Tropical neglected diseases caused by Trypanosoma and Leishmania parasites evoke significant morbidity and mortality among inhabitants of (sub-)tropical regions around the world. Currently, treatment of the accompanying diseases is limited to few, disadvantageous and often ancient chemotherapies. However, innovation remains low due to the poor investment of public and private initiatives on drug development despite a significant unmet need for new effective and safe drugs. Tetracyclic N5-substituted paullones are antiprotozoal agents acting through inhibition of a parasitic key redox enzyme, trypanothione synthetase (TryS), that has no mammalian homologue. In this work, we investigated the paullones’ benzene ring as a pharmacophore element and explored the structural requirements for TryS inhibition. To achieve this, we applied two molecular strategies: Firstly, we performed a structural simplification approach that has shown great outcomes in the optimization of polycyclic natural products. Therefore, we formally removed the paullones’ benzene ring, reducing the ring count to two. The resulting indolylacetamides possess an increased Fsp3 and more side chain flexibility than their parent compounds. Secondly, we formally opened the azepinone by disconnecting the lactam–benzene bond to obtain conformationally less restricted paullone analogues. In the course of our work, we discovered new indolylamide-based compound classes, some of which exhibited antitrypanosomal activity in the low micromolar concentration range. We were also able to determine important structural features of paullones that are required for TryS inhibition.

Structural exploration of polycyclic paullones leads to simplified antitrypanosomal indolylamides

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