Novel limonene and citral based 2,5-disubstituted-1,3,4-oxadiazoles: a natural product coupled approach to semicarbazones for antiepileptic activity.

Two novel series of N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide and N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide were synthesized to meet structural prerequisite indispensable for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. The rotorod test was conducted to evaluate neurotoxicity. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The outcome of the present investigations proved that the four binding sites pharmacophore model is vital for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among test compounds.

Enhancement of absorption and hepatoprotective potential through soya-phosphatidylcholine-andrographolide vesicular system.

Andrographis paniculata is a medicinal herb used extensively for various ailments and contains therapeutically active phytoconstituent, andrographolide (AN). Although hepatoprotective activity of AN is established, but their bioavailability is restricted due to its rapid clearance. The aim of this study, therefore, was to formulate AN herbosomes (ANH) through complexation with naturally occurring soya-phosphatidylcholine (SPC), in order to enhance absorption. Prepared andrographolide-soy phosphatidylcholine (AN-SPC) complex prepared was subjected for characterisation of complex and formation of vesicular system known as ANH using rotary evaporation techniques. This complex was subjected to in vitro study using everted small intestine sac technique which showed significantly increased absorption of AN from the ANH as compared to the plain AN. The hepatoprotective potential of ANH and plain AN was evaluated using carbon tetrachloride inducing hepatotoxicity rat model and compared, in which ANH equivalent to 50 mg/kg of plain AN significantly restore serum glutamate oxalacetate transaminase (112.4 ± 9.67 for AN whereas 90.2 ± 4.23 for ANH) and serum glutamate pyruvate transaminase (109.3 ± 7.89 for AN whereas 90.6 ± 4.34 for ANH) level as compared to control group. The ANH showed significantly better absorption than plain AN and this effect of ANH was also comparable to the standard drug (Silymarin). The findings of present study reveal that ANH has better bioavailability as shown by in vitro absorption study and hence improved hepatoprotection as compared to plain AN at equivalent dose.

Synthesis and antiepileptic activity of some novel semicarbazones containing 1,3,4-thiadiazole and quinazoline ring.

The incomplete seizure control with frequent adverse effects of current anticonvulsant drugs and the importance of semicarbazones, quinazolines and 2,5-disubstituted 1,3,4-thiadiazoles as anticonvulsant pharmacophore prompted us to carry out synthesis of three novel series of semicarbazones containing 1,3,4-thiadiazole and quinazoline ring. The chemical structures of these compounds were elucidated by elemental and spectral (IR, 1H NMR, 13C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The rotorod test was conducted to evaluate neurotoxicity. The majority of the compounds were found active in the biological screening. The outcome of the present investigations proved that the four binding sites pharmacophore model is decisive for antiepileptic activity. An attempt has also been performed to establish structure-activity relationships among synthesized compounds.

2,5-Disubstituted-1,3,4-oxadiazoles/thiadiazole as surface recognition moiety: design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors.

The enzymatic inhibition of histone deacetylase activity has come out as a novel and effectual means for the treatment of cancer. Two novel series of 2-[5-(4-substitutedphenyl)-[1,3,4]-oxadiazol/thiadiazol-2-ylamino]-pyrimidine-5-carboxylic acid (tetrahydro-pyran-2-yloxy)-amides were designed and synthesized as novel hydroxamic acid based histone deacetylase inhibitors. The antiproliferative activities of the compounds were investigated in vitro using histone deacetylase inhibitory assay and MTT assay. The synthesized compounds were also tested for antitumor activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present studying indicates 2,5-disubstituted 1,3,4-oxadiazole/thiadiazole as promising surface recognition moiety for development of newer hydroxamic acid based histone deacetylase inhibitor.

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 and anticonvulsant evaluation of some novel 2,5-disubstituted 1,3,4-thiadiazoles: pharmacophore model studies.

A novel series of N'-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-(4-substituted benzaldehyde)-semicarbazones, N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl)ethanone]-semicarbazones and N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazones were synthesized and evaluated for their anticonvulsant potential using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPFZ) models. The minimal motor impairment (neurotoxicity) was determined by rotorod test. The results of the present study confirmed the requirements of various structural features of four binding site pharmacophore model 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 of some novel oxadiazole and oxadiazoline analogues for their antiinflammatory activity.

The search for newer non-steroidal antiinflammatory drugs (NSAIDs) and the importance of oxadiazoles as antiinflammatory agents prompted us to undertake the synthesis of some novel oxadiazole and related analogues with unreported antiinflammatory activities. The antiinflammatory potential of the compounds was investigated using the carrageenan-induced rat paw edema method and cotton pellet-induced granuloma method. Some compounds demonstrated marked antiinflammatory activities. The antiinflammatory activity of oxadiazoles at doses of 100 mg/kg was shown by their ability to provide 28-55%, 21-36%, and 27-49% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the antiinflammatory properties of oxadiazolines at doses of 100 mg/kg was reflected by their ability to provide 15-47%, 22-39%, and 23-47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. Structure-activity relationships among synthesized compounds were also studied.

Glucose metabolism and diabetogenic gene expression analysis of chloroform fraction of Andrographis paniculata (Nees) whole herb in diabetic albino mice.

Exposure of rampant higher glucose level in diabetic condition could lead earlier and late diabetic complication eventually caused malign effect in body organs. The aim of the present work was to analyze the anti-diabetic potential of chloroform fraction of ethanol extract of Andrographis paniculata (AP) and diabetes laden gene expression alteration. In streptozotocin (60 mg/kg bw, i.p.) induced Type 2 diabetes albino mice, two weeks consecutive repeated dose treatment of chloroform fraction of AP at dose of 200 mg/kg, orally was evaluated for antidiabetic screening. Fasting blood glucose, oral glucose tolerance, serum lipid profile, tissues glycogen content, glucose 6-phosphatase and hexokinase enzymes level in liver, in vitro and in vivo insulin estimation were measured on last day of treatment. Subsequently presence of responsible phytoconstituents for respective activity was observed by HPLC. In diabetic mice, the fraction reduced the level of harmful cholesterol, while increased the favorable cholesterol significantly. Biochemical enzymes like glycogen, glucose-6-phosphatase and hexokinase were evaluated in body tissues. Apart from this in vitro, in vivo insulin estimation and diabetogenic gene expression analysis like GK, PEPCK, G-6pase, Glut-4, AR, PPAR-α,γ and TNF-α were evaluated using RT-PCR technique. Antidiabetic screening of fraction of AP at molecular level revealed significant antidiabetic activity.

A novel series of 2,5-disubstituted 1,3,4-oxadiazoles: synthesis and SAR study for their anticonvulsant activity.

In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, (1) H NMR, (13) C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity.

Synthesis and local anesthetic activity of some novel N-[5-(4-substituted)phenyl-1,3,4-oxadiazol-2-yl]-2-(substituted)-acetamides.

A novel series of acetamides carrying substituted-1,3,4-oxadiazole moiety were synthesized from reaction of 5-aryl-2-chloroacetamido-1,3,4-oxadiazoles with different secondary amines. The local anesthetic potential of the compounds was investigated using rabbit corneal reflex method and guinea pig's wheal derm method. The present work is the only one of its kind reporting local anesthetic activity in acetamide system combined with 1,3,4-oxadiazole nucleus. Lidocaine was selected as standard drug in evaluation of local anesthetic activity of synthesized oxadiazole analogues. Compound 19 was found to possess significant local anesthetic activity in both the models employed for evaluation of local anesthetic activity. Compound 20, 23, 28, 29 and 35 also demonstrated marked local anesthetic activities. Structure-activity relationships among synthesized compounds were also established.