New paracetamol hybrids as anticancer and COX‐2 inhibitors: Synthesis, biological evaluation and docking studies

• Published in: Archiv der Pharmazie (Weinheim) 2024-01, Vol.357 (1), p.e2300340-n/a
• Main Authors: Alam, Mohammad Mahboob, Alsenani, Nawaf I., Abdelhamid, Antar A., Ahmad, Abrar, Baothman, Othman A., Hosawi, Salman A., Altayeb, Hisham, Nadeem, Mohammad Shahid, Ahmad, Varish, Nazreen, Syed, Elhenawy, Ahmed A.
• Format: Article
• Language: English
• Subjects: 1,2,3‐triazole; 1,3,4‐oxadiazole; Acetaminophen - pharmacology; Analgesics; anticancer; Antineoplastic Agents - chemistry; Apoptosis; Cancer; Cell cycle; Cell Line, Tumor; Cell Proliferation; COX‐2; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Drug development; Drug Screening Assays, Antitumor; Molecular Docking Simulation; Molecular Structure; paracetamol; Structure-Activity Relationship
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202300340

Drug repurposing is an emerging field in drug development that has provided many successful drugs. In the current study, paracetamol, a known antipyretic and analgesic agent, was chemically modified to generate paracetamol derivatives as anticancer and anticyclooxygenase‐2 (COX‐2) agents. Compound 11 bearing a fluoro group was the best cytotoxic candidate with half‐maximal inhibitory concentration (IC50) values ranging from 1.51 to 6.31 μM and anti‐COX‐2 activity with IC50 = 0.29 μM, compared to the standard drugs, doxorubicin and celecoxib. The cell cycle and apoptosis studies revealed that compound 11 possesses the ability to induce cell cycle arrest in the S phase and apoptosis in colon Huh‐7 cells. These results were strongly supported by docking studies, which showed strong interactions with the amino acids of the COX‐2 protein, and in silico pharmacokinetic predictions were found to be favorable for these newly synthesized paracetamol derivatives. It can be concluded that compound 11 could block cell growth and proliferation by inhibiting the COX‐2 enzyme in cancer therapy. Paracetamol was chemically modified to generate derivatives with anticancer and anticyclooxygenase‐2 (COX‐2) activity. Compound 11 bearing a fluoro group was the best cytotoxic candidate compared to the standard drug, doxorubicin. It induces cell cycle arrest in the S phase and apoptosis in colon Huh‐7 cells. Compound 11 could block cell growth and proliferation by inhibiting the COX‐2 enzyme in cancer therapy.