Triazole-Linked Inhibitors of Inosine Monophosphate Dehydrogenase from Human and Mycobacterium tuberculosis

• Published in: Journal of medicinal chemistry 2010-06, Vol.53 (12), p.4768-4778
• Main Authors: Chen, Liqiang, Wilson, Daniel J, Xu, Yanli, Aldrich, Courtney C, Felczak, Krzysztof, Sham, Yuk Y, Pankiewicz, Krzysztof W
• Format: Article
• Language: English
• Subjects: Adenine Nucleotides - chemical synthesis; Adenine Nucleotides - chemistry; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Cloning, Molecular; Crystallography, X-Ray; Humans; IMP Dehydrogenase - antagonists & inhibitors; IMP Dehydrogenase - genetics; IMP Dehydrogenase - isolation & purification; Kinetics; Models, Molecular; Mycobacterium tuberculosis - enzymology; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - chemical synthesis; Mycophenolic Acid - chemistry; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100424m

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.