title: N-aryl-2-aminobenzimidazoles: novel, efficacious, antimalarial lead compounds.
abstract: From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biosciences, and §DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Shahul
authors.initials: S
authors.lastname: Hameed P
authors.forename: Abhishek
authors.initials: A
authors.lastname: Srivastava
authors.forename: Gajanan
authors.initials: G
authors.lastname: Shanbhag
authors.forename: Sapna
authors.initials: S
authors.lastname: Morayya
authors.forename: Nikhil
authors.initials: N
authors.lastname: Rautela
authors.forename: Disha
authors.initials: D
authors.lastname: Awasthy
authors.forename: Stefan
authors.initials: S
authors.lastname: Kavanagh
authors.forename: Sowmya
authors.initials: S
authors.lastname: Bharath
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.forename: K R
authors.initials: KR
authors.lastname: Prabhakar
authors.forename: Ramanatha
authors.initials: R
authors.lastname: Saralaya
authors.forename: Robert
authors.initials: R
authors.lastname: Nanduri
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.forename: Sreenivasaiah
authors.initials: S
authors.lastname: Menasinakai
authors.forename: Vijayashree
authors.initials: V
authors.lastname: Achar
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.forename: María Santos
authors.initials: MS
authors.lastname: Martínez
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: Laura María
authors.initials: LM
authors.lastname: Sanz
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo
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: Marcus C S
authors.initials: MC
authors.lastname: Lee
authors.forename: Olivia
authors.initials: O
authors.lastname: Coburn-Flynn
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Iyer
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.forename: Vinayak
authors.initials: V
authors.lastname: Hosagrahara
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
mesh_terms: D000631:Aminopyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000401:mortality; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C000594999:6-(1-methylpiperidin-4-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)-1H-benzo(d)imidazol-2-amine; D000631:Aminopyridines; D000962:Antimalarials; D001562:Benzimidazoles