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

Abstract

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 (EC = 0.55 ± 0.09 mM) was the most potent antioxidant as compared to the standard drug (EC = 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 (GI = 46.2 ± 1.2 μM) appeared to be more active than compound 3a (GI = 200 ± 2.8 μM) and 3b (GI = 1400 ± 7.8 μM). Interestingly, all tested compounds displayed a good α-amylase inhibitory activity in competitive manner with IC values ranging between 23.7 and 64.35 μM when compared to the standard drug acarbose (IC = 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.

Multifunctional isoxazolidine derivatives as α-amylase and α-glucosidase inhibitors

“…We can see that the rings are positioned in two different subpockets that embrace the complete PPA catalytic site. We think that the added benzaldehyde group in this compound contribute to the stabilization of the ligand by its orientation since they fit very well in the pocket facing the solvent and add stabilization to the binding energy found in the rings inside PPA catalytic site [22]. In summary, the more favorable predicted binding energy of the conformation 3g, suggest that this conformation was probably the actual binding modes of this compound.…”

“…[26] ADT was used to select a docking grid, the parameters for X, Y, Z grid center coordinates were 34.0, 20.0, and 53.3, respectively; and the parameters for the X,Y,Z grid dimensions were 30 by 30 by 30 Å. [22] The structures of compounds 3a-i were minimized using a conjugate gradient AMMP incorporated in VEGA ZZ. [27] The conversion of the file from PDB to PDBQT was done using ADT.…”

“…Inhibition assay for α-amylase activity All compounds were screened for their inhibitory potential against PAA (EC 3.2.1.1) and HPA (EC 3.2.1.1) using the same protocol as described in the literature [22] with slight modification.…”

Synthesis and Antitumor Evaluation of Menthone-Derived Pyrimidine-Urea Compounds as Potential PI3K/Akt/mTOR Signaling Pathway Inhibitor

“…It can also be conveniently prepared by oxidation of L- menthol, which is the dominant component of peppermint essential oil. L - menthone and its derivatives have been reported to have a wide range of biological activities, such as antiviral ( He et al, 2013 ), anti-inflammatory ( Sun et al, 2014 ), antidepressant ( Xue et al, 2015 ), antifungal ( Boni et al, 2016 ), and anticancer activities ( Bhalla et al, 2013 ; Chen et al, 2014 ; Mosbah et al, 2018 ; Qi et al, 2018 ). Herein, L - menthone has received growing interest from medicinal chemists due to their wide range of biological activities.…”

Synthesis of novel isoxazoline and isoxazolidine derivatives: carboxylic acids and delta bicyclic lactones via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles

“…Isoxazoline [1][2][3][4][5][6] and isoxazolidine [7][8][9][10][11] compounds represent an important class of five-membered heterocycles with contiguous nitrogen and oxygen atoms which have attracted significant attention, mainly due to their broad range of biological activities and potential application in the pharmaceutical industry. They are considered as privileged scaffolds in drug design and synthesis.…”