title: Endochin optimization: structure-activity and structure-property relationship studies of 3-substituted 2-methyl-4(1H)-quinolones with antimalarial activity.
abstract: Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC(50) against erythrocytic stages of multidrug resistant W2 and TM90-C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC(50) in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone.
authors.affiliation: Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, Florida 33620, USA.
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Cross
authors.forename: Andrii
authors.initials: A
authors.lastname: Monastyrskyi
authors.forename: Tina S
authors.initials: TS
authors.lastname: Mutka
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: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053626:Atovaquone / Q000494:pharmacology; D004351:Drug Resistance; D004355:Drug Stability; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D006912:Hydroxyquinolines; D015363:Quinolones; D053626:Atovaquone