Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

Using a scaffold‐hopping approach, imidazo[1,2‐a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3‐kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium‐cat...

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Published in:Chemistry, an Asian journal an Asian journal, 2019-04, Vol.14 (8), p.1249-1261
Main Authors: Gamage, Swarna A., Spicer, Julie A., Tsang, Kit Y., O'Connor, Patrick D., Flanagan, Jack U., Lee, Woo‐Jeong, Dickson, James M. J., Shepherd, Peter R., Denny, William A., Rewcastle, Gordon W.
Format: Article
Language:English
Subjects:
biological activity
cross-coupling
hydrogen bonds
inhibitors
kinases
scaffold hopping
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Summary:Using a scaffold‐hopping approach, imidazo[1,2‐a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3‐kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium‐catalysed coupling of 2‐(difluoromethyl)imidazo[1,2‐a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5‐triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency. One heck of a reaction: Imidazo[1,2‐a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3‐kinase (PI3K) inhibitors were synthesized for biological evaluation using a heteroaryl Heck reaction procedure. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.
ISSN:1861-4728
1861-471X
DOI:10.1002/asia.201801762