Mechanism-Based Designing, Synthesis and Evaluation of Nitrogen and Non-Nitrogen Derivatives of Bisphosphonates as Anti-Inflammatory Agents

Inflammatory mechanisms are complex due to the involvement of multiple pathways. The messengers, like PIP2 and IP3, are phosphonate-containing biomolecules that are desirable for the delivery of biological responses. In the present study, we designed a novel series of nitrogen and nonnitrogen-containing bisphosphonates fused with lipophilic chalcone moiety. Here, we intended to maintain the hydrophilic ratio of BPs with hydrophobic chalcone substitution. The synthesized compounds 1-11 demonstrated potential anti-inflammatory activity against the carrageenan-induced rat paw edema model and in vitro COX-2 assay. The modifications over the synthesized derivatives were supported by in silico studies and SAR of bisphosphonates. The in vitro study was carried out at a concentration of 1 μM, while the in vivo study was performed using the carrageenan-induced rat paw edema model. From the study, it was concluded that the binding pattern of synthesized derivatives was remarkably similar to the co-crystallized ligand, and also the anti-inflammatory effect of the compound was based on the interactions between bisphosphonates and amino acids. The distance between the P-C-P linkage of bisphosphonates to nitrogen and free carbon attached to nitrogen was found to be important for the maximum interaction and biological response considering the co-crystalized ligand in another enzyme. An assessment of cyclooxygenase inhibitory activity (in vitro) of compounds 1, 9, and 11 revealed a structure-activity relationship, while the in vivo inhibitory action of compounds 9, 11, 1, 10, and 3 is indicative of its inhibitory action on the prostaglandin synthesis which may be mediated through the inhibition of COX-2 enzyme.