A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

Ríos‐Gutiérrez, Mar; Barakat, Assem; Domingo, Luís R.

doi:10.3390/org3020010

Cited by 16 publications

(19 citation statements)

References 57 publications

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“…The chemical architecture was assigned based on a number of spectrophotometric tools including 1 HNMR, and 13 CNMR spectral analysis. The stereochemical and regio-specific outcomes of the 32CA reactions were confirmed by HNMR and X-ray single diffraction analysis for the compound 4m which has been published in our reported article [ 47 , 48 ].…”

Section: Resultssupporting

confidence: 64%

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies

Barakat

Mostafa

Ali

et al. 2022

IJMS

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The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC50 values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC50 against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC50 values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC50 = 3.275 µM and half maximal cytotoxic-concentration CC50 = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol.

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Section: Resultssupporting

confidence: 64%

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies

Barakat

Mostafa

Ali

et al. 2022

IJMS

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“…The chemical architecture was assigned, based on single-crystal X-ray-diffraction analysis and a set of spectroscopic tools, including NMR and IR spectra. The plausible mechanism is depicted in Scheme 2, based on the previously reported literatures [33][34][35][36][37][38][39].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Structure Elucidation of Novel Spirooxindole Linked to Ferrocene and Triazole Systems via [3 + 2] Cycloaddition Reaction

et al. 2022

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In the present work, a novel heterocyclic hybrid of a spirooxindole system was synthesized via the attachment of ferrocene and triazole motifs into an azomethine ylide by [3 + 2] cycloaddition reaction protocol. The X-ray structure of the heterocyclic hybrid (1’’R,2’’S,3R)-2’’-(1-(3-chloro-4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carbonyl)-5-methyl-1’’-(ferrocin-2-yl)-1’’,2’’,5’’,6’’,7’’,7a’’-hexahydrospiro[indoline-3,3’’-pyrrolizin]-2-one revealed very well the expected structure, by using different analytical tools (FTIR and NMR spectroscopy). It crystallized in the triclinic-crystal system and the P-1-space group. The unit cell parameters are a = 9.1442(2) Å, b = 12.0872(3) Å, c = 14.1223(4) Å, α = 102.1700(10)°, β = 97.4190(10)°, γ = 99.1600(10)°, and V = 1484.81(7) Å3. There are two molecules per unit cell and one formula unit per asymmetric unit. Hirshfeld analysis was used to study the molecular packing of the heterocyclic hybrid. H···H (50.8%), H···C (14.2%), Cl···H (8.9%), O···H (7.3%), and N···H (5.1%) are the most dominant intermolecular contacts in the crystal structure. O···H, N···H, H···C, F···H, F···C, and O···O are the only contacts that have the characteristic features of short and significant interactions. AIM study indicated predominant covalent characters for the Fe–C interactions. Also, the electron density (ρ(r)) at the bond critical point correlated inversely with the Fe–C distances.

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“…Other spectrophotometric tools were employed to prove the chemical structure. The plausible mechanism is depicted in Scheme based on the previous reported literature. − …”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Cytotoxicity of New Spirooxindoles Engrafted Furan Structural Motif as a Potential Anticancer Agent

et al. 2022

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A new series of spirooxindoles based on ethylene derivatives having furan aryl moiety are reported. The new hybrids were achieved via [3 + 2] cycloaddition reaction as an economic one-step efficient approach. The final constructed spirooxindoles have four contiguous asymmetric carbon centers. The structure of 3a is exclusively confirmed using X-ray single crystal diffraction. The supramolecular structure of 3a is controlled by O···H, H···H, and C···C intermolecular contacts. It includes layered molecules interconnected weak C–H···O (2.675 Å), H···H (2.269 Å), and relatively short Cl···Br interhalogen interactions [3.4500(11)Å]. Using Hirshfeld analysis, the percentages of these intermolecular contacts are 10.6, 25.7, 6.4, and 6.2%, respectively. The spirooxindoles along with ethylene derivatives having furan aryl moiety were assessed against breast (MCF7) and liver (HepG2) cancer cell lines. The results indicated that the new chalcone 3b showed excellent activity in both cell lines (MCF7 and HepG2) with IC50 = 4.1 ± 0.10 μM/mL (MCF7) and 3.5 ± 0.07 μM/mL (HepG2) compared to staurosporine with 4.3 and 2.92 folds. Spirooxindoles 6d (IC50 = 4.3 ± 0.18 μM/mL), 6f (IC50 = 10.3 ± 0.40 μM/mL), 6i (IC50 = 10.7 ± 0.38 μM/mL), and 6j (IC50 = 4.7 ± 0.18 μM/mL) exhibited potential activity against breast adenocarcinoma, while compounds 6d (IC50 = 6.9 ± 0.23 μM/mL) and 6f (IC50 = 3.5 ± 0.11 μM/mL) were the most active hybrids against human liver cancer cell line (HepG2) compared to staurosporine [IC50 = 17.8 ± 0.50 μM/mL (MCF7) and 10.3 ± 0.23 μM/mL (HepG2)]. Molecular docking study exhibited the virtual mechanism of binding of compound 3b as a dual inhibitor of EGFR/CDK-2 proteins, and this may highlight the molecular targets for its cytotoxic activity.

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A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

Cited by 16 publications

References 57 publications

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies

Synthesis and Structure Elucidation of Novel Spirooxindole Linked to Ferrocene and Triazole Systems via [3 + 2] Cycloaddition Reaction

Synthesis, Characterization, and Cytotoxicity of New Spirooxindoles Engrafted Furan Structural Motif as a Potential Anticancer Agent

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