title: Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: part 1.
abstract: A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch, 7701 Cape Town, South Africa.
authors.forename: Claire
authors.initials: C
authors.lastname: Le Manach
authors.forename: Diego
authors.initials: D
authors.lastname: Gonzàlez Cabrera
authors.forename: Frederic
authors.initials: F
authors.lastname: Douelle
authors.forename: Aloysius T
authors.initials: AT
authors.lastname: Nchinda
authors.forename: Yassir
authors.initials: Y
authors.lastname: Younis
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Corinne
authors.initials: C
authors.lastname: March
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Witty
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D015195:Drug Design; D004351:Drug Resistance; D004355:Drug Stability; D015723:Gene Library; D006207:Half-Life; D057166:High-Throughput Screening Assays; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000523:psychology; D051379:Mice; D016513:Mice, SCID; D021261:Parasitic Sensitivity Tests; D010961:Plasmodium / Q000187:drug effects*; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C000588586:6-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)imidazo(1,2-b)pyridazine; D000962:Antimalarials; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011494:Protein Kinases