Synthesis, characterization and bioactivity of new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives.

Mohammad M Ibrahim, Mohamad Nurul Azmi, Maram B Alhawarri, Nik Nur Syazni Nik Mohamed Kamal, Hasan AbuMahmoud
Author Information
  1. Mohammad M Ibrahim: Department of Chemistry, Faculty of Science, Al Al-Bayt University, P.O. BOX 130040, Al-Mafraq, 25113, Jordan. mohammadibrahim@aabu.edu.jo.
  2. Mohamad Nurul Azmi: School of Chemical Sciences, Universiti Sains Malaysia, 11800, Minden, Pulau Pinang, Malaysia.
  3. Maram B Alhawarri: Department of Pharmacy, Faculty of Pharmacy, Jadara University, P.O.Box 733, Irbid, 21110, Jordan.
  4. Nik Nur Syazni Nik Mohamed Kamal: Department of Toxicology, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia.
  5. Hasan AbuMahmoud: Department of Chemistry, Faculty of Science, Al Al-Bayt University, P.O. BOX 130040, Al-Mafraq, 25113, Jordan.

Abstract

Pyridone heterocycles, such as furo[2,3-b]pyridines, have emerged as prominent scaffolds in medicinal chemistry due to their versatile pharmacological properties, including significant anticancer activity. In this study, we successfully synthesized new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives from chalcones bearing 4-(benzyloxy)phenyl and dichlorothiophenyl subunits to explore their therapeutic potential against breast cancer. By employing a synthetic strategy involving Claisen-Schmidt condensation followed by sequential cyclizations and functional modifications, we synthesized and characterized four compounds (MI-S0, MI-S1, MI-S2, and MI-S3) using various spectroscopic methods, including FT-IR, H-NMR, C-NMR, DEPT, H,H- and C,H-COSY, and HRMS. The in vitro cytotoxic activity of these compounds was evaluated against two breast cancer cell lines, MCF-7 and MDA-MB-231, and compared with a noncancerous breast cell line, MCF-10A. All compounds exhibited potent cytotoxic activities with minimal selectivity toward normal cells. Molecular docking studies targeting the serine/threonine kinase AKT1, estrogen receptor alpha (ERα), and human epidermal growth factor receptor 2 (HER2) revealed strong binding affinities, suggesting a mechanism involving the disruption of key cellular signaling pathways. These findings underscore the potential of furo[2,3-b]pyridine derivatives as promising candidates for further development into anticancer agents, laying the groundwork for future investigations into their selective therapeutic efficacy and molecular mechanisms of action.

Keywords

References

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Grants

  1. REF: Dean's Council Decision No. 331/2022/2023, 10/05/2023/Al al-Bayt University

MeSH Term

Humans
Pyridines
Antineoplastic Agents
Molecular Docking Simulation
Cell Line, Tumor
Structure-Activity Relationship
Estrogen Receptor alpha
MCF-7 Cells
Breast Neoplasms
Cell Proliferation
Drug Screening Assays, Antitumor
Nitriles
Proto-Oncogene Proteins c-akt

Chemicals

Pyridines
Antineoplastic Agents
Estrogen Receptor alpha
Nitriles
Proto-Oncogene Proteins c-akt

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