Expedient synthesis of 8-membered azasultams: A combined synthetic, DFT, and in vitro study

Abstract

Herein we describe the novel approach to the synthesis of functionalized ind(az)olo-fused 1,2,4-thiadiazocine 1,1-dioxides through the CSIC (Carbanion-mediated Sulfonate (Sulfonamide) Intermolecular Coupling (Intramolecular Cyclization) reaction strategy. 1,2,4-Thiadiazocine 1,1-dioxides (put simply 8-membered azasultams) are increasingly popular but quite underrepresented in the literature compounds, were prepared in two simple steps and good yield from readily available reagents. Particularly, the alkylation of 7-functionalized ind(az)oles with N-(chloromethyl)-N-methylmethanesulfonamide gave the corresponding N-((1H-ind(az)ol-1-yl)methyl)-N-methylmethane-sulfonamides which underwent base-mediated cyclization affording the target 8-membered azasultams. The method worked well and provided azasultams decorated with a set of synthetically valuable handles. The conducted DFT calculations explained and rationalized the experimental data thus allowing us to formulate the rules of the structure‒activity relationship. Despite the prepared compounds showing weak cytotoxicity against the MDA-MB-231 breast cancer cell line, they are considered novel building blocks and perspective pharmacological templates prone to further optimization.

Keywords

• Anticancer activity
• CSIC reaction
• Cytotoxicity
• Medium-sized heterocycles
• Sulfonamides
• Sultams