title: Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium.
abstract: The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.
authors.affiliation: Department of Chemistry, University of South Florida , CHE 205, 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Cross
authors.forename: David L
authors.initials: DL
authors.lastname: Flanigan
authors.forename: Andrii
authors.initials: A
authors.lastname: Monastyrskyi
authors.forename: Alexis N
authors.initials: AN
authors.lastname: LaCrue
authors.forename: Fabián E
authors.initials: FE
authors.lastname: Sáenz
authors.forename: Jordany R
authors.initials: JR
authors.lastname: Maignan
authors.forename: Tina S
authors.initials: TS
authors.lastname: Mutka
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: Frank R
authors.initials: FR
authors.lastname: Fronczek
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wojtas
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Guida
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D018512:Parasitemia / Q000188:drug therapy; D010961:Plasmodium / Q000187:drug effects*; D010962:Plasmodium berghei; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D015363:Quinolones