Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors

•2,3,4,5-Tetrahydro[1,4]diazepino[1,2-a]indol-1-ones were synthesized.•CDK1/cyclin B, CDK5/p25 and GSK-3 inhibitory activities were evaluated.•Iodo derivatives displayed submicromolar CDK inhibitory activity.•The binding mode of the new CDK inhibitors was determined by docking studies.

New series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones and 3,4,5,10-tetrahydro-2H-diazepino[3,4-b]indol-1-ones have been synthesized through an iodolactonisation/lactone-to-lactam rearrangement sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 and GSK-3). 11-Iodo-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one derivatives exhibited sub-micromolar inhibitory activity against cyclin-dependent kinases. Docking studies were realized to determine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Our result highlighted two weak Van-der-Waals bonding interactions established between the iodine atom and both phenyl group of Phe 80 and ammonium end of Lys 33.

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