Sustainably Driven ZnO Nanocatalytic Paradigm for Assembling Novel Bis-Heteroaryl Indole Frameworks: Robust Cytotoxic Profiling against HCT116 and MCF-7 Cells

Abstract

The escalating global burden of cancer continues to demand the discovery of structurally novel anticancer pharmacophore supported by efficient and economically viable synthetic methodologies. Aligned with the pursuit of sustainable drug discovery, we report an atom-economical and environmentally benign Yonemitsu-type multicomponent strategy enabled by recyclable ZnO nanoparticles for the development of pharmaceutically relevant bis-heteroaryl indole conjugates. This operationally simple protocol proceeds under mild and green conditions and, for the first time, incorporates heteroaromatic aldehydes such as thiopehen-2-carbaldehyde and furan-2-carbaldehyde as key substrates. An array of novel bis-heteroaryl indole scaffolds were developed, and the structure of representative compound 5aa was unambiguously validated by single-crystal X-ray diffraction. Remarkably, targeted scaffolds (5aa, 5ab, and 5ag) showed profound cytotoxic action against colorectal (HCT116) and breast cancer (MCF-7) cells, exhibiting significantly low IC50 values. Overall, the current work discloses a sustainable synthetic approach for accessing previously unexplored bis-heteroaryl scaffolds with promising anticancer potential.