Neuroprotective evaluation of novel substituted 1,3,4-oxadiazole and aroylhydrazone derivatives.

The paper reports on the facile and convenient synthesis of a series of novel 2,5-substituted 1,3,4-oxadiazoles 3a-f and that of aroylhydrazone-based molecular hybrids 5a-g from readily available starting materials. The structure of the compounds was confirmed by IR, 1H NMR, 13C NMR and HRESI-MS spectral data. The toxicological potential of the compounds was evaluated by monitoring the synaptosomal viability and the levels of reduced glutathione in rat brain synaptosomes, isolated by Percoll gradient. The neuroprotective effects were assessed in vitro in a model of 6-hydroxydopamine-induced neurotoxicity. Administered alone, at a concentration of 40 µM, most of the 1,3,4-oxadiazole derivatives and all of the hydrazone derivatives exhibited weak statistically significant neurotoxic effects, compared to the control. Two of the compounds from the novel oxadiazoles 3a and 3d did not have any toxicity. In a model of 6-OHDA-induced oxidative stress, again 3a and 3d and all aroylhydrazone derivatives 5a-g revealed statistically significant neuroprotective effect by preserving the synaptosomal viability and the level of reduced glutathione, against the toxic agent. Some of the compounds may have neuroprotective effects due to possible stabilization of the synaptosomal membrane and/or because of the preserved reduced glutathione. Additionally, all the compounds display a good predicted ADME profile.

Discovery of novel indole-based aroylhydrazones as anticonvulsants: Pharmacophore-based design.

A number of novel melatonin derivatives, containing aroylhydrazone moieties, were synthesized and explored in vivo for anticonvulsant activity, neurotoxicity in ICR mice as well as in-vitro for cytoxicity and oxidative stress in rats. The structures and configurations were confirmed by NMR, FTIR, HRMS and crystal X-ray diffraction method. For selection of potent structures for synthesis a pharmacophore model was used. Two compounds 3e, with a 2-furyl moiety fragment and 3f with 2-thienyl fragment, showed a potency in maximal electroshock (MES) test (ED50 = 50.98 mg kg-1, PI > 5.88 and ED50 = 108.7 mg kg-1; PI > 2.76), respectively, higher than melatonin (ED50 = 160.3 mg kg-1, PI > 1.87). The compounds 3c, 3e, 3f and 3i suppressed psychomotor seizures in the 6 Hz test and 3c was the most potent with higher ED50 = 13.98 mg kg-1 and PI of > 21.46 compared to that of melatonin (ED50 = 49.76 mg kg-1 and PI of > 6.03) in mice. None of the compounds displayed neurotoxicity in the rota-rod test. The novel melatonin derivatives exerted weak cytotoxic effects while 3f showed the lowest hepatoxic effects comparable to that of the positive control melatonin in rats. The high affinities to the elucidated pharmacophore model of the novel melatonin compounds derived from the inclusion of aroylhydrazone moiety in the indole scaffold yielded suitable candidates with anticonvulsant activity in the MES and 6 Hz test of psychomotor seizures.

Recent Developments of Hydrazide/Hydrazone Derivatives and Their Analogs as Anticonvulsant Agents in Animal Models.

Preclinical Research Epilepsy is a chronic devastating neurological disorder characterized by synchronous interictal discharges. Treatment with antiepileptic drugs (AEDs) can alleviate spontaneous seizure activity without preventing the progression and development of epileptogenesis. Current design and development of new AEDs and strategies for the prevention of epilepsy is focused mainly on attenuating uncontrolled seizures, severe side effects and toxicity in chronic drug therapy. It has thus become necessary to discover new chemical pharmacophores with a broad spectrum of activity and less neurotoxicity. Hydrazide/hydrazone derivatives that possess a -CO-NHN=CH- group constitute an important class of compounds for drug development. This review highlights the specific characteristics of various hydrazide/hydrazone derivatives and structurally related semicarbazones, semicarbazides and Schiff base compounds and their anticonvulsant activities. It is focused on the influence of differently substituted pharmacophores developed through SAR studies and testing their activity against different pharmcological targets. Drug Dev Res 77 : 379-392, 2016. © 2016 Wiley Periodicals, Inc.