title: Selective inhibitors of human lactate dehydrogenases and lactate dehydrogenase from the malarial parasite Plasmodium falciparum.
abstract: Derivatives of the sesquiterpene 8-deoxyhemigossylic acid (2, 3-dihydroxy-6-methyl-4-(1-methylethyl)-1-naphthoic acid) were synthesized that contained altered alkyl groups in the 4-position and contained alkyl or aralkyl groups in the 7-position. These substituted dihydroxynaphthoic acids are selective inhibitors of human lactate dehydrogenase-H (LDH-H) and LDH-M and of lactate dehydrogenase from the malarial parasite Plasmodium falciparum (pLDH). All inhibitors are competitive with the binding of NADH. Selectivity for LDH-H, LDH-M, or pLDH is strongly dependent upon the groups that are in the 4- and 7-positions of the dihydroxynaphthoic acid backbone. Dissociation constants as low as 50 nM were observed, with selectivity as high as 400-fold.
authors.affiliation: Departments of Chemistry and of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131.
authors.forename: L M
authors.initials: LM
authors.lastname: Deck
authors.forename: R E
authors.initials: RE
authors.lastname: Royer
authors.forename: B B
authors.initials: BB
authors.lastname: Chamblee
authors.forename: V M
authors.initials: VM
authors.lastname: Hernandez
authors.forename: R R
authors.initials: RR
authors.lastname: Malone
authors.forename: J E
authors.initials: JE
authors.lastname: Torres
authors.forename: L A
authors.initials: LA
authors.lastname: Hunsaker
authors.forename: R C
authors.initials: RC
authors.lastname: Piper
authors.forename: M T
authors.initials: MT
authors.lastname: Makler
authors.forename: D L
authors.initials: DL
authors.lastname: Vander Jagt
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors*; D019344:Lactic Acid / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000201:enzymology*; D019289:Pyruvic Acid / Q000378:metabolism; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: C114815:8-deoxyhemigossylic acid; D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; D009243:NAD; D019344:Lactic Acid; D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase