Molecular Design, Synthesis and Anti-cancer Activity of Novel Pyrazolo[3,4-b]pyridine-based Glycohybrid Molecules

Abstract

Molecular hybridization is an emerging strategy in medicinal chemistry for designing new bioactive molecules that link pharmacophores covalently and shows synergistic enhanced properties. Herein, we have developed pyrazolo[3,4-b]pyridine-based new glycohybrids considering the Warburg effect. A microwave-assisted, copper-catalyzed efficient synthesis of new triazole-linked glycohybrids based on pyrazolo[3,4-b]pyridines scaffold was achieved successfully in high yields with inherent stereochemical diversity from d-glucose, d-galactose, and d-mannose. The twenty-three distinct new glycohybrids, incorporating various electron-donating and electron-withdrawing groups with stereochemical diversities, were prepared using developed synthetic protocol. This efficient synthesis significantly reduced reaction time and furnished products with high isolated yields, showcasing its potential for glycohybrids synthesis. In-vitro study revealed that among the synthesized glycohybrids, compound 8e emerged as a potential compound against MDA-MB231 (SI > 31) and MCF-7 (SI > 434) with an IC₅₀ value of 19.58 µM and 1.42 µM respectively. The molecular docking study predicts the binding interaction of the chemical probe with the target protein HCK. The enzyme inhibition assay revealed that compound 8e is having strong inhibitory potency against HCK enzyme. This article highlights the synthetic utility of this strategy and the potential applications of these newly designed and prepared glycohybrids.