Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents Articles uri icon

authors

  • FERRER BAZAGA, SANTIAGO
  • HAMEED, SHAHUL P.
  • BARDE, SHUBHADA P.
  • RAUTELA, NIKHIL
  • AWASTHY, DISHA
  • MORAYYA, SAPNA
  • NARAYAN, CHANDAN
  • KAVANAGH, STEFAN
  • SARALAYA, RAMANATHA
  • BHARATH, SOWMYA
  • VISWANATH, PAVITHRA
  • MUKHERJEE, KAKOKI
  • CHINNAPATTU, MURUGAN
  • BANDODKAR, BALACHANDRA
  • SHANBAG, GAJANAN
  • MANJREKAR, PRAVEENA
  • KOUSHIK, KRISHNA
  • RAICHURKAR, ANANDKUMAR
  • PATIL, VIKAS
  • JATHEENDRANATH, SANDESH
  • RUDRAPATNA, SURESH S.

publication date

  • July 2014

start page

  • 5702

end page

  • 5713

issue

  • 13

volume

  • 57

International Standard Serial Number (ISSN)

  • 0022-2623

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

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. (copyright) 2014 American Chemical Society.

subjects

  • Biology and Biomedicine
  • Medicine

keywords

  • anatomy; antimicrobial agents; parasites; rodent models; toxicity