Organocatalytic[3 + 2]Cycloaddition: Synthesis of Quinazoline Containing Sulfonyl 1,2,3‐Triazoles as Potent EGFR Targeting Anti‐Breast Cancer Agents.

ABSTRACT A general strategy was developed for the synthesis of new fully decorated 1,2,3‐triazoles (<bold>4a–4m</bold> and <bold>5a–5g</bold>) containing quinazolines from 1‐(4‐nitrophenyl)‐2‐(quinazolin‐8‐ylsulfonyl) ethan‐1‐one and several azides using Ramachary organocatalytic azide‐ketone cycloaddition method. This reaction is reported for the synthesis of fully substituted sulfonyl‐1,2,3‐triazolyl quinazolins at a temperature of 100°C and the yields of the products produced are satisfactory to excellent. In vitro anticancer activity of all these derivatives demonstrated that six compounds, <bold>4d</bold>, <bold>4f</bold>, <bold>4i</bold>, <bold>4j</bold>, <bold>5d</bold>, and <bold>5e</bold>, were effective against two human breast cancer cell lines, MCF‐7 and MDA‐MB‐231. Compounds <bold>4f</bold>, <bold>4j</bold>, and <bold>5d</bold> had more action against both cell lines than Erlotinib. Later, the findings of inhibitory assays of potent compounds <bold>4d</bold>, <bold>4f</bold>, <bold>4i</bold>, <bold>4j</bold>, <bold>5d</bold>, and <bold>5e</bold> against the tyrosine kinase EGFR revealed that compound <bold>5d</bold> proved more potent than the reference erlotinib, while <bold>4f</bold> and <bold>4j</bold> had comparable efficacy. In silico molecular docking studies were also performed on six strong medicines to identify interactions with the EGFR receptor, and the energy estimations were shown to be comparable with the observed IC50 values. Ultimately, using SWISS/ADME and pkCSM, the in silico pharmacokinetic profile of potent compounds <bold>4d</bold>, <bold>4f</bold>, <bold>4i</bold>, <bold>4j</bold>, <bold>5d</bold>, and <bold>5e</bold> was predicted. All of the compounds precisely followed the principles established by Lipinski, Veber, Egan, and Muegge. [ABSTRACT FROM AUTHOR]