The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Chem.
Sec. Organic Chemistry
Volume 12 - 2024 |
doi: 10.3389/fchem.2024.1460384
Novel Spirooxindole-Triazole Derivatives: Unveiling [3+2] Cycloaddition Reactivity Through Molecular Electron Density Theory and Investigating Their Potential Cytotoxicity Against HepG2 and MDA-MB-231 Cell Lines
Provisionally accepted- 1 Prince Sultan University, Riyadh, Saudi Arabia
- 2 Alexandria University, Alexandria, Alexandria, Egypt
- 3 King Saud University, Riyadh, Riyadh, Saudi Arabia
- 4 Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, Florida, United States
- 5 Mansoura University, Mansoura, Dakahlia, Egypt
- 6 University of Valencia, Valencia, Valencian Community, Spain
- 7 King Faisal University, Al-Ahsa, Eastern Province, Saudi Arabia
A novel analogue of hybrid spirooxindoles was synthesized employing a systematic multistep synthetic approach. The synthetic protocol was designed to obtain a series of spirooxindole derivatives incorporating triazolyl-s-triazine framework via [3+2] cycloaddition (32CA) reaction of azomethine ylide (AY) with the corresponding chalcones (6a-d). Unexpectedly, the reaction underwent an alternate route, leading to the cleavage of the s-triazine moiety and yielding a series of spirooxindole derivatives incorporating a triazole motif. A comprehensive investigation of the 32CA reaction mechanism was conducted using the Molecular Electron Density Theory (MEDT). The viability of all compounds was evaluated through an MTT assay, and the IC50 values were determined using Prism Software. The antiproliferative efficacy of the synthesized chalcones and the corresponding spirooxindole derivatives was assessed against two cancer cell lines: MDA-MB-231 (late-stage breast cancer) and HepG2 (human hepatoma). These findings were compared with Sorafenib, which was used as a positive control. The results revealed that chalcones (6c and 6d) were the most active among the tested chalcones, with IC50 values of 7.2 ± 0.56 and 7.5 ± 0.281 µM for (6c) and of 11.1 ± 0.37 and 11.0 ± 0.282 µM for (6d), against MDA-MB-231 and HepG2, respectively. Spirooxindoles (9b, 9c, 9h, and 9i) exhibited the highest activity with IC50 values in the range ranging from 16.8 ± 0.37 µM to 31.3 ± 0.86 µM against MDA-MB-231 and 13.5 ± 0.92 µM to 24.2 ± 0.21 µM against HepG2. Particularly, In particular, spirooxindole derivatives incorporating 2,4dichlorophenyl moiety were the most active, with an IC50 of µM of 16.8 ± 0.37 µM for (9h) against MDA-MB-23 and 13.5 ± 0.92 µM for (9i) against HepG2. Interestingly, the IC50 of compound 6c (7.2 µM) exhibited better activity than that of Sorafenib (positive control) (9.98 µM) against MDA-MB-231. Molecular docking, ADMET, and molecular dynamic simulation explored for the promising candidates 6b, 6c, and 9h for binding affinity in the EGFR active site. Molecular docking, ADMET, and molecular dynamic simulations were conducted for the promising candidates (6b, 6c, and 9h) to explore their binding affinity in the EGFR active site.
Keywords: Spirooxindole, 32CA reactions, anticancer, Molecular electron density (MED), Cytotoxcicity
Received: 06 Jul 2024; Accepted: 30 Aug 2024.
Copyright: © 2024 Shawish, Alayoubi, El-Faham, Aldalbahi, Elsenduny, Badria, Ríos Gutiérrez, Hammud and Barakat. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ihab Shawish, Prince Sultan University, Riyadh, Saudi Arabia
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.