title: Design, synthesis, and biological evaluation of Plasmodium falciparum lactate dehydrogenase inhibitors.
abstract: Plasmodium falciparum lactate dehydrogenase (pfLDH) is a key enzyme for energy generation of malarial parasites and is a potential antimalarial chemotherapeutic target. It is known that the oxamate moiety, a pyruvate analog, alone shows higher inhibition against pfLDH than human LDHs, suggesting that it can be used for the development of selective inhibitors. Oxamic acid derivatives were designed and synthesized. Derivatives 5 and 7 demonstrated activities against pfLDH with IC50 values of 3.13 and 1.75 muM, respectively, and have 59- and 7-fold selectivity over mammalian LDH, respectively. They also have micromolar range activities against Plasmodium falciparum malate dehydrogenase (pfMDH), which may fill the role of pfLDH when the activity of pfLDH is reduced. Thus, certain members of these oxamic acid derivatives may have dual inhibitory activities against both pfLDH and pfMDH. It is presumed that dual LDH/MDH inhibitors would have enhanced potential as antimalarial drugs.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, National Center for Natural Products Research, and Department of Chemistry & Biochemistry, University of Mississippi, University, MS 38677-1848, USA.
authors.forename: Seoung-ryoung
authors.initials: SR
authors.lastname: Choi
authors.forename: Anupam
authors.initials: A
authors.lastname: Pradhan
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Hammond
authors.forename: Amar G
authors.initials: AG
authors.lastname: Chittiboyina
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002417:Cattle; D015195:Drug Design; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D010072:Oxamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000962:Antimalarials; D011994:Recombinant Proteins; D007770:L-Lactate Dehydrogenase; D008291:Malate Dehydrogenase; D010072:Oxamic Acid