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Regioselective Domino C–C/C–O Arylation of 1,2,3-Triiodobenzenes and 1,3-Diketones: Synthesis and In Silico Evaluation of 7-Iodobenzo[b]furan as Potential ALK Inhibitors

journal contribution
submitted on 2025-01-23, 05:53 and posted on 2025-01-23, 05:56 authored by Raed M. Al-Zoubi, Walid K. Al-Jammal, Mohanad Shkoor, Abdulilah D. Bani-Yaseen, Abbas Khan, Abdelali Agouni, Robert McDonald

We report a simple, direct, and regioselective protocol for the synthesis of 2,3-disubstituted 7-iodobenzo[b]furans via domino double C-C/C-O arylations of 1,2,3-triiodobenzene and 1,3-dicarbonyl compounds. Remarkably, the C-arylation occurred exclusively at the terminal positions, which are the most reactive and least sterically hindered. The O-arylation reactions were selectively performed with the more reactive carbonyl group. This domino process demonstrated excellent substrate tolerance. Under optimized conditions, the reaction of electron-deficient 1,2,3-triiodoarenes with dicarbonyl compounds afforded the highest isolated yields. Furthermore, the designed novel compounds were screened against ALK, revealing that among the 17 tested, ALK-9p, ALK-9b, ALK-9n, and ALK-9m exhibited the best docking scores using the extra-precision docking method. Molecular simulations of these compounds with ALK confirmed their stable binding behavior, compact topology, and minimal residue flexibility. Finally, binding free energy calculations using MM/PBSA and MM/GBSA methods further validated the pharmacological potential of these shortlisted hits as ALK inhibitors. These results demand prompt experimental validation to determine the promising clinical applications of these compounds in the management of cancer.

Other Information

Published in: Journal of Organometallic Chemistry
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1016/j.jorganchem.2025.123526

Funding

Open Access funding provided by the Qatar National Library.

History

Language

  • English

Publisher

Elsevier

Publication Year

  • 2025

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Medical Corporation
  • Qatar University
  • Qatar University Health - QU
  • College of Health Sciences - QU HEALTH
  • College of Pharmacy - QU HEALTH
  • College of Arts and Sciences - QU

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