Synthesis of Analogs of Waltheriones S and T and Their Activity Against Trypanosoma cruzi

Several alkaloids of the waltherione family exhibit antitrypanosomal activity in the sub-micromolar or nanomolar range. While the overwhelming majority of waltheriones are based on a quinoline core structure, two structurally simpler pyridone-based congeners, waltheriones S and T, have recently been isolated and found to inhibit Trypanosoma cruzi with single-digit micromolar potency. Here, we report on the synthesis of a series of analogs of waltheriones S and T based on pyridone ring formation via cyclization of an appropriate triketone precursor with ammonia and the assessment of their activity against Trypanosoma cruzi. The data show that the methoxy group at the C(3)-position of the pyridone ring can be removed without significant loss in potency. Further modification of 3-desmethoxy waltherione T through methoxylation at the C(1') position of the C(6)-side chain or double methoxylation at the C(1')-position and the pyridone nitrogen had no significant impact on antitrypanosomal activity. These findings contrast with the activity differences between the corresponding quinoline-based natural waltheriones M, Q, and H, where the methoxy-bearing waltheriones Q and H are one order of magnitude more potent than the unsubstituted parent compound waltherione M. Our data indicate that the SAR for monocyclic waltheriones S and T does not simply parallel that of the quinoline-based congeners and they point to the importance of a rigid quinoline core for potent activity against T. cruzi.