Novel Oleanolic Acid-Phtalimidines Tethered 1,2,3 Triazole Hybrids as Promising Antibacterial Agents: Design, Synthesis, In Vitro Experiments and In Silico Docking Studies

Abstract

As part of the valorization of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3β-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a–u bearing 1,2,3-triazole moieties were designed and synthesized by treating an azide 4 previously prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues, 18a–u, were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes, and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained, notably against L. monocytogenes. Compounds 18d, 18g, and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. A molecular docking study was performed to explore the binding mode of the most active derivatives into the active site of the ABC substrate-binding protein Lmo0181 from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor of the experimental data.

Design, semi-synthesis and molecular docking of new antibacterial and antibiofilm triazole conjugates from hydroxy-triterpene acids and fluoroquinolones

“…Based on all these observations and in continuation of our work on MA or OA-based hybrid compounds, 13,14 we report herein the first QN/FQNs hybrid molecules involving a triazole linker at C-2/C-3 or C-2 of isolated MA and OA, respectively. Overall, 22 conjugates were semi-synthesized and were in vitro and in silico evaluated for their antibacterial and antibiofilm activities.…”

“…Maslinic and oleanolic acids were isolated from solid waste resulting from olive oil production in Tunisia (olive pomace O. europaea L.). As previously described by our team, 14 the extraction process was carried out using a low-cost method: 4 kg of solid waste (olive pomace) was subjected to maceration in a mixture of solvent (dichloromethane/acetone: 6/4) for 48 h. After the filtration of the extract, the obtained liquid was concentrated under reduced pressure then retained in a fridge for two days and led to a precipitate that was subjected to SiO 2 column chromatography for further purification. Two purification steps led to 21 g of MA ( 1 ) and 8.5 g of OA ( 2 ) that were characterized by spectroscopic analysis such as 1D and 2D NMR, HRMS (Scheme 1).…”