Synthesis and In Vitro/In silico Evaluation of Novel 2‑Aryl-6-carboxamide-Substituted Benzoxazole Derivatives with Anticancer Effects and mTOR Inhibitory Potential

  • ACS Omega. 2026 May 22;11(22):32096-32117. doi: 10.1021/acsomega.5c12045.
Ceylan Hepokur  1 ,  Okan Aykaç  2 ,  Sema Misir  1 ,  Şeyda Akin  3 ,  Burak Kuzu  4 ,  Naveen Kosar  5  6 ,  Recep Kurnaz  7 ,  Öztekin Algül  8
Affiliations
  • 1. Faculty of Pharmacy, Department of Biochemistry, Sivas Cumhuriyet University, 58140 Sivas, Turkey.
  • 2. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Sivas Cumhuriyet University, 58140 Sivas, Turkey.
  • 3. Faculty of Medicine, Department of Medical Biology, Sivas Cumhuriyet University, 58140, Sivas, Turkey.
  • 4. Pharmaceutical Chemistry Section, Van Yuzuncu Yil University, 65080 Van, Turkey.
  • 5. Chemistry Department,King Fahd University of Petroleum & Minerals, Dhahran 31261, Saudi Arabia.
  • 6. Interdisciplinary Research Center for Refining and Advanced Chemicals, King Fahd University of Petroleum & Minerals, Dhahran 31261, Saudi Arabia.
  • 7. Department of Orthopaedics and Traumatology, Acıbadem State Hospital, Eskişehir 34718,Turkey.
  • 8. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mersin 33343,Türkiye.
PMID: 42294223 DOI: 10.1021/acsomega.5c12045
Abstract

In this study, we synthesized novel 2-aryl-6-carboxamide-substituted benzoxazole derivatives and evaluated their Anticancer potential against breast Cancer cell lines, with a focus on mTOR inhibitory activity. The compounds were synthesized via a three-step method and characterized by NMR analysis. In silico studiesincluding molecular docking, molecular dynamics simulations, and ADMET predictionswere conducted to predict interactions with the target protein and support the observed biological activity. IC50 values were determined in MCF-7 and MDA-MB-231 cells, with MCF-7 cells exhibiting greater sensitivity to the compound. The most active compounds, COH-17 and COH-19, demonstrated cytotoxicity as indicated by LDH release assays. Apoptotic effects were investigated at both molecular and cellular levels: Western blot analysis assessed key apoptotic proteins (Bcl-2, Bax, Caspase-3, and p53), while RT-qPCR quantified the expression of BRCA1, BRCA2, PTEN, TP53, Bcl-2, Bax, Caspase-3, PI3K, Akt, and BRAD1 genes. Morphological changes associated with Apoptosis were confirmed by DAPI staining and fluorescence microscopy, and early and late Apoptosis were quantified using Annexin V-FITC/PI flow cytometry. Cell cycle analysis revealed phase-specific arrest, further supporting the antiproliferative activity of the compound. Overall, COH-17 and COH-19 demonstrated potent Anticancer effects through mTOR inhibition, induction of Apoptosis, and cell cycle arrest, highlighting their potential as targeted therapeutic agents for breast Cancer.

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