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Highly Facile, Regio‐ and Stereoselective Synthesis of Spiropyrrolidine‐5‐aza‐2‐oxindole Derivatives through Multicomponent 1,3‐Dipolar Cycloaddition Reaction and Their In‐Vitro and In‐Silico Biological Studies
Author(s) -
Shinoj Kumar P. P.,
Krishnaswamy G.,
Desai Nivedita R.,
Sreenivasa S.,
Aruna Kumar D. B.
Publication year - 2021
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202102118
Subject(s) - cycloaddition , chemistry , oxindole , antimycobacterial , isatin , stereochemistry , combinatorial chemistry , docking (animal) , isoxazole , stereoselectivity , organic chemistry , mycobacterium tuberculosis , pathology , catalysis , medicine , tuberculosis , nursing
Highly facile one pot synthesis of an assortment of novel spiropyrrolidine 5‐aza‐2‐oxindole derivatives via 1, 3‐di polar cycloaddition reaction has been reported. The underlying concept of Huisgen reaction was applied wherein the azomethine ylides (1,3‐dipoles), generated in‐situ from isatin‐derived compounds and cyclic / acyclic α‐amino acids through the thermal decarboxylation, reacted with exo ‐cyclic benzylidine derivatives (dipolarophiles) of 5‐aza‐2‐oxindole afforded plethora of spiropyrrolidine 5‐aza‐2‐oxindoles in excellent yield. High regio‐ and stereo selectivity were accomplished employing this methodology and optimum yield was obtained when reaction carried out under methanol reflux in presence of triethylamine. Furthermore, the compounds were tested for their in‐vitro biological potency as anti‐microbial and anti‐mycobacterial. Antibacterial screening result reveals that out of fifteen compounds four compounds emerged with moderate to reasonable activity against gram negative E. coli and P. aeruginosa . Antifungal screening resulted in identification of two compounds as moderate antifungal agents against A. niger . Antimycobacterial activity results revealed that the four compounds displayed good to moderate in‐vitro activity with MIC= 12.5 μg/mL against H37Rv strain as compared to standard pyrazinamide (MIC= 3.12 μg/mL). Additionally, molecular docking study was carried out to understand the possible binding modes of the synthesized derivatives within the active site of antibacterial (PDB ID : 3ACX), antifungal (PDB ID : 1IYL) and antimycobacterial (PDB ID : 4TZT) target proteins and were found to display good docking energies. Besides, ADMET properties of the synthesized compounds have shown drug likeness with good oral absorption and moderate BBB permeability.