ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity
| Autor: | Roman Manetsch, Paul Willis, Debora Casandra, James Giarrusso, Dennis E. Kyle, Alexis N. LaCrue, Cynthia L. Lichorowic, Jeremy N. Burrows, Jordany R. Maignan, Tina S. Mutka, Lynn D. Blake |
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| Rok vydání: | 2016 |
| Předmět: |
Plasmodium berghei
Pharmacology Biology Quinolones 010402 general chemistry 01 natural sciences Article Antimalarials Mice Structure-Activity Relationship Parasitic Sensitivity Tests In vivo Drug Discovery medicine Structure–activity relationship Animals Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Drug candidate medicine.disease biology.organism_classification 0104 chemical sciences Molecular Medicine Malaria Atovaquone medicine.drug |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 |
| Popis: | Malaria is estimated to have caused 584,000 deaths and 198 million cases of the disease globally in 2013. Though mortality rates are down 47% globally since 2000 and significant progress has been made in the quest for eradication, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials which 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 schizontocidal activity against P. berghei. Rapid induction of parasite resistance in rodent malaria models however, stalled its further development. We have completed a full structure-activity relationship study on ICI 56,780 focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B. The optimization work focusing primarily on the 3-, 6-, and 7-positions of the 4(1H)-quinolone core. The best compound 16c, a 3-bromo-substituted 4(1H)-quinolone, was found to possess low nanomolar EC(50) values against the blood stages of the P. falciparum strains W2 and TM90-C2B, as well as low digit nanomolar inhibitory constant against P. berghei liver stages. Furthermore, this bromo compound 16c was also shown in an in vivo efficacy study to reduce the parasitemia by 61 % on day 6 post-exposure, whereas the original 4(1H)-quinolone displayed no inhibition. |
| Databáze: | OpenAIRE |
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