Targeting GAPDH with small molecule inhibitors: 2-phenoxynaphthoquinones as lead candidates for Trypanosomatid diseases

Trypanosomatid diseases cause severe socioeconomic impact and a high medical cost worldwide. Despite this, they have not historically received much attention in terms of drug discovery investment and research effort. In very recent years, thanks to the appearance of new funding sources and non-profit product development partnerships, the drug pipeline has been restarted and several drug development projects have been advanced. Trypanosoma and Leishmania parasites, which are responsible for these diseases, have a fascinating biology, and many potential biochemical targets are now apparent. In the search for new drugs, metabolic peculiarities in the Trypanosomatid family guided drug discovery. At present, the majority of approaches are directed to the glycolithic pathway due to he fact that the bloodstream form of parasites rely on glycolysis as a sole source of energy supply and to its unusual compartmentalization in the glycosomes. In particular, the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays a crucial role in the control of the parasite’s glycolytic flux and represents an attractive molecular target. Thus, inhibitors of GAPDH are a main area of drug discovery complicated by the need to exhibit minimal affinity for the human enzyme. As part of a project aimed at the design of small molecules for inhibiting Trypanosoma brucei GAPDH. 2-phenoxynaphthoquinone analogues were synthesized and tested to establish structure-activity relationships. Interestingly, by replacing the phenoxy group, the intrinsic reactivity towards protein thiols is abrogated, while at the same time the formation of a covalent adduct is eliminated.