Unveiling anticancer potential of imidazo-pyridine/pyrazine-fused bicyclic heterocycles: Insights from in silico and in vitro studies

Cancer is a significant global health challenge and the second leading cause of death worldwide, responsible for millions of fatalities annually. Despite advances in diagnostics and treatments in cancer, complexities like tumor biology, drug resistance, and toxicity limit its effective management. Herein, we focused on new imidazo-pyridine/pyrazine-fused bicyclic heterocycles. The anticancer potential of the identified bicyclic heterocycles against colorectal cancer (CRC) is established utilizing a multi-faceted approach integrating in silico network pharmacology, ADMET profiling and in vitro cytotoxicity assay. Network pharmacology analysis using the test compounds and CRC cell lines (HCT-116 and CT-26) revealed important molecular targets, such as HSP90AA1, SRC, and PIK3R1 which plays an important role in signaling pathways like PI3K/AKT and MAPK in CRC progression. Gene ontology and KEGG pathway enrichment analyses highlighted the ability of the target compounds to modulate biological processes involved in cell proliferation, apoptosis, and oxidative stress in CRC pathogenesis. ADMET profiling through GastroPlus® demonstrated that these compounds possess favorable pharmacokinetic properties, such as enhanced absorption, bioavailability, and systemic exposure. In vitro cytotoxicity studies on CRC cell lines showed dose-dependent antiproliferative effects. The findings highlight potential of imidazo-pyridine/pyrazine-fused bicyclic heterocycles as promising candidates for treating CRC.