title: Aminoazabenzimidazoles, a novel class of orally active antimalarial agents.
abstract: Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biosciences, and §Drug Metabolism and Pharmacokinetics (DMPK) and Animal Sciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Shahul
authors.initials: S
authors.lastname: Hameed P
authors.forename: Murugan
authors.initials: M
authors.lastname: Chinnapattu
authors.forename: Gajanan
authors.initials: G
authors.lastname: Shanbag
authors.forename: Praveena
authors.initials: P
authors.lastname: Manjrekar
authors.forename: Krishna
authors.initials: K
authors.lastname: Koushik
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.forename: Vikas
authors.initials: V
authors.lastname: Patil
authors.forename: Sandesh
authors.initials: S
authors.lastname: Jatheendranath
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Rudrapatna
authors.forename: Shubhada P
authors.initials: SP
authors.lastname: Barde
authors.forename: Nikhil
authors.initials: N
authors.lastname: Rautela
authors.forename: Disha
authors.initials: D
authors.lastname: Awasthy
authors.forename: Sapna
authors.initials: S
authors.lastname: Morayya
authors.forename: Chandan
authors.initials: C
authors.lastname: Narayan
authors.forename: Stefan
authors.initials: S
authors.lastname: Kavanagh
authors.forename: Ramanatha
authors.initials: R
authors.lastname: Saralaya
authors.forename: Sowmya
authors.initials: S
authors.lastname: Bharath
authors.forename: Pavithra
authors.initials: P
authors.lastname: Viswanath
authors.forename: Kakoli
authors.initials: K
authors.lastname: Mukherjee
authors.forename: Balachandra
authors.initials: B
authors.lastname: Bandodkar
authors.forename: Abhishek
authors.initials: A
authors.lastname: Srivastava
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.forename: Jitender
authors.initials: J
authors.lastname: Reddy
authors.forename: K R
authors.initials: KR
authors.lastname: Prabhakar
authors.forename: Achyut
authors.initials: A
authors.lastname: Sinha
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: Pamela A
authors.initials: PA
authors.lastname: Magistrado
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Lukens
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
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
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Ramachandran
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001562:Benzimidazoles; D054852:Small Molecule Libraries