Development of bioactive heterocyclic compounds from trimethoprim: A new approach toward anticancer agents

This study presents the synthesis and characterization of novel heterocyclic derivatives derived from trimethoprim through diazotization, aldol condensation, and cyclization reactions. Azo (A1), chalcone (A2, A6), pyrazoline (A3, A7), thiazine (A4, A8), and oxazine (A5, A9) derivatives were successfully prepared and structurally confirmed using FT-IR, ¹H-NMR, and ¹³C-NMR spectroscopy. The synthesized compounds displayed diverse physical properties, indicating structural complexity and variation in polarity and thermal stability. Their biological evaluation against colon cancer (HRT) cells revealed significant cytotoxic activity. Thiazine derivative (A8) exhibited an IC₅₀ value of 206.7 µg/mL. The oxazine derivative (A9) demonstrated superior activity with an IC₅₀ of 0.1669 µg/mL (0.231 µmol/L), compared to the reference drug 5-fluorouracil (IC₅₀ = 3.73 µmol/L). These results highlight the potential of trimethoprim-derived heterocyclic scaffolds as anticancer agents. The study contributes to ongoing efforts in medicinal chemistry to develop effective therapeutic compounds by modifying existing antibiotic structures to enhance biological activity and target specificity in cancer treatment.