Design and In Silico Evaluation of Chalcone–Schiff Base Hybrids as Multi-Target Agents for Inflammatory, Cancer, and Neurodegenerative Diseases

The increasing global burden of inflammatory disorders, cancer, and neurodegenerative diseases necessitates the development of therapeutic agents capable of simultaneously modulating multiple pathological pathways. Multi-target drug design has emerged as an effective strategy to address disease complexity, improve therapeutic outcomes, and minimize treatment resistance. Chalcone and Schiff base scaffolds are privileged pharmacophores known for their diverse biological activities and suitability for molecular hybridization. In the present study, a series of ten chalcone–Schiff base hybrid derivatives (CSB1–CSB10) were rationally designed and evaluated using an integrated in silico approach. Molecular docking was performed against key therapeutic targets associated with inflammation (COX-2, TNF-α), cancer (EGFR, BCL-2, Topoisomerase II), and neurodegeneration (AChE, BACE1). Several compounds exhibited strong binding affinities and stable interactions with critical active-site residues, demonstrating comparable or improved performance relative to standard inhibitors. Pharmacokinetic and drug-likeness predictions using SwissADME indicated favorable physicochemical properties, high gastrointestinal absorption, and compliance with Lipinski’s rule of five. Among the series, CSB4, CSB6, CSB7, and CSB9 showed superior multi-target binding profiles. These findings highlight chalcone–Schiff base hybrids as promising multifunctional scaffolds for the development of novel therapeutic candidates targeting complex chronic diseases.