Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells.

[Display omitted] • Small molecule-based design and synthesis of carboxamide-appended pyrazole conjugates. • 5g exhibited multifaceted potential (nuclear fragmentation, upregulation of caspase 3 and 9 etc.) against MDA-MB-231 cells. • The synergistic combination of paclitaxel and 5g has demonstrated improved efficacy by several folds. • The non-toxic nature of 5g was established in zebrafish embryos. We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, N -(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1 H -pyrazole-5-carboxamide (5 g) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC 50 value of 15.08 ± 0.04 µM. The MDA‐MB‐231 cells, upon treatment with compound 5 g , exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in 5 g treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound 5 g has exhibited improved activity by several folds via their synergistic effects. [ABSTRACT FROM AUTHOR]