Authors

M CERONEH de-KoningM L Bolognesi³; G Ebiloma¹; E Uliassi³; L A Romeiro⁴; F Prati²;  ¹ Institute of Infection, Immunity and Inflammation, University of Glasgow;  ² School of Life Sciences University of Dundee;  ³ University of Bologna, Italy;  ⁴ University of Brasilia, Brazil;  ⁵ University of Glasgow

Discussion

In a search for new effective and low-cost drug-hybrids for Neglected Tropical Diseases, we aimed at designing and synthezing a focused combinatorial chemical library of 15 naphtoquinone-anacarcic acid hybrids to treat trypanosomiases. By following a merging strategy, the naphthoquinone scaffold derived from an in-house hit anti-trypanosomatid compound, named B6, has been combined to the natural phenols of cardanol derivatives, a renewable food production waste product from Anacardum Occidentale. In particular, B6 has been identified (i) to inhibit trypanosomal glyceraldehyde-3-phpsphate dehydrogenase (GAPDH) (IC50 of 7.25 µM); (ii) to exhibit potent trypanocidal activity (EC50 of 80 nM against T. brucei rhodesiense); (iii) to possess a promising selectivity index (SI of 74); (iv) to generate oxygen radicals in the trypanosomal mitochondrion.1 Furthermore, the anacardic acid derivatives, extracted from cashew nut shell liquid (CNSL), are endowed of many biological activities. They proved to be micromolar inhibitors (IC50 28.0 µM) of GAPDH of Trypanosoma cruzi. 2 Some of the newly synthetized compound have been preliminary tested against T. brucei GAPDH, showing an interesting inhibitory activity (micromolar range).3 Given the profile of the starting hit compounds, we decide to evaluate their mechanism of action at the mitochondrial level, as the drug design strategy is inspired to be a synergistic inhibition of energy metabolism. All compounds are designed on