Palladium–benzodiazepine derivatives as promising metallodrugs for the development of antiepileptic therapies

• Diazepam-palladacycles were prepared by C-H activation of diazepam with palladium salts.
• Palladacycles[(DZP)PdCl]2 and[(DZP)PdOAc]2 display significant anticonvulsant action.
• The antiepileptic potential of the complexes were assessed via the two animal models.
• Two promising prototypes of metallodrugs to treat patients with epilepsy were prepared.

We synthesized two organometallic diazepam–palladium(II) derivatives by C–H activation of diazepam (DZP) with palladium salts, i.e., PdCl2 and Pd(OAc)2 (OAc = acetate). Both compounds obtained are air stable and were isolated in good yields. The anticonvulsant potential of the complexes, labeled [(DZP)PdCl]2 and [(DZP)PdOAc]2, was evaluated through two animal models: pentylenetetrazole (PTZ)- and picrotoxin (PTX)-induced convulsions. The organometallic DZP–palladium(II) acetate complex, [(DZP)PdOAc]2, significantly increased (p < 0.01 or p < 0.001) latencies and protected the animals against convulsions induced by PTZ and PTX, while the analogous chloro derivative, [(DZP)PdCl]2, was effective (p < 0.01) only in the PTZ model. These effects appear to be mediated through the GABAergic system. The possible mechanism of action of the DZP–palladium(II) complexes was also confirmed with the use of flumazenil (FLU), a GABAA-benzodiazepine receptor complex site antagonist. Herein, we present the first report of the anticonvulsant properties of organometallic DZP–palladium(II) complexes as well as evidence that these compounds may play an important role in the study of new drugs to treat patients with epilepsy.

Two diazepam-palladacycle derivatives, prepared by C–H activation of diazepam (DZP) in the presence of palladium salts, display anticonvulsant action, these compounds may play an important role in the study of new drugs to treat patients with epilepsy.Figure optionsDownload as PowerPoint slide