title: Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2).
abstract: Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Suet C
authors.initials: SC
authors.lastname: Leung
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbons
authors.forename: Richard
authors.initials: R
authors.lastname: Amewu
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Nixon
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Pidathala
authors.forename: W David
authors.initials: WD
authors.lastname: Hong
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Pacorel
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; D053626:Atovaquone / Q000494:pharmacology; D018360:Crystallography, X-Ray; D045303:Cytochromes b / Q000235:genetics; D015195:Drug Design; D004351:Drug Resistance; D006801:Humans; 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* / Q000235:genetics; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011725:Pyridines; D015363:Quinolones; C573284:SL-2-25; D045303:Cytochromes b; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D053626:Atovaquone