Title : Targeting resistance: New 4-substituted pyrazolidine and isoxazolidine as antibiotics with interesting antimicrobial activities
Abstract:
A series of new isoxazolidine and pyrazolidine compounds were synthesized in very good yields of 76-99.2% by Michael and Aza-Michael reactions, respectively, and all compounds were characterized by 1H NMR, 13C NMR. we discovered that the pyrrolidine/benzoic acid catalyzed in Michael/Aza-Michael reactions between ?-substituted propenals such as methacrolein and 2-benzylpropenal and activated appropriate nucleophilic substrates, to afford a new 4-substituted isoxazolidin-3-olsand 4-substituted pyrazolidin-3-ols as diastereomer mixtures; subsequent oxidation with PCC affords the corresponding Isoxazolidines and Pyrazolidinones compounds in essentially quantitative yields. The use of chiral commercial catalysts allowed the synthesis of several of these compounds in optically active forms using Jørgensen-Hayashi orgnocatalysts.
The conducted screening studies of the in vitro antimicrobial activities of the new Isoxazolidine and Pyrazolidine compounds that five newly synthesized compounds show antimicrobial activities, using the disk diffusion and microdilution actions, against six bacteria: Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus and Baccillus subtillus Spizizenii; and two fungi: Candida albicans and Cryptococcus neoformans. In particular, the isoxazolidine compounds, 7d which is prepared with good yield 80%, is considered as a potential antimicrobial agent, it showed antimicrobial activity against Candida albicans with a MIC of 16 μg/mL with no toxicity and no hemolytic activities against HEK293 and human red blood cells, respectively.
In- silico investigations, we found that QSAR processing of 17 pyrazolidines compounds showed the best model for predicting their antimicrobial activities on Acinetobacter baumannii activity. Moreover, the DFT study against Isoxazolidine and Pyrazolidine, and their inclusion complexes, compounds offered a strategic framework for guiding future experimental processes to identify the potential antimicrobial candidates.
