Ultrasound-Assisted Synthesis of Polyfunctionalized Pyridine Derivatives Catalyzed by Silica-Supported Perchloric Acid: In Vitro Anticancer Studies and Molecular Docking

Objective: To synthesize polyfunctionalized pyridine derivatives via a four-component reaction involving 1-tetralone, malononitrile, aldehydes, and ammonium acetate, catalyzed by silica-supported perchloric acid under ultrasound irradiation and conventional methods. Methods: The sonochemical method offers several advantages, including a cleaner reaction profile, an inexpensive catalyst, mild reaction conditions, rapid reaction times, high yields, catalyst reusability, and straightforward experimental and work-up procedures. Results and Discussion: The structures of all pyridine derivatives were confirmed using various characterization techniques, including IR, ¹H and ¹³C NMR spectroscopy, and mass spectrometry. The synthesized derivatives were evaluated for their anticancer potential through molecular docking studies against CSF1R and EGFR inhibitors. The results indicated that compounds (IVb) and (IVj) exhibited the most favorable binding energies, while compound (IVg) formed the highest number of hydrogen bonds with the EGFR protein. Conclusions: This study presents a simple and eco-friendly approach for synthesizing 2-amino-3-cyanopyridine derivatives using both conventional and ultrasonic techniques, with silica-supported perchloric acid as a reusable catalyst. According to docking studies, all derivatives exhibited stronger interactions with EGFR than with CSF1R. Furthermore, the anticancer activity of the synthesized compounds was assessed against MCF-7 cancer cell lines using the MTT assay. Compounds (IVd) and (IVj) demonstrated the highest anticancer activity.