ULTRASOUND-ASSISTED SYNTHESIS, SPECTROSCOPIC CHARACTERIZATION, AND MOLECULAR DOCKING OF NOVEL BENZO[G]PTERIN-BASED HETEROCYCLIC DERIVATIVES TOWARD HUMAN DIHYDROFOLATE REDUCTASE

Abstract

A series of Benzo[g]pterin-based heterocyclic derivatives was prepared through an ultrasound-assisted synthetic strategy. Five Schiff-base intermediates generated from an amino-Benzo[g]pterin scaffold and substituted aromatic aldehydes were used as key precursors for subsequent ring-forming reactions. Three families of cyclized products were obtained: azetidin-2-one (beta-lactam) derivatives L1–L5, imidazole derivatives G1–G5, and tetrazole derivatives T1 T5. The reported reactions were generally completed after 40 min of ultrasonic irradiation, and the isolated yields of the listed Schiff bases and cyclized compounds ranged from 60 to 85%. Structural assignments were supported by melting point data, FT-IR spectroscopy, 1H NMR, and 13C NMR spectroscopy. Schiff-base formation was indicated by the appearance of azomethine resonances, whereas cyclization was supported by the loss or transformation of the azomethine environment and the appearance of new saturated-ring carbon/proton signals together with diagnostic carbonyl or heterocyclic features. Computational evaluation was performed against human dihydrofolate reductase (hDHFR; PDB ID 1U72) using CB-Dock2 and post-docking visualization with BIOVIA Discovery Studio Visualizer. The three best reported docking scores were -11.2, -11.1, and -10.8 kcal mol-1, corresponding to a brominated beta lactam derivative (L2), a methylenedioxy-substituted imidazole derivative (G4), and a brominated tetrazole derivative (T2), respectively. These molecular docking results suggest that compounds L2, G4, and T2 possess promising binding affinity towards hDHFR, making them potential candidates for further biological evaluation.