Mechanism Based Designing, Synthesis and Evaluation of Nitrogen and Non-nitrogen Derivatives of Biphosphonates as Anti-inflammatory Agents

Abstract The inflammatory mechanisms are complex due to the involvement of multiple pathways. The messengers like PIP2 and IP3 are phosphonate containing biomolecules which are desirable for the delivery of biological responses. In the present study, we designed a novel series of nitrogen and non-nitrogen containing bisphosphonates fused with more lipophilic chalcone moiety. We assume to maintain the hydrophilic ratio of BPs with hydrophobic chalcone substitution. The synthesized compounds 1–11, demonstrated potential anti-inflammatory activity against 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. In vitro study was carried out at concentration of 1µM while 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 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 were 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 in vivo inhibitory action of compound 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.