Design, synthesis and in vitro evaluation of coumarin–imidazo[1,2-a]pyridine derivatives against cancer induced osteoporosis

Abstract

A series of biologically important 6-(imidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one derivatives were synthesized by employing the silver(I) catalysed Groebke–Blackburn–Bienayme multicomponent reaction. The synthesized compounds were tested in a primary calvarial osteoblast cells by alkaline phosphatase assay and an alizarin red-S staining assay for their possible osteoprotective properties. Further, the effects of active compounds 6h, 6l, and 6o on the expression of osteogenic genes BMP2, RUNX2, COL1, and OCN were measured by qPCR. Out of three promising compounds, 6l and 6o significantly induced apoptosis in MDA-MB-231 cancer cells via mitochondrial depolarisation without affecting normal cells. In an in vitro co-culture model of bone metastasis, we investigated the ability of coumarin–imidazo[1,2-a]pyridine hybrids to reverse the negative impact of MDA-MB-231 cancer cells on osteoblast differentiation. The results illustrate the potential of designed hybrids to re-establish the bone homeostasis. These findings demonstrate the significance of newly synthesized hybrids as lead molecules, possessing both antiosteoporotic and anticancer properties that can be developed into new therapeutic agents to alleviate osteoporosis and bone metastasis.