Comprehensive exploration of novel imidazopyrimidine derivatives: Design, synthesis, computational assessment, and anti-breast cancer activity

Breast cancer (BC) accounts for a significant portion of all cancer diagnoses. According to the World Health Organization (WHO), it is the leading cancer among women, making up about 25 % of all female cancer cases globally. Researchers have long investigated heterocyclic compounds as potential treatments for cancer. This study delves into a series of novel imidazopyrimidine derivatives, specifically carbonyl tethered, exploring their potential as anticancer agents against BC. We found that the investigated derivatives effectively modulate the activity of tumor pyruvate kinase M2 (PKM2), a pivotal enzyme in the metabolic reprogramming and fine-tuning of the tumor microenvironment in BC. We used a lactate dehydrogenase (LDH)-coupled enzyme assay to identify these compounds as PKM2 activators, with an AC50 value of <8 mu M. Evaluation of antiproliferative activity against human breast cancer cells (MCF-7) at varying concentrations revealed promising and selective cytotoxicity, with some derivatives like 5b exhibiting efficacy as low as 0.28 <mu>M in 2D cultures and 2.26 mu M in 3D tumor spheroids while maintaining relative safety for normal human breast cells (MCF-10A) with high selectivity index of 160. We conducted cell cycle analysis on both 2D and 3D systems, which revealed a G1-phase arrest. Additionally, molecular docking studies and molecular dynamics (MD) simulations predicted a high binding affinity of the compounds to the activator binding site. This study positions the imidazopyrimidine derivatives as promising candidates for targeted therapy against BC.