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.