title: Identification, design and biological evaluation of bisaryl quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2).
abstract: A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress.
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Pidathala
authors.forename: Richard
authors.initials: R
authors.lastname: Amewu
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Pacorel
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Nixon
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbons
authors.forename: W David
authors.initials: WD
authors.lastname: Hong
authors.forename: Suet C
authors.initials: SC
authors.lastname: Leung
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stocks
authors.forename: Abhishek
authors.initials: A
authors.lastname: Srivastava
authors.forename: Alison E
authors.initials: AE
authors.lastname: Shone
authors.forename: Sitthivut
authors.initials: S
authors.lastname: Charoensutthivarakul
authors.forename: Lee
authors.initials: L
authors.lastname: Taylor
authors.forename: Olivier
authors.initials: O
authors.lastname: Berger
authors.forename: Alison
authors.initials: A
authors.lastname: Mbekeani
authors.forename: Alasdair
authors.initials: A
authors.lastname: Hill
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Fisher
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Warman
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C573283:7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one; D000962:Antimalarials; D015363:Quinolones; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D014450:Electron Transport Complex III