Open AccessICI 56,780 Optimization: Structure–Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity
Author(s) -
Jordany R. Maignan,
Cynthia L. Lichorowic,
James Giarrusso,
Lynn D. Blake,
Debora Casandra,
Tina Mutka,
Alexis N. LaCrue,
Jeremy N. Burrows,
Paul Willis,
Dennis E. Kyle,
Roman Manetsch
Publication year - 2016
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/acs.jmedchem.6b00759
Subject(s) - chemistry , structure–activity relationship , stereochemistry , pharmacology , combinatorial chemistry , biochemistry , in vitro , medicine
Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days.