title: Lead optimization of 3-carboxyl-4(1H)-quinolones to deliver orally bioavailable antimalarials.
abstract: Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Julie A
authors.initials: JA
authors.lastname: Clark
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.forename: Anupam
authors.initials: A
authors.lastname: Pradhan
authors.forename: Lalitha
authors.initials: L
authors.lastname: Iyer
authors.forename: Anna
authors.initials: A
authors.lastname: Furimsky
authors.forename: Jason
authors.initials: J
authors.lastname: Gow
authors.forename: Toufan
authors.initials: T
authors.lastname: Parman
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.forename: Jon
authors.initials: J
authors.lastname: Mirsalis
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001682:Biological Availability; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008813:Mice, Inbred ICR; D019906:Nuclear Magnetic Resonance, Biomolecular; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000302:isolation & purification*; D011804:Quinolines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011804:Quinolines