Design, synthesis and biological evaluation of new class of pyrazoles-dihydropyrimidinone derivatives as bone...

This study explores a series of twenty-four newly synthesized pyrzole-dihydropyrimidinone hybrids as potential bone anabolic agents. Initially, an alkaline phosphatase assay, a common marker of bone formation, was used to screen all compounds for their ability to stimulate osteogenic potential. Initial screening identified three promising candidates (5f, 5u and 5w) that were subsequently confirmed to be non-toxic to osteoblasts. Further investigation revealed that compound 5w displayed the most potent osteoanabolic effect, promoting osteoblast differentiation and upregulating mRNAs expression of osteogenic gene. Based on the promising in vitro and in vivo activity, structure-activity relationship (SAR) analysis revealed a furan ring on the dihydropyrimidinone unit and electron-donating groups on the N-phenyl ring of the pyrazole moiety to be crucial for osteogenic activity. Additionally, molecular docking, favorable pharmacokinetic properties and In silico ADME predictions suggest potential oral bioavailability. These findings establish the pyrazole-dihydropyrimidinone scaffold as a promising hit for developing a new class of orally active bone anabolic agents.