Synthesis and in vitro evaluation of fused heterocycles and triazine analogues

Abstract

In the present investigation, we have combined the structural artifacts of benzimidazole with triazine, pyrrolopyridines, quinazolinones and pyrazolopyrimidines moieties to make a hybrid and substituted them with different secondary and primary amines in order to observe the effect of electron-donor and acceptor nitrogen groups within the moieties. Introduction of benzyl group at 1- or 3-position of benzimidazole are also known to increase lipid solubility of polar compounds, a character very much needed for the activity. The strategy of using substituted azoles linked to triazine derivatives or other fused heterocycles are particularly attractive as it is expected to provide a scope of preparing more interactions with the target site and thus, further affect the activity. Characterizations of these molecules were done with different spectroscopic techniques such as NMR and mass spectrometry. In the quest for biologically potent agents, these synthesized molecules were evaluated in vitro over 60 human cancer cell lines and dihydrofolate reductase inhibition. These compounds were further evaluated for their interactions with DNA and bovine albumin. SAR study was used to identify the structural features required for the antitumor properties of these new hybrid series and also the role of different structural fragments in affecting the properties of the drug. In order to have an insight into the molecular interaction of compounds, their docking were also planned to scrutinize the mode of interactions of compound with amino acids in the active site of the enzyme.