Synthesis and oral hypoglycemic effect of novel thiazine containing trisubstituted benzenesulfonylurea derivatives.

A new series of 3-(4-substituted phenyl)-1-(4-(4,6-dimethyl-6H-1,3-thiazin-2-yl)phenylsulfonyl)-1-substituted urea (5a-o) was synthesized by an effectual route via sulfonylcarbamates and explores the novel site for substitution in sulfonylurea as well as the way of thiazine can be prepared. The molecules were established by elemental analysis and spectroscopic viz. IR, (1)H NMR, (13)C NMR and MS techniques. All the fifteen derivatives were shown very prominent oral hypoglycemic effect at the dose of 40 mg/kg body weight (p.o.) in respect of standard drug glibenclamide and control. The hypoglycemic effect was studied using oral glucose tolerance test in normal and NIDDM in STZ-rat model. The compounds 5a, 5d, 5f, 5i, 5k and 5n were dominant out of fifteen derivatives for blood glucose lowering activity (more than 80%) when comparing with NIDDM control. These derivatives were either containing simply phenyl ring (5a, 5f and 5k) on to the second amine of sulfonylurea (R' = H) or nitro group at the para position in compound 5d, 5i and 5n (R' = NO2 ) to produce significant oral hypoglycemic effect. Other structural activity relationship is also observed regarding the heteroaromatic and substituted aromatic group at R and R' position respectively.

Novel semicarbazones based 2,5-disubstituted-1,3,4-oxadiazoles: one more step towards establishing four binding site pharmacophoric model hypothesis for anticonvulsant activity.

A series of novel N(1)-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N(4)-(4-substitutedbenzaldehyde)-semicarbazone, N(1)-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N(4)-[1-(4-substitutedphenyl)ethanone]-semicarbazone and N(1)-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N(4)-[1-(4-substitutedphenyl) (phenyl) methanone]-semicarbazone were designed and synthesized on the basis of semicarbazone based pharmacophoric model to meet the structural requirements necessary for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The efforts were also made to establish structure activity relationships among synthesized compounds. The results of the present studying validated that the pharmacophoric model with four binding sites is essential for anticonvulsant activity.

Synthesis of novel 2,5-disubstituted 1,3,4-thiadiazoles for their potential anticonvulsant activity: pharmacophoric model studies.

A series of novel N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-(4-substituted benzaldehyde)-semicarbazone 1-12, N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-[1-(4-substituted phenyl)ethanone]-semicarbazone 13-16, and N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazone 17-20 were synthesized for their anticonvulsant activity. The chemical structures of the compounds were proved by elemental and spectral (IR, (1)H-NMR,( 13)C-NMR, and MS) analysis. The anticonvulsant potential of the compounds was investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both the models employed for anticonvulsant evaluation. Compounds 8, 13, 15, and 16 also demonstrated a marked anticonvulsant property. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among the synthesized compounds.

Synthesis and Anticonvulsant Effect of Novel Thiazolidinedione Containing Benzene-sulfonylurea and Sulfonylthiourea Derivatives.

A newer series of 1-(4-substitutedphenyl)-3-(4-((2,4-dioxothiazolidin-5-lidene)methyl)phenyl sulfonyl)urea/thiourea (4a-l) were synthesized for their anticonvulsant activity. The activity is attributed to its potential to restrain astrocytic Na+, 2HCl, and K+ co-transport similar to torasemide which has sulfonylurea in its structure. Torasemide having the similar action as the furosemide that obstructs kainic acid-induced electrical discharges observed from cortex and it has neuroprotective agents, for instance antagonizing the N-methyl-D-aspartate (NMDA) and non-NMDA receptors for evaluating antiepileptic activity. The structures of new derivatives were established by elemental analysis and spectroscopic techniques viz. FTIR, 1H NMR and LC-MS. The all twelve derivatives were assessed for anticonvulsant activity at three different doses at 30, 100 and 300 mg/kg body weight into maximal electroshock (MES) and subcutaneous pentylenetetrazole (sports) models. Compounds 4c and 4e were formed to be most active among all the derivatives for both the models of anticonvulsant activity. Beside these compounds 4g, 4i and 4k also possessed the prominent anticonvulsant activity devoid of any neurotoxicity. The sulfonylurea and sulfonylthiourea both were proved to be effective anticonvulsant pharmacophore. Other structure activity relationships were established by considering the aspect of substitution in the lead.

Anticonvulsant and Neurotoxicity of Some Novel 1-([1,3,4]thiadiazino[6,5- b]indol-3-yl Semicarbazides.

In the present study a series of new N(4)-(4-substituted benzylidene)-N(1)-([1,3,4]thiadiazino [6,5-b]indol-3-yl)semicarbazide (1-6), N(4)-([1,3,4]thiadiazino[6,5-b]indol-3-yl)-N(1)-(1-(4-substituted phenyl)ethylidene)semicarbazide (7-10), N(4)-([1,3,4]thiadiazino[6,5-b]indol-3-yl)-N(1)-((4-substituted phenyl)(phenyl)methylene) semicarbazide. (11-14) have been synthesized from isatin and thiosemicarbazide through multiple steps to meet structural necessities for the anticonvulsant activity. All the newly prepared compounds were characterized by spectral techniques like FT-IR, (1)H and (13)C NMR, EI-MS and elemental analysis. All the newly synthesized compounds were investigated for the anticonvulsant activity against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) models and their neurotoxicity were also evaluated by rotarod test. The results obtained showed that 64% of the compounds showed protection in the MES test and 36% of the compounds showed protection in ScPTZ test. Some of the compounds also showed good activity after oral administration. Among the synthesized compounds, compound 14 was shown to be the most active compound showing activity at 100 and 300 mg/kg in MES and ScPTZ test with prolonged duration of action. In the present study, semicarbazones of hydroxy containing carbonyl compounds were depicted to be the potent molecule with low neurotoxicity and prolong duration of action on oral administration. The result of the present study may be used for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity.