title: 3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs: a novel cluster of antimalarials targeting the liver stage of Plasmodium falciparum.
abstract: Drug resistance is a major challenge in antimalarial chemotherapy. In addition, a complete cure of malaria requires intervention at various stages in the development of the parasite within the host. There are only a few antimalarials that target the liver stage of the Plasmodium species which is an essential part of the life cycle of the malarial parasite. We report a series of antimalarial 3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs 1-5, a number of which exhibit potent in vitro growth-inhibiting properties towards drug-sensitive D6 and drug-resistant C235 strains of Plasmodium falciparum as well as inhibiting the liver stage development of the malarial life cycle. The compounds 2b (IC50: 165 ng/mL), 3b (IC50: 186 ng/mL), 5c (IC50: 159 ng/mL) and 5d (IC50: 93.5 ng/mL) emerged as lead molecules that inhibit liver stage Plasmodium berghei and are significantly more potent than chloroquine (IC50: >2000 ng/mL) and mefloquine (IC50: >2000 ng/mL) in this screen. All the compounds that showed potent inhibitory activity against the P. berghei liver stage were nontoxic to human HepG2 liver cells (IC50: >2000 ng/mL). The compounds 5a and 5b exhibit comparable metabolic stability as chloroquine and mefloquine in human plasma and the most potent compound 5d demonstrated suitable permeability characteristics using the MDCK monolayer. These results emphasize the value of 3,5-bis(benzylidene)-4-piperidones as novel antimalarials for further drug development.
authors.affiliation: Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. Electronic address: umashankar.das@usask.ca.
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.forename: Ravi S P
authors.initials: RS
authors.lastname: Singh
authors.forename: Jane
authors.initials: J
authors.lastname: Alcorn
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hickman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sciotti
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leed
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lee
authors.forename: Norma
authors.initials: N
authors.lastname: Roncal
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D010881:Piperidones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: C526290:3,5-bis(benzylidene)-4-piperidone; D000962:Antimalarials; D010881:Piperidones
keywords: 3,5-Bis(benzylidene)-4-piperidones; Antimalarials; Drug resistance; Permeability; Plasmodium berghei; Plasmodium falciparum; Stability