title: Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores.
abstract: A series of novel keto-enamine chalcone-chloroquine based hybrids were synthesized following new methodology developed in our laboratory. The synthesized compounds were screened against chloroquine sensitive strain (3D7) of Plasmodium falciparum in an in vitro model. Some of the compounds were showing comparable antimalarial activity at par with chloroquine. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii (chloroquine resistant N-67 strain), wherein compounds 25 and 27 each showed an in vivo suppression of 99.9% parasitaemia on day 4. Biochemical studies reveal that inhibition of hemozoin formation is the primary mechanism of action of these analogues.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, India. kv_sashidhara@cdri.res.in
authors.forename: Koneni V
authors.initials: KV
authors.lastname: Sashidhara
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Ram K
authors.initials: RK
authors.lastname: Modukuri
authors.forename: Rajeev Kumar
authors.initials: RK
authors.lastname: Srivastava
authors.forename: Awakash
authors.initials: A
authors.lastname: Soni
authors.forename: Kumkum
authors.initials: K
authors.lastname: Srivastava
authors.forename: Shiv Vardan
authors.initials: SV
authors.lastname: Singh
authors.forename: J K
authors.initials: JK
authors.lastname: Saxena
authors.forename: Harsh M
authors.initials: HM
authors.lastname: Gauniyal
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Puri
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry*; D002460:Cell Line; D002599:Chalcone / Q000737:chemistry*; D002522:Chlorocebus aethiops; D002738:Chloroquine / Q000737:chemistry*; D002739:Chloroquinolinols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D053138:Cyclohexenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance; D007093:Imidazoles / Q000737:chemistry*; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects*; D010967:Plasmodium yoelii / Q000187:drug effects*; D014709:Vero Cells
chemical_list: C574184:(E)-2-tert-butyl-6-((2-(7-chloroquinolin-4-ylamino)ethylamino)methylene)-4-((E)-3-(4-fluorophenyl)-3-oxoprop-1-enyl)cyclohexa-2,4-dienone; C574183:(E)-4-((E)-3-(4-bromophenyl)-3-oxoprop-1-enyl)-2-tert-butyl-6-((2-(7-chloroquinolin-4-ylamino)ethylamino)methylene)cyclohexa-2,4-dienone; D000962:Antimalarials; D001713:Biphenyl Compounds; D002739:Chloroquinolinols; D053138:Cyclohexenes; D007093:Imidazoles; D002599:Chalcone; D002738:Chloroquine