Synthesis of Tetracyclic Spirooxindolepyrrolidine-Engrafted Hydantoin Scaffolds: Crystallographic Analysis, Molecular Docking Studies and Evaluation of Their Antimicrobial, Anti-Inflammatory and Analgesic Activities

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out

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

International audienceIn 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