Sustainable anti-trypanosomatid drugs: An aspirational goal for medicinal chemistry

Although the progress made, poverty-related trypanosomatid diseases remain an area of concern for the drug discovery community. The inadequacy of available treatments, especially in terms of low access, high toxicity and complicated administration regimens, calls for endeavors focused on sustainable principles. These should guide all involved stakeholders, including medicinal chemists. Accordingly, a strategy exploiting privileged-structures-based phenotypic libraries might be useful to identify hits in a cost- and time-effective manner. On these bases, we generated a library by fast assembling phenothiazine, biphenyl and phenylpiperazine privileged fragments via a Huisgen cycloaddition. Thanks to available screening facilities, the library was screened for activity against Trypanosoma brucei and cruzi, Leishmania infantum and donovani, for selectivity against mammalian cells, and for ADME-Tox properties. Despite the small number of synthesized compounds, this strategy led to the successful identification of interesting hits with promising profiles. Another extraordinary possibility is the development of new drugs based on food industry wastes as sustainable starting materials. Toward this aim, we developed a series of novel T. brucei hits obtained by combining a 2-phenoxy-1,4-naphthoquinone scaffold with phenolic constituents from the cashew nut shell liquid (CNSL), a by-product and a pollutant from cashew nut processing factories. We envisage that such compounds, easily obtained from a waste material produced in high quantity in the endemic countries, might be ethically, environmentally and economically sustainable starting point for the development of new anti-trypanosomatid drugs.