s, mycobacteria have emerged with resistance patterns rendering all currently available antibiotics ineffectual. The pharmaceutical industry has mostly abandoned TB drug development due to perceived non-profitable consumer market and the diminishing number of companies engaged in anti-infective research. The public sector and infectious disease researchers have responded to advance fundamental science and to create new chemical entities as early drug candidates. With support from research funding agencies, philanthropic donors, and the STOP-TB Partnership, new chemical tools and new approaches to effectively implement TB control programs are evolving. Advanced preclinical development and strategies for Phase III clinical trials remain gap areas that will require additional engagement from all sectors.

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N(2)-Substituted D,L-Cycloserine Derivatives: Synthesis and Evaluation as Alanine Racemase Inhibitors.

Cited by 23 publications

References 18 publications

Inhibitors of alanine racemase enzyme: a review

Inhibitors of alanine racemase enzyme: a review

Cytoplasmic steps of peptidoglycan biosynthesis

New Tuberculosis Drugs in Development

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