9- and 11-substituted 4-azapaullones are potent and selective inhibitors of African trypanosoma

• 4-Azapaullones with α,β-unsaturated carbonyl side chains were synthesized.
• Some derivatives inhibited Trypanosoma brucei brucei parasites in submicromolar concentrations.
• Trypanothione synthetase was eliminated as intracellular target.

Trypanosomes from the “brucei” complex are pathogenic parasites endemic in sub-Saharan Africa and causative agents of severe diseases in humans and livestock. In order to identify new antitrypanosomal chemotypes against African trypanosomes, 4-azapaullones carrying α,β-unsaturated carbonyl chains in 9- or 11-position were synthesized employing a procedure with a Heck reaction as key step. Among the so prepared compounds, 5a and 5e proved to be potent antiparasitic agents with antitrypanosomal activity in the submicromolar range.

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