Synthesis, biological evaluation, and in silico studies of novel chalcone- and pyrazoline-based 1,3,5-triazines as potential anticancer agents

Abstract

A novel series of triazin-chalcones (7,8)a–g and triazin-N-(3,5-dichlorophenyl)pyrazolines (9,10)a–g were synthesized and evaluated for their anticancer activity against nine different cancer strains. Triazine ketones 5 and 6 were synthesized from the cyanuric chloride 1 by using stepwise nucleophilic substitution of the chlorine atom. These ketones were subsequently subjected to a Claisen–Schmidt condensation reaction with aromatic aldehydes affording chalcones (7,8)a–g. Then, N-(3,5-dichlorophenyl)pyrazolines (9,10)a–g were obtained by cyclocondensation reactions of the respective chalcones (7,8)a–g with 3,5-dichlorophenylhydrazine. Among all the evaluated compounds, chalcones 7d,g and 8g exhibited more potent in vitro anticancer activity, with outstanding GI₅₀ values ranging from 0.422 to 14.9 μM and LC₅₀ values ranging from 5.08 μM to >100 μM. In silico studies, for both ligand- and structure-based, were executed to explore the inhibitory nature of chalcones and triazine derivatives. The results suggested that the evaluated compounds could act as modulators of the human thymidylate synthase enzyme.