The synthesis of Waltherione F and analogues with modifications at the 2- and 3-positions as potential antitrypanosomal agents

Chagas disease also know as American Trypanosomiasis (AT) is a tropical parasitic disease endemic in South America, is caused by Trypanosoma cruzi which is transmitted by the blood-sucking insect vectors called triatomine bugs. Quinoline alkaloids from the root extract of Waltheria indica are known to possess antitrypanosomal activity. Waltherione F 3, one of those alkaloids, was synthesised in 5 steps in 11% overall yield. A key step in the sequence utilised the Conrad-Limpach synthesis for the formation of the quinolin-4(1H)-one ring system. Our synthetic strategy was designed to enable the modification of the 2- and 3-positions of the scaffold, allowing the generation of a diverse library of analogues to support our on-going medicinal chemistry program that is looking for new agents to tackle this devastating disease.