Total Synthesis of the Natural Chalcone Lophirone E, Synthetic Studies toward Benzofuran and Indole-Based Analogues, and Investigation of Anti-Leishmanial Activity

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure-activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC50 = 15.3, 27.2, 15.9 mu M, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.

Automated summary

The potential of natural and synthetic chalcones as therapeutic leads against various diseases has been explored, and they have shown interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. This study focuses on investigating the anti-leishmanial activity of natural chalcone lophirone E and its derivatives. The synthesis of lophirone E and a small set of chalcones with different substitution patterns has been described, and the compounds were evaluated for their activity against Leishmania infantum promastigotes. The study highlights the potential of this class of compounds as antiparasitic hits and suggests further investigation.