SELECTIVE INHIBITORS OF HUMAN LACTATE-DEHYDROGENASES AND LACTATE-DEHYDROGENASE FROM THE MALARIAL PARASITE PLASMODIUM-FALCIPARUM

Derivatives of the sesquiterpene 8-deoxyhemigossylic acid 3-dihydroxy- 6-methyl-4-(1-methylethyl)-1-naphthoic acid) were synthesized that con tained altered alkyl groups in the 4-position and contained alkyl or a ralkyl groups in the 7-position. These substituted dihydroxynaphthoic acids are selective inhibitors of human lactate dehydrogenase-H (LDHH) and LDH-M and of lactate dehydrogenase from the malarial parasite Pla smodium falciparum (pLDH). All inhibitors are competitive with the bin ding of NADH. Selectivity for LDH-H, LDH-M, or pLDH is strongly depend ent upon the groups that are in the 4- and 7-positions of the dihydrox ynaphthoic acid backbone. Dissociation constants as low as 50 nM were observed, with selectivity as high as 400-fold.