Chalcone-Based Bioactive Scaffolds: Comparative Antioxidant, Antibacterial, and Anti-Alzheimer Activities Supported by Docking Analysis

Abstract

Chalcone derivatives constitute an important pharmacophore class with a broad spectrum of biological activities, including antibacterial, antifungal, antimutagenic, antitumoral, and anti-inflammatory effects. In this study, the inhibitory potentials of a series of chalcone derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were comprehensively evaluated through enzyme inhibition assays, antibacterial and antioxidant analyses, and molecular docking simulations. Among the tested derivatives, compound 7 demonstrated the most potent inhibitory activity against AChE (Ki = 4.12 +/- 0.84 nM) and BChE (Ki = 6.87 +/- 2.61 nM). The molecular docking results further substantiated the in vitro findings, revealing that compound 7 and compound 1 displayed the highest binding affinities toward AChE (-11.3 kcal/mol). In contrast, compound 1 exhibited the strongest interaction with BChE (-9.9 kcal/mol). Detailed interaction mapping showed that compound 7 engages in multiple stabilizing it-it stacking, it-it- alkyl, and hydrogen-bonding interactions with key catalytic residues of AChE, including TRP86, TYR341, TYR337, PHE295, and TRP286, supporting its high inhibitory efficiency. Similarly, the strong BChE affinity of compound 1 was attributed to pronounced it-it stacking interactions with TRP82 and TYR332, highlighting the structural suitability of chalcone scaffolds for cholinesterase binding. In addition to its cholinesterase inhibition potential, compound 7 also exhibited superior antioxidant performance, surpassing standard antioxidants in both DPPH (RSE%: 87.43; IC50: 14.57 mu M) and ABTS (RSE%: 93.93; IC50: 4.34 mu M) assays. Antibacterial screening indicated that the electronic and steric influences of substituent type and position on the chalcone backbone are critical determinants of antibacterial potency. Notably, compounds 1 (zone diameter: 22.13-23.43 mm) and 2 (zone diameter: 22.06-23.06 mm) displayed greater antibacterial effects than the standard reference drug against all tested bacterial strains. Overall, the integrated biological, biochemical, and computational results highlight chalcone derivatives, particularly compound 7, as promising multifunctional candidates with therapeutic relevance for diseases associated with cholinergic dysfunction, including Alzheimer's disease, while also offering valuable structural features for the development of antibacterial and antioxidant drugs.