title: Antimalarial pyrido[1,2-a]benzimidazoles.
abstract: A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Ndakala
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gessner
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Gitari
authors.forename: Natasha
authors.initials: N
authors.lastname: October
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Alan
authors.initials: A
authors.lastname: Hudson
authors.forename: Foluke
authors.initials: F
authors.lastname: Fakorede
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Clive
authors.initials: C
authors.lastname: Yeates
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007739:L Cells; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001562:Benzimidazoles; D011725:Pyridines