Design, Synthesis, and Mechanistic Pharmacological Evaluation of Novel Quinazolinone–Thiazolidinone Hybrid Scaffolds Targeting PI3K/Akt/mTOR Signaling in Chemoresistant Carcinoma Models

Background:Chemoresistance remains a major challenge in cancer therapy, often resulting in treatment failure and tumor recurrence. One of the key molecular mechanisms responsible for cancer progression and drug resistance involves dysregulation of the PI3K/Akt/mTOR signaling pathway, which regulates cellular growth, proliferation, and survival. Targeting this signaling cascade has therefore emerged as an important strategy for the development of novel anticancer agents. Heterocyclic scaffolds such as quinazolinone and thiazolidinone have demonstrated significant pharmacological potential in medicinal chemistry, particularly for anticancer drug discovery. Objective:The present study aimed to design, synthesize, and evaluate novel quinazolinone–thiazolidinone hybrid compounds as potential inhibitors of the PI3K/Akt/mTOR signaling pathway in chemoresistant carcinoma models. Methods:A series of hybrid derivatives were designed using computational modeling approaches and synthesized through a multistep synthetic pathway involving quinazolinone intermediate formation, Schiff base condensation, and cyclization with thioglycolic acid. The synthesized compounds were characterized using spectroscopic techniques including infrared spectroscopy, proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, and mass spectrometry. Molecular docking studies were conducted to investigate interactions with proteins involved in the PI3K/Akt/mTOR signaling cascade. Biological evaluation was performed using chemoresistant carcinoma cell lines. Cytotoxic activity was determined using the MTT assay, while apoptosis induction and cell cycle distribution were analyzed using Flow Cytometry. Mechanistic studies were conducted through Western blot analysis and gene expression analysis to examine modulation of signaling proteins. Results:The synthesized quinazolinone–thiazolidinone hybrid compounds demonstrated variable cytotoxic activity against chemoresistant carcinoma cells. Among the tested derivatives, selected compounds exhibited comparatively stronger antiproliferative activity and induced significant apoptosis in treated cells. Cell cycle analysis indicated arrest at specific phases of the cell cycle, suggesting inhibition of cellular proliferation. Molecular docking studies revealed favorable binding interactions between the hybrid molecules and key proteins of the PI3K/Akt/mTOR signaling pathway. Western blot analysis further indicated reduced phosphorylation levels of Akt and mTOR proteins, supporting inhibition of the signaling cascade. Conclusion:The findings of this study demonstrate that quinazolinone–thiazolidinone hybrid scaffolds represent promising candidates for anticancer drug development. The observed cytotoxic activity and mechanistic evidence suggest that these compounds may exert their effects through modulation of the PI3K/Akt/mTOR signaling pathway. Further pharmacological investigations and preclinical studies are warranted to explore their therapeutic potential in cancer treatment