Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis.
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.
Chen
Liqiang
L
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, Minnesota 55455, USA. chenx462@umn.edu
Wilson
Daniel J
DJ
Xu
Yanli
Y
Aldrich
Courtney C
CC
Felczak
Krzysztof
K
Sham
Yuk Y
YY
Pankiewicz
Krzysztof W
KW
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D007700:Kinetics; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry
D000227:Adenine Nucleotides; D000995:Antitubercular Agents; D011994:Recombinant Proteins; D014230:Triazoles; C110804:mycophenolic adenine dinucleotide; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid