Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase.
A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium falciparum. Brequinar was essentially inactive against PfDHODH (IC(50) 880 microM) whereas several members of the series inhibited PfDHODH. Unexpectedly, replacement of the carboxylic acid required for brequinar to inhibit hDHODH was not essential in the diisopropylamides that inhibited PfDHODH.
Boa
Andrew N
AN
Department of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, UK. a.n.boa@hull.ac.uk
Canavan
Shane P
SP
Hirst
Paul R
PR
Ramsey
Christopher
C
Stead
Andrew M W
AM
McConkey
Glenn A
GA
D000478:Alkylation; D000586:Amination; D000818:Animals; D016227:Benzoquinones / Q000737:chemistry; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000469:parasitology*; D008745:Methylation; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D011798:Quinaldines
D016227:Benzoquinones; D001713:Biphenyl Compounds; D002264:Carboxylic Acids; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; C029322:phenylbenzoquinone; C046943:brequinar; D011798:Quinaldines