Synthesis and Pharmacological Evaluation of New 3,4-Dihydroisoquinolin Derivatives Containing Heterocycle as Potential Anticonvulsant Agents

Abstract

Two novel series of 3,4-dihydroisoquinolin with heterocycle derivatives (4a-t and 9a-e) were synthesized and evaluated for their anticonvulsant activity using maximal electroshock (MES) test and pentylenetetrazole (PTZ)-induced seizure test. All compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, and mass spectral data. Among them, 9-(exyloxy)-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (9a) showed significant anticonvulsant activity in MES tests with an ED₅₀ value of 63.31 mg/kg and it showed wide margins of safety with protective index (PI > 7.9). It showed much higher anticonvulsant activity than that of valproate. It also demonstrated potent activity against PTZ-induced seizures. A docking study of compound 9a in the benzodiazepine (BZD)-binding site of γ-aminobutyric acid_A (GABA_A) receptor confirmed possible binding of compound 9a with the BZD receptors.

Keywords: MES; anticonvulsant; isoquinoline; molecular docking; synthesis.

Figure 1

The structure of Lead compounds.

Scheme 1

The synthesis of target compounds 4a–t (A) and 9a–e (B).

Figure 2

The structures of diazepam, estazolam, and the target compounds. (The dotted line was used to mark the special group).

Figure 3

Images of docked complexes of GABA_A with diazepam and compound 9a (thick color sticks) making interactions (color dotted lines) with residues at the BZD-binding site (silver-white sticks). (A) The complexes of GABA_A with diazepam; (B) The complexes of GABA_A with compound 9a.