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Biological Activities Evaluation of Enantiopure Isoxazolidine Derivatives: In Vitro, In Vivo and In Silico Studies

Mosbah, Habib, Chahdoura, Hassiba, Mannai, Asma, Snoussi, Mejdi, Aouadi, Kaïss, Abreu, Rui M. V., Bouslama, Ali, Achour, Lotfi, Selmi, Boulbaba
Applied biochemistry and biotechnology 2019 v.187 no.3 pp. 1113-1130
acarbose, active ingredients, acute toxicity, alkenes, alpha-amylase, animals, anti-infective agents, antimicrobial properties, antioxidant activity, antioxidants, bleaching, cell proliferation, computer simulation, cycloaddition reactions, cytotoxicity, death, drugs, enantiomers, enzyme inhibition, human cell lines, inhibitory concentration 50, lipid peroxidation, median effective concentration, thiobarbituric acid-reactive substances
A series of enantiopure isoxazolidines (3a–c) were synthesized by 1,3-dipolar cycloaddition between a (−)-menthone-derived nitrone and various terminal alkenes. The screened compounds were evaluated for their antioxidant activity by two in vitro antioxidant assays, including β-carotene/linoleic acid bleaching, and inhibition of lipid peroxidation (thiobarbituric acid reactive species, TBARS). The results revealed that compound 3b (EC₅₀ = 0.55 ± 0.09 mM) was the most potent antioxidant as compared to the standard drug (EC₅₀ = 2.73 ± 0.07 mM) using the TBARS assay. Furthermore, the antimicrobial activity was assessed using disc diffusion and microdilution methods. Among the synthesized compounds, 3c was found to be the most potent antimicrobial agent as compared to the standard drug. Subsequently, the acute toxicity study has also been carried out for the newly synthesized compounds and the experimental studies revealed that all compounds were safe up to 500 mg/kg and no death of animals were recorded. The cytotoxicity of these compounds was assessed by the MTT cell proliferation assay against the continuous human cell lines HeLa and compound 3c (GI₅₀ = 46.2 ± 1.2 μM) appeared to be more active than compound 3a (GI₅₀ = 200 ± 2.8 μM) and 3b (GI₅₀ = 1400 ± 7.8 μM). Interestingly, all tested compounds displayed a good α-amylase inhibitory activity in competitive manner with IC₅₀ values ranging between 23.7 and 64.35 μM when compared to the standard drug acarbose (IC₅₀ = 282.12 μM). In addition, molecular docking studies were performed to understand the possible binding and the interaction of the most active compounds to the α-amylase pocket.