Discovery of novel indole-based aroylhydrazones as anticonvulsants: Pharmacophore-based design
Institution:
1. Faculty of Pharmacy, Medical University-Sofia (MU-Sofia), Bulgaria;2. Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences (BAS), Sofia, Bulgaria;3. Institute of Biodiversity and Ecosystem Research, BAS, Sofia, Bulgaria;4. Department of Pharmacology and Toxicology, Medical University of Sofia, Bulgaria;5. Institute of Mineralogy and Crystallography, BAS, Sofia, Bulgaria;6. Institute of Neurobiology, BAS, 1113 Sofia, Bulgaria;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India;2. Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box no. 114, Jazan University, Jazan, Saudi Arabia;1. Department of Organic Chemistry, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria;2. Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;3. Department of Analytical Chemistry, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria;4. Department of Chemistry, Biochemistry, Physiology and Pathophysiology, Faculty of Medicine, Sofia University “St. Kliment Ohridski”, 1407 Sofia, Bulgaria;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, 35040 Izmir, Turkey;2. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, 35040 Izmir, Turkey;3. Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany;1. Chemistry Department, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia;2. Chemistry Department, Faculty of Science, Sohag University, Sohag 82534, Egypt;3. Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt;4. Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;5. Chemistry Department, Faculty of Science, Umm Al-Qura University, Makkah, Saudi Arabia;1. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, 35100 Izmir, Turkey;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandogan 06100, Ankara, Turkey;3. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;4. Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
Abstract:
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.
