Computationally Guided Structural Modification of Centaureidin: A Novel Approach for Enhancing Antioxidant and Antitumor Activities for Drug Development

The development of novel therapeutic drugs with enhanced efficacy has gained significant attention in recent years. In this study, we aimed to enhance the radical scavenging and antitumor activities of centaureidin through computationally guided structural modifications. Centaureidin was initially isolated through extensive phytochemical fractionation from Centaurea scoparia. We employed Density Functional Theory (DFT) and multitarget molecular modeling to explore how modifying the carbon-8 (C-8) position influences bond dissociation enthalpies, radical scavenging mechanisms, and the structure-antitumor activity relationships. Guided by computational analysis, we then modified the core skeleton of centaureidin using a facile multicomponent Mannich-type synthesis, resulting in two newly substituted centaureidin analogues. The radical scavenging properties of centaureidin and its analogues CA1 and CA4 were investigated using DPPH and ABTS assays. CA1 and CA4 revealed more potent radical scavenging activities. In addition, both analogues were more effective in inhibiting the proliferation of the MCF-7 cancer cell line. All tested compounds exhibited binding affinity towards caspase-3 and the receptors EGFR, HER2 and VEGFR. In conclusion, structural modification of centaureidin resulted in enhanced antioxidant and cytotoxic activities. This comprehensive approach offers a streamlined and cost-effective pathway for drug design and development, providing valuable insights for researchers in the field of therapeutic drug production.