Hybrid molecules of ibuprofen and piperidone: a rational approach toward anti-cancer drug development

Abstract

The persistent challenge of cancer treatment, exacerbated by multidrug resistance and the limited effectiveness of monotherapies, underscores the need for innovative therapeutic strategies. This study details the design, synthesis, and biological evaluation of a novel series of twelve hybrid conjugates (7a-l) that combine a curcumin-mimic scaffold (3,5-diarylidene-4-piperidinone), ibuprofen, and amino acid linkers. By employing a molecular hybridization approach, the synthesized compounds were thoroughly characterized and assessed for their antiproliferative activity against diverse cancer cell lines, including A431 (skin), HCT116 (colon), and MCF7 (breast). Flow cytometry results suggest that these potent hybrids induce G1-phase cell cycle arrest and apoptosis. Among them, compound 7b emerged as the most effective candidate. Both in vitro and in vivo studies demonstrated that 7b exhibited superior efficacy compared to cisplatin in melanoma models, significantly reducing tumor growth and improving survival rates. Mechanistic investigations indicate that MDM2 inhibition and p53 activation may be key mechanisms of action, supported by enzymatic assays, molecular docking analyses, and dynamic simulations. Quantitative Structure-Activity Relationship (QSAR) modeling further elucidated the critical structural descriptors influencing bioactivity. These findings underscore the therapeutic potential of curcumin-inspired hybrid conjugates as multi-target anticancer agents and establish a solid foundation for future preclinical development.

Keywords: 3,5-Bis(ylidene)-4-piperidone; Antiproliferation; Ibuprofen; MDM2; Molecular modeling.