Abstract
Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d–f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO2NH2 or SO2Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0.5, 0.75, respectively), to celecoxib (UI: 0.50). Most of tested compounds showed potent central and/or peripheral analgesic activities. Histopathological investigations were done to evaluate test compounds effect on rat's gastric tissue. The obtained results were in consistent with the in vitro data on COX evaluation. Docking study was also done for all the target compounds inside COX-2-active site.
Highlights
Tetrazole represents an important class of heterocyclic compounds for biological and pharmacological applications
The tetrazole ring is a bioisostere of the carboxylic acid (–COOH) group so they have close pKa values, it has similar planar skeleton structure and nitrogen-rich multi-electron conjugated system[1,2,3,4]. It does not have the acidic –COOH properties, and so, it helps in decreasing toxic properties of drugs5. 1,2,3,4-Tetrazole derivatives possess potent pharmacological activities such as antimicrobial[6,7,8,9], antihypertensive[10,11], anticonvulsant[12,13], anticancer[14,15], analgesic[4,16], antiulcer[17] and anti-inflammatory[3,18,19,20,21,22]
Non-steroidal anti-inflammatory drugs (NSAIDs) are of great importance in the treatment of inflammation and pain. They act by inhibiting cyclooxygenase enzymes (COXs) – a membrane-bound haeme protein – that control the conversion of arachidonic acid to prostaglandins and thromboxanes
Summary
Tetrazole represents an important class of heterocyclic compounds for biological and pharmacological applications. 1,2,3,4-Tetrazole derivatives possess potent pharmacological activities such as antimicrobial[6,7,8,9], antihypertensive[10,11], anticonvulsant[12,13], anticancer[14,15], analgesic[4,16], antiulcer[17] and anti-inflammatory[3,18,19,20,21,22]. Non-steroidal anti-inflammatory drugs (NSAIDs) are of great importance in the treatment of inflammation and pain. They act by inhibiting cyclooxygenase enzymes (COXs) – a membrane-bound haeme protein – that control the conversion of arachidonic acid to prostaglandins and thromboxanes. Two distinct isoforms of COX enzyme are present, a constitutive form (COX-1), associated with several side effects such as haemorrhagia and gastrointestinal (GI)
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