Synthesis and characterization of new tetrakisphosphonic acid derivatives as FPPS inhibitors and evaluation of their anti-osteoclastogenic potential for prevention of osteoporosis

Abstract

Numerous bone illnesses, including osteoporosis, are brought on by abnormal osteoclast differentiation. The identification of effective strategies for preventing osteoporosis involves focusing on the production and activation of osteoclasts. Herein, we synthesized a new series of tetrakisphosphonic acid derivatives and assessed their farnesyl pyrophosphate synthase inhibitory activity (FPPS) and anti-osteoclastogenic properties in vitro using the MTT assay and the Tartrate-Resistant Acid Phosphatase (TRAP) staining test. Among the synthesized novel tetrakisphosphonic acid derivatives, the unsubstituted benzylidene derivative 2a and the 2-brominated benzylidene derivative 2g exhibited the most promising bioactivity on the FPPS. All the synthesized compounds were proven to have the capacity to decrease the osteoclastogenesis process. Furthermore, both compounds 2a and 2g displayed the highest antiosteoclastogenic activity when compared to the reference compound, zoledronate. Molecular docking investigations revealed the probable interaction patterns between the potent derivatives 2a and 2g in the hFPPS binding pocket. The results of this investigation indicated that these novel compounds might be useful as FPPS-targeting and antiosteoclastogenic medications.