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Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis.

ABSTRACT: The modular nature of nicotinamide adenine dinucleotide (NAD)-mimicking inosine monophsophate dehydrogenase (IMPDH) inhibitors has prompted us to investigate novel mycophenolic adenine dinucleotides (MAD) in which 1,2,3-triazole linkers were incorporated as isosteric replacements of the pyrophosphate linker. Synthesis and evaluation of these inhibitors led to identification of low nanomolar inhibitors of human IMPDH and more importantly the first potent inhibitor of IMPDH from Mycobacterium tuberculosis (mtIMPDH). Computational studies of these IMPDH enzymes helped rationalize the observed structure-activity relationships. Additionally, the first cloning, expression, purification and characterization of mtIMPDH is reported.

SUBMITTER: Chen L

PROVIDER: S-EPMC2903443 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis.

Chen Liqiang L Wilson Daniel J DJ Xu Yanli Y Aldrich Courtney C CC Felczak Krzysztof K Sham Yuk Y YY Pankiewicz Krzysztof W KW

Journal of medicinal chemistry 20100601 12

The modular nature of nicotinamide adenine dinucleotide (NAD)-mimicking inosine monophsophate dehydrogenase (IMPDH) inhibitors has prompted us to investigate novel mycophenolic adenine dinucleotides (MAD) in which 1,2,3-triazole linkers were incorporated as isosteric replacements of the pyrophosphate linker. Synthesis and evaluation of these inhibitors led to identification of low nanomolar inhibitors of human IMPDH and more importantly the first potent inhibitor of IMPDH from Mycobacterium tube ...[more]

PMID: 20491506

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