ABSTRACT
Benzodiazepines have a various behavioral effects in addition to their anxiolytic action. There is every reason to believe that the BZ/GABA receptor complex is involved in these effects, since GABAmimetic manipulations modify the effect of BZ in tests of convulsive activity, motor function, and appetitive behavior. 1,5-Benzodiazepines are biologically important molecules and are extensively used clinically as analgesic, hypnotic, sedative, and antidepressive agents. Hence, 1,5-Benzodiazepines were synthesized by condensation of o-phenylenediamine and ketones, for example, cyclohexanone and acetone in presence of sulfated zirconia (catalyst). Mannich bases were synthesized with acetophenone, p-nitroacetophenone, p-chloroacetophenone, and formaldehyde. Schiff bases were synthesized using Mannich base of 1,5-benzodiazepines with p-chloroaniline and p-chlorophenylsemicarbazide in the presence of glacial acetic acid. All the synthesized compounds were characterized by (1)H NMR and IR spectral analyses. All the synthesized derivatives were evaluated at the dose of 30 mg/kg b.w for anticonvulsant activity by isoniazid induced convulsion model, and the compounds NBZD-3 and NBZD-8 were found to be the most active among all compounds. Among all the synthesized derivatives, compounds NBZD-13 and NBZD-17 were found to be the most active among all compounds using thiosemicarbazide induced model. Although NBZD-8, NBZD-10, and NBZD-18 are the compounds which had shown good anticonvulsant activity and have an advantage over that, they were not sedative.
ABSTRACT
Thirty new 2-(substituted)-3-{[substituted]amino}quinazolin-4(3H)-one were designed and synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The most active compound of the series was 3-({(E)-[3-(4-chloro-3-methylphenoxy)phenyl]methylidene}amino)-2-phenylquinazolin-4(3H)-one PhQZ 7, which showed 100% protection (4/4, 0.5 h) and 75% protection (3/4, 0.25 h) at a dose of 100 mg/kg in mice. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta and GABA (A) alpha-1 receptors, in Lamarckian genetic algorithm based flexible docking studies.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Drug Design , Epilepsy, Complex Partial/drug therapy , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Algorithms , Animals , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Anticonvulsants/toxicity , Genetics , Humans , Hydrogen Bonding , Ligands , Male , Mice , Models, Molecular , Molecular Conformation , Nervous System/drug effects , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Quinazolines/toxicity , Rats , Structure-Activity RelationshipABSTRACT
A series of sulphonamide derivatives (1-11) were synthesized in good yield and evaluated for their possible anticonvulsant activity and neurotoxic study. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Majority of the compounds were active in MES and scPTZ tests. All the compounds were less toxic than the standard drug phenytoin.
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Sulfonamides/chemistry , Animals , Anticonvulsants/chemical synthesis , Hydrophobic and Hydrophilic Interactions , Male , Mice , Mice, Inbred Strains , Rats , Rats, Sprague-Dawley , Rats, Wistar , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
A series of 4-N-substituted arylsemicarbazones with increased lipophilicity were synthesized and evaluated for anticonvulsant activity. The compounds provided significant protection against maximal electroshock induced seizures (MES) and seizures indicated by sc pentetrazole administration (sc PTZ) at 300 mg/kg after 0.5 h. The compounds 8 and 4 were active in MES and sc PTZ indicated seizure. The study has shown that introduction of alkyl (ethyl) at the terminal amino group and alkoxy (methoxy) moiety at the distal aryl ring led to increased activity and decreased toxicity.
Subject(s)
Anticonvulsants/pharmacology , Semicarbazones/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Electroshock , Hypnotics and Sedatives/chemical synthesis , Hypnotics and Sedatives/chemistry , Hypnotics and Sedatives/pharmacology , Mice , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Pentylenetetrazole , Seizures/etiology , Seizures/prevention & control , Semicarbazones/chemical synthesis , Semicarbazones/chemistry , Sleep/drug effects , Structure-Activity Relationship , Time FactorsABSTRACT
A series of N-methyl/acetyl, 5-(un)-substituted isatin-3-semicarbazones were screened for anticonvulsant and sedative-hypnotic activities. The results revealed that protection was obtained in all the screens i.e., MES, scPTZ, and scSTY. Compounds 2, 4, 6, 10 but not 1 and 3 showed low neurotoxicity when compared to clinically used drugs. Compounds 5, 7, 8 and 9 were completely non-toxic. Compound 6 showed good activity in the rat oral MES screen. Among all the compounds, 3 and 6 emerged as the most active compounds as indicated by the protection they exhibit in MES, scSTY, and scPTZ screens. All the compounds showed significant sedativehypnotic activity.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Hypnotics and Sedatives/chemical synthesis , Hypnotics and Sedatives/pharmacology , Isatin/chemical synthesis , Isatin/pharmacology , Semicarbazones/chemical synthesis , Semicarbazones/pharmacology , Animals , Anticonvulsants/toxicity , Chemical Phenomena , Chemistry, Physical , Convulsants , Hypnotics and Sedatives/toxicity , Isatin/toxicity , Magnetic Resonance Spectroscopy , Male , Pentylenetetrazole , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/prevention & control , Semicarbazones/toxicity , Spectrophotometry, InfraredABSTRACT
In the present study, anticonvulsant activity of hydrazones, Schiff and Mannich bases of isatin were evaluated by maximal electroshock method (MES) and metrazol-induced convulsions (MET) at 30, 100 and 300 mg/kg dose levels. Neurotoxicity of the compounds was also assessed at the same dose levels. Eight compounds of the series exhibited significant anticonvulsant activity at 30 mg/kg dose level. 3-(4-chloro-phenylimino)-5-methyl-1,3-dihydro-indol-2-one (compound 10) was found to be the most potent compound of the series with 87% protection at 100 mg/kg and an ED(50) of 53.61 mg/kg (MET). All the compounds exhibited lesser neurotoxicity compared to phenytoin. All the active compounds showed greater protection than sodium valproate. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.
Subject(s)
Anticonvulsants/chemistry , Hydrazones/chemistry , Isatin/analogs & derivatives , Isatin/chemistry , Animals , Anticonvulsants/pharmacology , Electroshock/methods , Hydrazones/pharmacology , Isatin/pharmacology , Male , Mannich Bases/chemistry , Mice , Rats , Rats, Sprague-Dawley , Schiff Bases/chemistryABSTRACT
4-Bromophenyl semicarbazone derivatives have been synthesized and their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analyses. The in vitro evaluation in the 3-cell line, one dose primary anticancer assay is described. The 4-bromo substituted p-nitrobenzylidene phenyl semicarbazone (5) showed significant activity against breast MCF7 cell line and was further evaluated for potential anticancer activity in an in vitro human disease-oriented tumour cell line screening panel that consisted of 59 human tumour cell lines arranged in nine subpanels, representing diverse histologies. Melanoma UACC-62 cell line was relatively more sensitive to compounds 5 (growth inhibitions: GI50 = 15.3 mumol/l).
