Bisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, anti-inflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1,2, finding moderate edema inhibition by oral and topical administration on Balb/C mice. Thus, in this work, the bioisosteric replacement of an amide functional group for an ester afforded the new bisphosphonates 3-6 which had moderate oral edema inhibition (25 mg/kg dose) and significative topical anti-inflammatory activity (2 mg/ear) on Balb/C mice, being 6 the more potent hit (55.9 % edema inhibition), comparable to positive control (55.5 % edema inhibition) on TPA topical model. Next, to assess acute toxicity of synthesized derivatives, test animals were administrated with 50-100 mg/kg of 3-6 by oral route, and after 14 days neither lethality or a significative loss weight were observed. Finally, a ligand structure-activity relationship and molecular docking analysis of 3-6 helped us to explain the trend observed in biological tests. Considering all these, we propose the inhibition of MMP-8 and MMP-9 as a possible action mechanism of the synthesized derivatives.

Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors

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