Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐b]pyrazole‐7‐carboxamides

The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2‐b]pyrazole‐7‐carboxamides were investigated. Following a hit‐to‐lead optimization exploiting 2D and 3D cultures of MCF‐7 human breast, 4T1 mammary gland, and HL‐60 human promyelocytic leukemia cancer cell lines, a 67‐membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub‐micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL‐60 sensitivity (IC50 = 0.183 μM). A 67‐membered library of novel imidazo[1,2‐b]pyrazole‐7‐carboxamides was constructed and exerted cytotoxic effects against MCF‐7, 4T1, and HL‐60 cancer cells using in vitro 2D and 3D models. The crucial substitution patterns on the imidazo[1,2‐b]pyrazole framework were characterized. From the tested primary and secondary/tertiary amides, seven compounds showed submicromolar activities, with compound 63 demonstrating the highest HL‐60 potency in the nanomolar range.