Integrated synthesis, molecular mechanics, quantum mechanics and in vitro studies of triazine derivatives as...

Two novel triazine-based scaffolds, 9a and 9b, were synthesized through sequential substitution on cyanuric chloride. The resulting compounds were characterized using ¹H NMR, ¹³C NMR, IR, UV-Vis, and Mass spectrometry. Subsequently, target prediction was performed to identify their potential biological targets using the SwissTargetPrediction tool. To explore the mechanism of action of these synthesized compounds and identify the putative drug target, molecular docking calculations were performed on the seven shortlisted druggable targets. Based on docking studies, mammalian target of rapamycin (mTOR) was selected as the target for the synthesized molecules 9a and 9b with docking scores of -7.367 kcal/mol and -9.022 kcal/mol, respectively. Extensive molecular dynamics simulations were conducted on the docked complexes to understand the dynamic behaviour. Moreover, molecules, 9a and 9b were also subjected to density functional theory (DFT) calculations to analyse the Molecular electrostatic potential and study the electronic density distribution over the scaffolds of these molecules. Subsequent biological evaluation in MCF-7 (cancerous), HeLa (cervical cancer cells), HepG2 (liver cancer cells) and WS1 (non-cancerous) cell lines were performed. Collectively across all studies, it was concluded that 9b is a promising antiproliferative agent, with an IC₅₀ of 90 μM against all three cancer cell lines. Furthermore, compound 9b exhibited little to no cytotoxicity towards the WS1 cell line, indicating an acceptable safety profile and selective cytotoxicity against cancer cells. Hence, these findings highlight the potential of 9b as a promising anticancer lead candidate for further structural optimisation and therapeutic development.