Design, synthesis and biological evaluation of N-substituted α-hydroxyimides and 1,2,3-oxathiazolidine-4-one-2,2-dioxides with anticonvulsant activity.

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED50 = 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents.

The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N, N'-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N, N'-diphenethylsulfamide.

Synthesis and anticonvulsant activity of bioisosteres of trimethadione, N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides from α-hydroxyamides.

The synthesis and anticonvulsant activity of novel heterocycles N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides, bioisosteres of trimethadione (TMD, oxazolidine-2,4-dione) and phenytoin (PHE), are described. TMD is an anticonvulsant drug widely used against absences seizures in the early 80's and PHE is an antiepileptic drug with a wide spectrum activity. The intermediates of synthesis of N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides, α-hydroxyamides, were obtained using microwave assisted synthesis. Anticonvulsant screening was performed in mice after intraperitoneal administration in the maximal electroshock seizure test (MES) and subcutaneous pentylenetetrazole seizures test (scPTZ). These new compounds showed a wide spectrum activity and were no neurotoxic in the RotoRod test. α-Hydroxyamides and N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides were 3-4700 times more potent than valproic acid in the MES test. Quantification of anticonvulsant protection was calculated (ED(50)) for the most active candidates; α-hydroxyamides 3a-c and 3e, and N-derivative-oxathiazolidine-4-one-2,2-dioxides 5a-c with ED(50) values of 9.1, 53.9, 44.6, 25.2, 15.1, 91.1 and 0.06mg/kg, respectively, in the MES test.