A growing number of reports demonstrate that a pro-inflammatory and oxidative condition is related to the pathogenesis and the progression of endotoxin-induced septic shock and that antioxidants may have therapeutic potential in lipopolysaccharide (LPS)-induced sepsis. Melatonin has been shown to possess potent antioxidant properties in several models of inflammation in mice and rats. In the present study we focused on the possible protective mechanism of melatonin in preventing gastrointestinal (GI) disturbances induced by LPS in mice. In fact, mice treated with LPS showed a reduced gastric emptying of solid beads. Also the geometric center, representing the relative distribution of the solid beads throughout the entire GI tract, was significantly reduced in LPS-treated mice confirming that sepsis leads to a disturbed GI motility in mice. Melatonin completely reversed the LPS-induced motility disturbance. This beneficial effect of melatonin is associated with a reduction in lipid peroxidation, MAPK activation, NF-kappaB activation, iNOS transcription and expression and nitrite production in intestinal tissue from septic mice. These results demonstrate that melatonin prevents the LPS-induced GI disturbances in mice switching off the pro-oxidant pathways induced by the endotoxin. Therefore, it is reasonable to propose melatonin as a molecule with therapeutic potential for the treatment of systemic inflammation by interfering at the earliest steps of activation of the oxidative and pro-inflammatory cascade.
In the present study we have designed a new pharmacophore 'Chalconesemicarbazone' by pharmacophore hybridization approach of drug design. A series of novel chalconesemicarbazones was synthesized and evaluated for their antioxidant activity by reducing power assay. Most of the compounds were found to be potent antioxidants. Free radicals play an important role in various pathological and xenotoxic effects so antioxidant may have protective role in these pathological conditions. Based on the results of reducing power assay 1-[1-(2,4-dihydroxyphenyl)-3-(2-hydroxyphenyl)allylidene]-4-(4-methylphenyl)semicarbazide (compound 18) and 1-[1-(2,5-dihydroxyphenyl)-3-(6-hydroxyphenyl)allylidene]-4-(4-methylphenyl)semicarbazide (compound 21) were the most active lead compounds. It was found that methoxy and hydroxyl substituted chalconesemicarbazones exhibited potent reducing power and unsubstituted compound showed less reducing potential.
We have used phannacophore hybridization technique of drag design and designed a pharmacophoie model 2-inethylphenyIsemicarbazone which is having hydrogen acceptor site, hydrogen donor site, Iipophilic site etc using Ii^ndscout-2.02 software. A series of 2-iiiiethylphenyl-semicarbazone was synthesized and evaluated for their antipyretic activity using boiled cow milk induced pyrexia in rabbits. Compound 11 was, the most active compound. The possible metabolites of some selected syntheazed chalconesemicarbazones ware predicted by computational method using Pallas veirsion-3.1 ADME-Tax prediction software. The major pathway of metabolism was found to be phydroxylation and amide hydrolysis.' This work is licensed under a Creative Comrr«ns Attribution 3.0 License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor.
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