Asymmetric synthesis of enantiopure tetracyclic dispirooxindolopyrrolidine-piperidones via microwave-assisted multicomponent reaction: Crystallographic analysis, antimicrobial activity and in silico studies

• Published in: Journal of molecular structure Vol. 1308; p. 138104
• Main Authors: Jelizi, Hanen, Toumi, Amani, Abdella, Faiza I.A., Daoud, Ismail, Boudriga, Sarra, Alshamari, Asma K., Alanazi, Tahani Y.A., Alrashdi, Ahlam Abdulrahman, Edziri, Hayet, Knorr, Michael, Kirchhoff, Jan-Lukas, Strohmann, Carsten
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.07.2024; Elsevier
• Subjects: 1,3-dipolar cycloaddition; Antimicrobial activity; Chemical Sciences; Microwave-assisted synthesis; Molecular docking studies; Multicomponent reaction; Piperidone; SC-XRD analysis; Spirooxindole; Spirooxindole; Antimicrobial activity; Multicomponent reaction; SC-XRD analysis; Microwave-assisted synthesis; Molecular docking studies; Piperidone; 1,3-dipolar cycloaddition; 1; spirooxindole; molecular docking studies; 3-dipolar cycloaddition; 1SC-XRD analysis; antimicrobial activity; multicomponent reaction; piperidone
• ISSN: 0022-2860; 0022-2860
• DOI: 10.1016/j.molstruc.2024.138104

•Unprecedented short time microwave-assisted asymmetric synthesis of enantiopure dispirooxindolopyrrolidine-piperidones in a one-step operation.•A series of new analogues of optically active dispirooxindolopyrrolidine-piperidones was synthesized and characterized.•Promising antimicrobial activities of the synthesized compounds.•Hirshfeld surface, drug-likeness and molecular docking studies were performed to substantiate the experimental results. In an attempt towards the development of new antimicrobials, we synthesized by microwave-assisted multicomponent reaction (MCR) of enantiopure (E,E)-3,5-bisarylidene-N-[(S)-(-)-methylbenzyl]-4-piperidones, isatin and α-amino esters a series of optically active tetracyclic dispirooxindolopyrrolidine-piperidones. The beneficial and promising features of this protocol such as simple operational procedure, short reaction time (10 min), and high product yields (up to 97 %) make it an efficient eco-friendly approach offering a powerful mean to expand the structural diversity of spirooxindoles. This approach appears hugely advantageous for high-throughput screening processes in drug discovery research. In addition, crystallographic parameters and inter- and intramolecular interactions occurring in spiropyrrolidine-fused piperidone derivative 4g were examined through single-crystal XRD analysis allowing to determine the absolute configuration of the enantiopure compound. The preliminary biological assessment of their antimicrobial activity indicates that most of the screened products display higher activity than the standard reference drugs Ampicillin and Griseofulvin. Some of them exhibited good to moderate activity against both bacteria and fungi. In addition, in silico molecular docking and predictive ADMET studies for the most active spirocompounds were carried out. Molecular docking confirmed the binding efficacy of candidates 4c and 4l through low score energy values and the establishment of diverse bonding interactions with the active site residues. Finally, the ADMET profiling of the most active spiroheterocycles proved their remarkable drug-like and pharmacokinetic properties. [Display omitted]