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

Abstract

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 μM, 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.

In Vitro and In Silico Evaluation of the Anti-leishmanial Activity of Novel Synthetic Chalcones

“…The anti-leishmania activity of chalcones is widely described in the literature, from which we can highlight the results obtained with: Lophirone E (Figure 1), which presented an IC50 of 15.3 μM against L. infantum promastigote forms [18]; Licochalcone A (Figure 1) was tested together with analogous molecules in in vitro assays against L. amazonensis promastigotes and amastigotes, proving to be the most active, with IC50 values of 3.88 and 36.84 μM, respectively; Licochalcone A also presented IC50 values of 12.47 and 29.58 μM against L. infantum promastigotes and amastigotes, respectively. When administered at 50 mg/kg in the in vivo study, it was able to reduce the parasite load by 43.67% and 39.81% in the liver and spleen, respectively [13]; Margherita Otalli et al (2018) [9] analyzed the anti-Leishmania potential of 31 chalcones, of which two stood out (compounds 6 and 16 -Figure 1) as being active against four Leishmania species (L. donovani, L. tropica, L. major and L. infantum).…”

Antiviral and antimicrobial applications of chalcones and their derivatives: From nature to greener synthesis

“…Accordingly, an efficient synthesis technique was suggested for the development of lophirone E as well as the synthesis of a number of chalcone derivatives with various substituents in the A and heterocyclic B rings. The resultant molecules were screened for their impact against the promastigotes of Leishmania infantum (IC 50 values of the most active compounds were reported to be 15.3, 27.2, and 15.9 μM) [ 170 ]. The antileishmanial effects of 12 benzimidazolylchalcones against promastigote strains of L. donovani were investigated using molecular docking, quantitative structure-activity relationship (QSAR) analyses, and ADME prediction models.…”

Synthetic derivatives of natural cinnamic acids as potential anti‐colorectal cancer agents

“…Natural compounds display a plethora of amazing biological properties (Carullo et al., 2022; Pozzetti et al., 2022; Spizzirri et al., 2019). Among them, phenolic, hydroxycinnamic, and benzoic acids (general structure 1 , Figure 1) have been strongly investigated, and their role in both disease prevention and therapy has been extensively demonstrated (Carullo, Ahmed, et al., 2020; Carullo et al., 2021; Carullo, Governa, et al., 2019; Carullo, Perri, et al., 2019; Heleno et al., 2015; Mazzotta et al., 2021; Spizzirri et al., 2019).…”