ICI 56,780 Optimization: Structure–Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity

Abstract

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.

Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure–Activity and Structure–Property Relationship Studies

“…Encouragingly, the piperazinyl-4(l H )-quinolones were much more soluble (average solubility ≥50 μ M) than the previously described phenoxyethoxy-4(l H )-quinolones (average solubility ≤5 μ M) or 3-phenyl-susbstituted analogues (average solubility ≤5 μ M). 17 As expected, the solubility of all compounds was affected by pH, with better solubility under more acidic conditions.…”

“…These results clearly underscore the significant advantages the piperazinyl-substituted 4(1 H )-quinolones have over the previously reported 4(l H )-quinolone esters. 17…”

“…In vivo antimalarial activity against blood stage parasites was determined as previously reported. 9,17,37 We used a “modified Thompson model”, in which infections were established by an intraperitoneal inoculation of 2 × 10 6 P. berghei (GFP)-infected red blood cells. By day 3, the first day of drug treatment, parasitemia typically reached 1% (i.e., 1% of the RBC will be parasitized).…”

“…Lead compound 3-bromo-6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1 H )-one ( 2 , Figure 1) addressed atovaquone cross resistance concerns over 1 by lowering the resistance index (RI) to 4.7 and exemplified a potent liver stage activity of 2.12 nM. 17 It further exemplified the need to not only improve potency but also optimize aqueous solubility. Therefore, the main objective for the next optimization phase focused on the design and synthesis of a series of 6- and 7- substituted 4(1 H )-quinolones with enhanced aqueous solubility without compromising blood and liver stage activity.…”

Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of uniquely functionalized pyrroles and quinolones

“…Ciprofloxacin 5 (3, Fig. 1) is one of the more important quinolone anti-infective drugs on the commercial market while Endochin 6 (4, Fig. 1) exhibits significant anti-malarial properties.…”