Design, Synthesis, In Vivo, and In Silico Evaluation of Benzothiazoles Bearing a 1,3,4-Oxadiazole Moiety as New Antiepileptic Agents

Abstract

In the presented manuscript, a new series of 2-[4-methoxy-3-(5-substituted phenyl-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-benzothiazoles (6a-n) have been synthesized and studied in vivo and in silico for their anticonvulsant potential. Maximum electroshocks (MES) and subcutaneous pentylenetetrazol (scPTZ) models have been used for in vivo anticonvulsant activity. Auto Dock 4.2 software was used for in silico studies, and the targeted protein was 5IOV.sThe antidepressant activity of selected compounds (most active) was determined as a reduction in locomotor activity through an actophotometer. In vivo and In silico studies proved that among all the synthesized compounds, 6f, 6h, 6j, and 6l were the most potent with no neurotoxicity as compared to conventional drugs (phenytoin and phenobarbital). The in silico studies also indicated about different binding interactions of synthetic compounds to localize the binding receptors. The most likely mode of action for these drugs, according to the docking analysis of active compounds with various targets, is their binding to the VGCC and NMDA receptors.

Figure 1

Structural requirements (pharmacophore model) of anticonvulsant activity.

Scheme 1. Synthesis of Target Compounds (6a–n)

Figure 2

Structure–activity relationship of synthesized compounds.

Figure 3

2D interaction of compound 6f on the site of 5IOV.

Figure 4

2D interaction of compound 6h on the site of 5IOV.

Figure 5

2D interaction of compound 6j on the site of 5IOV.

Figure 6

2D interaction of compound 6l on the site of 5IOV.

Figure 7

2D interaction of compound phenytoin on the site of 5IOV.

Figure 8

2D interaction of compound phenobarbital on the site of 5IOV.