title: Synthesis and structure-activity relationships of antimalarial 4-oxo-3-carboxyl quinolones.
abstract: Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, United States.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.forename: Martina
authors.initials: M
authors.lastname: Sigal
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Solomon
authors.initials: S
authors.lastname: Nwaka
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D015767:Mefloquine / Q000494:pharmacology; D008567:Membranes, Artificial; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D007202:Indicators and Reagents; D008567:Membranes, Artificial; D015363:Quinolones; D015767:Mefloquine