thiosemicarbazide and Edema

Oxidative stress due to high levels of reactive organic species is the cause of the progression of inflammation in various diseases. The molecules possessing both anti-inflammatory and antioxidant activity can be the promising key to treat inflammatory diseases. Phthalimide and hydrazinecarbothioamide are anti-inflammatory and anti-oxidant pharmacophores.. Molecular hybrids possessing above two pharmacophores were designed. A series of N-phenyl substituted 2-(2-(1,3-dioxoisoindolin-2-yl)acetyl)-N-phenylhydrazine-1-carbothioamide (CGS compounds) was synthesized and evaluated for biological activities.. N-phthaloylglycyl hydrazide was reacted with unsubstituted/substituted phenyl isothiocyanates to yield CGS compounds. Synthesized compounds were evaluated for in vivo anti-inflammatory activity in carrageenan rat paw edema model, and in vitro anti-oxidant activity by DPPH assay. Levels of TNF-α and oxidative stress at the site of inflammation were measured. The genetic algorithm-PLS regression based QSAR model correlating the effect of N-phenyl substituent on the anti-inflammatory activity was developed. Further, the interaction of the active compound in the TNF-α binding pocket was studied by in silico docking.. Compound containing the 2-OCH3, 4-NO2 (CGS-5); 4-CF3 (CGS-9); 4-NO2 (CGS-3) showed significant anti-inflammatory activity (percentage inhibition of paw edema after 3 hour = 58.24, 50.38, 40.05, respectively) and potent anti-oxidant activity (IC50 =0.045, 0.998, 0.285 μg/ml, respectively). Reduced levels of TNF- α and increased levels of GSH were observed for the above three compounds. Descriptors for QSAR model identified by GA-PLS were WPSA1, Weta1unity, WDunity, SC3, VC5, MlogP, and WTPT3. The identified model was highly predictive, and value of root mean square error of prediction for internal (leave one out) and external validation was: 1.579, 1.325.. Molecular hybrids of phthalimide and hydrazinecarbothioamide were synthesized. Some of the compounds possessed promising anti-inflammatory and anti-oxidant activities.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Chemistry Techniques, Synthetic; Drug Design; Edema; Hydrazines; Models, Molecular; Oxidative Stress; Phthalimides; Rats, Wistar; Thioamides

A variety of bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarboxamides) 2a-h were prepared via reaction of bis(2-propen-1-ones) 1a-h with thiosemicarbazide in ethanolic KOH solution. Meanwhile, bis(3-aryl-4,5-dihydro-1H-pyrazole-1-carboxamides) 3a-d were obtained through reaction of 1a-d with semicarbazide hydrochloride in refluxing with acetic acid. Anti-inflammatory activity screening of the synthesized compounds 2a-f,h; 3a-d (at a dose of 50mg/kg of body weight) utilizing in vivo acute carrageenan-induced paw oedema standard method in rats exhibited that many of the tested compounds reveal considerable anti-inflammatory properties, especially 2e and f which reveal remarkable activities relative to indomethacin (which was used as a reference standard at a dose of 10mg/kg of body weight). Ulcerogenic liability for the most promising prepared anti-inflammatory active agents (2b,c,e and f) (at a dose of 50mg/kg of body weight) using indomethacin as a reference standard (at a dose of 10mg/kg of body weight) indicated that compounds 2b and c exhibit lower ulcer index values than the used reference standard itself. PGE(2) inhibitory properties of the highly promising synthesized anti-inflammatory active agents (2b,c,e and f) were determined by PGE(2) assay kit technique, which reveal remarkable activities coincide greatly with the observed anti-inflammatory properties.

Topics: Amides; Animals; Anti-Inflammatory Agents; Dinoprostone; Drug Evaluation, Preclinical; Edema; Pyrazoles; Rats; Semicarbazides; Structure-Activity Relationship

Acetic acid hydrazide containing 5-methyl-2-benzoxazolinone (4) was synthesized by the condensation of 2-(5-methyl-2-benzoxazolinone-3-yl)acetate with hydrazine hydrate. Thiosemicarbazide derivatives (5a-5d) were afforded by the reaction of corresponding compound 4 with substituted isothiocyanates. The cyclization of compounds 5a-5d in the presence of triethylamine resulted in the formation of compounds 6a-6d containing 1,2,4-triazole ring. On the other hand, the treatment of compounds 5a-5d with orthophosphoric acid caused the conversion of side chain of compounds 5a-5d into 1,3,4-thiadiazole ring: thus, compounds 7a-7c were obtained. The treatment of compound 4 with aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (8a-8e). The structures of the compounds were elucidated by spectral and elemental analysis. While most compounds were exhibiting high activity in the analgesic-anti-inflammatory field, most of them were found to be inactive against bacteria and fungi.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Benzoxazoles; Crystallography, X-Ray; Edema; Hindlimb; Hydrazones; Methylation; Mice; Microbial Viability; Models, Molecular; Molecular Structure; Semicarbazides; Structure-Activity Relationship; Thiadiazoles; Triazoles

Topics: Edema; Lung Diseases; Pulmonary Edema; Semicarbazides; Thiosemicarbazones