title: Synthesis and biological evaluation of nonionic substrate mimics of UDP-Galp as candidate inhibitors of UDP galactopyranose mutase (UGM).
abstract: The synthesis of 1-[5-O-(α-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione and 1-[(5-O-(β-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione as non-ionic substrate mimics of UDP-Galp are described. UDP-Galp is a precursor of Galf, which is a primary component of the cell-wall glycans of several microorganisms. The interconversion of UDP-Galp and UDP-Galf is catalyzed by UDP galactopyranose mutase (UGM); its inhibition comprises a mode of compromising the microorganisms. The nonionic polyhydroxylated chain was intended to mimic the ionic pyrophosphate group and the ribose moiety in UDP-Galp and increase the bioavailabilities of the candidate inhibitors. Inhibition assays with UGM of Mycobacterium tuberculosis showed only weak inhibition of the enzyme by these compounds.
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kuppala
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Borrelli
authors.affiliation: Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Slowski
authors.affiliation: Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
authors.forename: David A R
authors.initials: DA
authors.lastname: Sanders
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: K P
authors.initials: KP
authors.lastname: Ravindranathan Kartha
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada. Electronic address: bpinto@sfu.ca.
authors.forename: B Mario
authors.initials: BM
authors.lastname: Pinto
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005690:Galactose / Q000378:metabolism*; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008968:Molecular Conformation; D009005:Monosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D013329:Structure-Activity Relationship; D014530:Uridine Diphosphate / Q000378:metabolism*
chemical_list: C000605011:1-(5-O-(alpha-D-galactopyranosyl)-D-glucityl)pyrimidine-2,4(3H)-dione; D004791:Enzyme Inhibitors; D009005:Monosaccharides; D014530:Uridine Diphosphate; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase; D005690:Galactose
keywords: Galactofuranose; Mycobacterium tuberculosis; Nonionic UGM inhibitors; UDP-Galf; UDP-Galp; UDP-galactopyranose mutase (UGM)