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

Arch Pharm (Weinheim). 2018 Jul;351(7):e1800062. doi: 10.1002/ardp.201800062. Epub 2018 Jun 10.

Abstract

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).

Keywords: Groebke-Blackburn-Bienaymé reaction; anticancer agents; cytotoxic; imidazo[1,2-b]pyrazole; multicomponent reaction.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • HL-60 Cells
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Leukemia, Promyelocytic, Acute / drug therapy*
  • Leukemia, Promyelocytic, Acute / pathology
  • MCF-7 Cells
  • Mice
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Pyrazoles