Benzoxazole–benzamide hybrids: synthesis, structure–activity relationships, and multi-biological evaluation
4 affiliations
- 1Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology Trg Marka Marulića 19 10 00 Zagreb Croatia [email protected].
- 2Molecular Genetics and Therapeutics in Virology and Oncology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research KU Leuven Leuven Belgium.
- 3KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute Leuven Belgium.
- 4Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb Zagreb Croatia.
Abstract
Benzamides containing benzoxazole nuclei were synthesized using two complementary synthetic approaches and subsequently evaluated for their in vitro antiproliferative, antibacterial, and antioxidant activities. Several compounds exhibited pronounced antiproliferative activity across a panel of solid and hematological cancer cell lines, with IC₅₀ values in the low micromolar range. Among these, compounds 12, 13, and 17 were identified as the most potent derivatives, displaying consistent activity across multiple cell lines, while showing no cytotoxicity toward normal peripheral blood mononuclear cells (PBMCs) up to 100 μM. Their activity was further confirmed in cancer cell spheroids, where the 2-hydroxy-4-methoxy-substituted benzamide derivative 17 retained its potency. Cell cycle analysis revealed an accumulation of cells in the S and G2/M phases, suggesting interference with cell cycle progression as a contributing mechanism of action. In antibacterial assays, compound 17 also demonstrated the most promising profile, with potent activity against E. coli (MIC 1 μg mL⁻¹), S. aureus (MIC 2 μg mL⁻¹), and MRSA (MIC 2 μg mL⁻¹). Additionally, the unsubstituted derivative 11 showed notable antibacterial effects. Compound 18 exhibited strong antioxidant activity in the FRAP assay, surpassing the reference compound BHT through efficient reduction of the ferric tripyridyltriazine (TPTZ) complex. Overall, the benzoxazole-benzamide scaffold demonstrated significant potential for further development of biologically active compounds. Structure-activity relationship analysis showed that minor modifications in substituent type and position on the phenyl ring have a pronounced impact on biological activity.
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BibTeX
@article{galic2026benzoxazolebenzamide,
title = {{Benzoxazole–benzamide hybrids: synthesis, structure–activity relationships, and multi-biological evaluation}},
author = {Marina Galić and Leentje Persoons and Dirk Daelemans and Mihailo Banjanac and Tea Bruketa and Kristina Starčević and Marijana Hranjec},
journal = {RSC medicinal chemistry},
year = {2026},
month = oct,
doi = {10.1039/d6md00455e},
url = {https://europepmc.org/article/PMC/PMC13725857},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Benzoxazole–benzamide hybrids: synthesis, structure–activity relationships, and multi-biological evaluation
AU - Marina Galić
AU - Leentje Persoons
AU - Dirk Daelemans
AU - Mihailo Banjanac
AU - Tea Bruketa
AU - Kristina Starčević
AU - Marijana Hranjec
PY - 2026
DA - 2026/10/22
JO - RSC medicinal chemistry
DO - 10.1039/d6md00455e
UR - https://europepmc.org/article/PMC/PMC13725857
AB - Benzamides containing benzoxazole nuclei were synthesized using two complementary synthetic approaches and subsequently evaluated for their in vitro antiproliferative, antibacterial, and antioxidant activities. Several compounds exhibited pronounced antiproliferative activity across a panel of solid and hematological cancer cell lines, with IC₅₀ values in the low micromolar range. Among these, compounds 12, 13, and 17 were identified as the most potent derivatives, displaying consistent activity across multiple cell lines, while showing no cytotoxicity toward normal peripheral blood mononuclear cells (PBMCs) up to 100 μM. Their activity was further confirmed in cancer cell spheroids, where the 2-hydroxy-4-methoxy-substituted benzamide derivative 17 retained its potency. Cell cycle analysis revealed an accumulation of cells in the S and G2/M phases, suggesting interference with cell cycle progression as a contributing mechanism of action. In antibacterial assays, compound 17 also demonstrated the most promising profile, with potent activity against E. coli (MIC 1 μg mL⁻¹), S. aureus (MIC 2 μg mL⁻¹), and MRSA (MIC 2 μg mL⁻¹). Additionally, the unsubstituted derivative 11 showed notable antibacterial effects. Compound 18 exhibited strong antioxidant activity in the FRAP assay, surpassing the reference compound BHT through efficient reduction of the ferric tripyridyltriazine (TPTZ) complex. Overall, the benzoxazole-benzamide scaffold demonstrated significant potential for further development of biologically active compounds. Structure-activity relationship analysis showed that minor modifications in substituent type and position on the phenyl ring have a pronounced impact on biological activity.
SN - 2632-8682
ER -