1,3,5-Triazine ring has a long history of successful implementation as a skeleton for the construction of bioactive compounds, including several marketed drugs. This heterocyclic ring became a privileged scaffold for the drug development. Among 1,3,5-triazine derivatives, N,6-disubtituted-1,3,5-triazine-2,4-diamines have found to be an interesting scaffold for the construction of chemotherapeutic agents. In our study, we developed a new one-pot synthesis of N,6-disubtituted-1,3,5-triazine-2,4-diamines (1) by the three-component condensation of cyanoguanidine with aldehydes and primary amines in the presence of acid, followed by the Dimroth rearrangement and dehydrogenative aromatisation. The scope of the method was demonstrated by the successful synthesis of a representative library consisting of more than 100 targeted compounds 1. The anti-proliferative activity of the prepared compounds was evaluated using three breast cancer cell lines, namely MDA-MB-231, SKBR-3 and MCF-7. In general, MDA-MD-231 cells were more sensitive to the compounds as compared to MCF-7 and SKBR-3. Most active compounds have a 3-order selectivity towards the cancer cells as compared to normal breast cells (MCF-10A). Two compounds emerged as the most active in the prepared series against MDA-MB-231 cells. They were found to possess IC50 values of 1.7 nM and 7.3 nM, respectively. Furthermore, a QSAR model was built to comprehend the structural requirements controlling the anti-proliferative activity and to assist in the further design of anticancer agents based on this scaffold.

Combinatorial approach for synthesis of novel 1,3,5-triazine-2,4-diamines with potent and selective anti-proliferative activity

2019 Fall National Meeting

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