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The human African trypanosomiasis is a devastating parasitic infection, which is caused by the protozoan Trypanosoma brucei and transmitted by the bite of the tsetse fly. An untreated infection usually results in death and only few drugs with significant drawbacks are currently available for treatment. Previous investigations revealed the quinolone amide MB007 as a lead compound with an excellent selectivity for T. b. brucei. Here, new quinolone amides were synthesized for deeper insights into the structure-activity relationship. Furthermore, the aqueous solubility of the compounds was analyzed, as the poor solubility of previous quinolone amides impeded in vivo studies for target identification. The biological evaluation led to the new lead structure 9f, which exhibits a promising in vitro activity against T. b. brucei (IC50 = 22 nM) and showed no cytotoxicity against macrophages. Moreover, compounds 10b and 10c were discovered, which possessed an improved solubility combined with a decent selectivity. Copyright © 2023 Elsevier Masson SAS. All rights reserved.


Joshua Weinmann, Lukas Kirchner, Markus Engstler, Lorenz Meinel, Ulrike Holzgrabe. Design, synthesis and biological evaluations of quinolone amides against African trypanosomiasis with improved solubility. European journal of medicinal chemistry. 2023 Mar 15;250:115176

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PMID: 36805945

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