Design, Synthesis and Pharmacological Evaluation of Novel 2-[2-(2-Chlorophenoxy) phenyl]-1,3,4-oxadiazole Derivatives as Benzodiazepine Receptor Agonists

Abstract

New derivatives of 2-[2-(2-Chlorophenoxy)phenyl]-1,3,4-oxadiazole as candidates for agonistic effect on benzodiazepine receptors were synthesized. Conformational analysis and superimposition of energy minima conformers of the novel compounds on estazolam, a known benzodiazepine agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. In pharmacological evaluation, anticonvulsant activity of the compounds determined by pentylenetetrazole-induced lethal convulsion and maximal electroshock tests. The results showed that the introduction of an amino substituent in position 5 of 1,3,4- oxadiazole ring generates compound 6 that has a considerable effect. Compound 8 with a hydroxyl substituent on position 5 of 1,3,4- oxadiazole ring showed a relatively mild anticonvulsant activity, which was significantly weaker than that of diazepam and compound 6. Anticonvulsant effects of active compounds were antagonized by flumazenil, an antagonist of benzodiazepine receptors, indicating the involvement of benzodiazepine receptors in these effects.

Keywords: 1,3,4-Oxadiazoles; Anticonvulsant; Benzodiazepine receptors; Conformational analysis; Synthesis.

Figure 1

The structure of designed compounds 6-11 and estazolam. The main pharmacophores have been conserved

Figure 2

Reagents: (a) 1) Na, dry methanol, rt, 2h; 2) DMF, Cu, reflux; (b) methanol, H2SO4, reflux, 7 h; (c) methanol, NH2NH2.H2O, stir, rt, 12 h; (d) formic acid, reflux, 4 h; (e) P2O5, xylene, reflux, 3 h; (f) BrCN, dioxan, stir, rt, overnight; (g) CS2, ethanol, KOH, reflux, 7 h; (h) 1,1΄-carbonyldiimidazole, triethylamine, dry THF, 0°C, 5h then rt, overnight; (i) toluene, phenylisocyanate, DCC, reflux, 7 h; (j) methyl iodide, ethanol, NaOH, ultrasonication, 5 min; (k) benzyl chloride, ethanol, NaOH, ultrasonication, 5 min

Figure 3

Stereoview of the superimposition of the energy minima conformers of estazolam (top left) and compound 6 (top right).