Products Cited in Publications Worldwide Optimization of New Pyridone Annelated-Isoindigos as FLT3 Inhibitors

Optimization of New Pyridone Annelated-Isoindigos as FLT3 Inhibitors

Rama Joudeh

Abstract

FLT3 is an important target for leukemia, mainly acute myeloid leukemia that accounts for up to a third of all acute myeloid leukemia cases. The objective of the present research was the preparation of new pyridone annelated isoindigo derivatives. A series of isoindigos together with their annelated pyridone analogs were synthesized and characterized by MS/NMR spectroscopy. Their inhibitory activity were evaluated in vitro against FLT3 and FLT3 D835Y at 10 μM. The pyridone annelated isoindigos (10a-f) showed 85-100% inhibition. At lower concentrations, compound 10f exhibited excellent inhibitory activity with IC50 (48 nM against FLT3, 84 nM against FLT3D835Y). The isoindigos (14a-j) were inactive (< 28% inhibition), Docking studies for the pyridone annelated isoindigo derivatives (10a-f) showed that this series fit into the binding pocket of FLT3 and FLT3 D835Y. While 10f additionally form stacking with the DFG region. However, isoindigos (14a-j) don’t fit into the binding pocket. Also, they don’t form stacks with the DFG region. Hence, this would explain why isoindigos (14a-j) were inactive.

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