The synthesis of a conjugate molecule between an unusual red‐fluorescent diketopyrrolopyrrole (DPP) unit and a bis‐phosphonate (BP) precursor by a click‐chemistry strategy to target bone tissue and monitor the interaction is reported. After thorough investigation, conjugation through a triazole unit between a γ‐azido rather than a β‐azido BP and an alkyne‐functionalized DPP fluorophore group turned out to be the winning strategy. Visualization of the DPP‐BP conjugate on osteoclasts and specific antiresorption activity were successfully demonstrated.

Scheme 1. Chemical structures of bisphosphonates, pyrophosphoric acid, alendronic acid, zoledronic acid, and VBP.

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Bisphosphonates, particularly those with N-substituted groups, are currently the most popular drugs for the treatment of osteoporosis. However, their chemical structures are still rather simple and new synthetic methods are needed to expand their molecular complexity and also improve their specificity of action towards other targets as anticancer, antibacterial, and antimalarial drugs. Herein, we report a new class of potential antiresorption bisphosphonate drugs that have a pyrrolidine unit with different substituents, obtained through a simple dipolar cycloaddition reaction between azomethine ylides and vinylidenebisphosphonate derivatives as precursors. The methodology led to the efficient preparation of a wide range of (1-methylpyrrolidine-3,3-diyl)bis(phosphonic esters) derivatives with different substituents in position 4.