Design, synthesis, and cytotoxicity of ibuprofen-appended benzoxazole analogues against human breast adenocarcinoma

Abstract

A library of novel ibuprofen-appended benzoxazole analogues (7a-l) was synthesized via a series of nitration, reduction, and condensation-cyclization reactions and screened for their in vitro anticancer activity against human breast cancer MCF-7 and MDA-MB-231 cell lines using doxorubicin as a standard reference. Compounds 7h and 7j displayed outstanding activity against the MCF-7 cell line with an IC₅₀ value of 8.92 ± 0.91 μM and 9.14 ± 8.22 μM, respectively, compared to the doxorubicin IC₅₀ value of 9.29 ± 1.02 μM. Compound 7h also exhibited outstanding activity against the MDA-MB-231 cell line with an IC₅₀ value of 7.54 ± 0.95 μM compared to the doxorubicin IC₅₀ value of 7.68 ± 5.36 μM. Compounds 7h, 7i, 7j, and 7g showed identical morphological changes to those showed by doxorubicin. The molecular docking study against ERα unveiled their best docking scores and binding interactions in agreement to experimental results. Pharmacokinetics prediction envisaged their drug-like properties suitable for therapeutic applications.

Fig. 1. Marketed drugs containing the benzoxazole structural block.

Fig. 2. Representative examples of ibuprofen hybrids.

Fig. 3. Designed molecule of ibuprofen-tethered benzoxazole.

Scheme 1. Synthesis of 1-(2-(thiosubstituted)-6-hydroxybenzo[d]oxazol-5-yl)-2-(4-isobutylphenyl)propan-1-one derivatives (7a–l).

Fig. 4. Analogues of target compounds (7a–l).

Fig. 5. % Cell viability of the MCF-7 cell line upon the treatment of 7a–l. The data are derived from three replicates and presented as mean ± SEM. All data were statistically evaluated by one-way ANOVA at a significance level of p < 0.05.

Fig. 6. % Cell viability of the MDA-MB-231 cell line upon treatment of 7a–l. The data are derived from three replicates and presented as mean ± SEM. All data were statistically evaluated by one-way ANOVA at a significance level of p < 0.05.

Fig. 7. Morphological screening of compounds 7g, 7h, and 7j against MCF-7 cell lines.

Fig. 8. Morphological screening of compounds 7g, 7h, and 7i against MDA-MB-231 cell lines.

Fig. 9. Docking pose and binding interactions of compound 7h in the cavity of Erα.

Fig. 10. Docking pose and binding interactions of 4-hydroxytamoxifen in the cavity of Erα.