Open AccessSynthesis, Antimalarial Activity, and Structure–Activity Relationship of 7-(2-Phenoxyethoxy)-4(1H)-quinolones
Author(s) -
R. Matthew Cross,
Niranjan K. Namelikonda,
Tina Mutka,
Lisa Luong,
Dennis E. Kyle,
Roman Manetsch
Publication year - 2011
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm200718m
Subject(s) - chemistry , quinolone , plasmodium berghei , atovaquone , structure–activity relationship , pharmacology , stereochemistry , ed50 , chemical synthesis , ec50 , malaria , plasmodium falciparum , biochemistry , in vitro , antibiotics , immunology , biology
ICI 56,780 (5) displayed causal prophylactic and blood schizonticidal activity (ED50=0.05 mg/kg) in rodent malaria models but produced rapid acquisition of parasitological resistance in P. berghei infected mice. Herein we describe the synthesis of analogues of 5 with EC50 as low as 0.15 nM against multidrug resistant P. falciparum. Optimal activity with low cross-resistance indexes (RI) to atovaquone was achieved by introducing ortho-substituted aryl moieties at the 3-position of the 7-(2-phenoxyethoxy)-4(1H)-quinolone core.