Synthesis, Quantitative Structure–Activity Relationship, and Anti-Inflammatory Profiles of Substituted 5- and 6-N-Heterocycle Bisphosphonate Esters

Abstract

A modified multicomponent reaction in a one-pot synthesis of a new series of substituted N-heterocyclic aminomethylene bisphosphonates, in high rates, was described. Accordingly, synthesis of α-aminobisphosphonates was achieved, via the Kabachnik–Fields reaction, from the substituted amine with triethyl orthoformate, and followed by treating the product mixture with a toluene solution containing diethyl phosphite–sodium salt. The design of potentially anti-inflammatory bisphosphonates (BPs) relied on the results of computer-assisted molecular modeling. If Later, new BPs were evaluated in animal model of chronic inflammation using the delayed-type hypersensitivity granuloma reaction.

GRAPHICAL ABSTRACT

Keywords:

• α-Aminomethylenebisphosphonates
• bone mineral affinity
• Kabachnik–Fields reaction

ACKNOWLEDGMENTS

Financial support from the Egyptian Academy of Scientific Research and Technology is gratefully acknowledged. We are grateful for the National Central Laboratory of Toxicology, Cairo, Egypt.

Notes

^a ***p < 0.001, **p < 0.01, *p < 0.05; p is the percentage of inhibition.

^b Sc, subcutaneously.

^c N, not tested.