Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory, analgesic and antimicrobial agents. 2009

Sherif A F Rostom, and Ibrahim M el-Ashmawy, and Heba A Abd el Razik, and Mona H Badr, and Hayam M A Ashour
Department of Medicinal Chemistry, Faculty of Medicine, King Abdulaziz University, PO Box 80205, Jeddah 21589, Saudi Arabia. sherifrostom@yahoo.com

The synthesis of two groups of structure hybrids comprising basically the antipyrine moiety attached to either polysubstituted thiazole or 2,5-disubstituted-1,3,4-thiadiazole counterparts through various linkages is described. Twelve out of the newly synthesized compounds were evaluated for their anti-inflammatory activity using two different screening protocols; namely, the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays, using diclofenac Na as a reference standard. The ulcerogenic effects and acute toxicity (ALD(50)) values of these compounds were also determined. Meanwhile, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity. In general, compounds belonging to the thiazolylantipyrine series exhibited better biological activities than their thiadiazolyl structure variants. Collectively, compounds 6, 10, 26, and 27 proved to display distinctive anti-inflammatory and analgesic profiles with a fast onset of action. All of the tested compounds revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD(50)>3.0 g/kg). Meanwhile, compounds 7, 10, 11, and 23 are considered to be the most active broad spectrum antimicrobial members in this study. Compound 10 could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic and antibacterial profile.

UI MeSH Term Description Entries
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D000700 Analgesics Compounds capable of relieving pain without the loss of CONSCIOUSNESS. Analgesic,Anodynes,Antinociceptive Agents,Analgesic Agents,Analgesic Drugs,Agents, Analgesic,Agents, Antinociceptive,Drugs, Analgesic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000894 Anti-Inflammatory Agents, Non-Steroidal Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. Analgesics, Anti-Inflammatory,Aspirin-Like Agent,Aspirin-Like Agents,NSAID,Non-Steroidal Anti-Inflammatory Agent,Non-Steroidal Anti-Inflammatory Agents,Nonsteroidal Anti-Inflammatory Agent,Anti Inflammatory Agents, Nonsteroidal,Antiinflammatory Agents, Non Steroidal,Antiinflammatory Agents, Nonsteroidal,NSAIDs,Nonsteroidal Anti-Inflammatory Agents,Agent, Aspirin-Like,Agent, Non-Steroidal Anti-Inflammatory,Agent, Nonsteroidal Anti-Inflammatory,Anti-Inflammatory Agent, Non-Steroidal,Anti-Inflammatory Agent, Nonsteroidal,Anti-Inflammatory Analgesics,Aspirin Like Agent,Aspirin Like Agents,Non Steroidal Anti Inflammatory Agent,Non Steroidal Anti Inflammatory Agents,Nonsteroidal Anti Inflammatory Agent,Nonsteroidal Anti Inflammatory Agents,Nonsteroidal Antiinflammatory Agents
D000900 Anti-Bacterial Agents Substances that inhibit the growth or reproduction of BACTERIA. Anti-Bacterial Agent,Anti-Bacterial Compound,Anti-Mycobacterial Agent,Antibacterial Agent,Antibiotics,Antimycobacterial Agent,Bacteriocidal Agent,Bacteriocide,Anti-Bacterial Compounds,Anti-Mycobacterial Agents,Antibacterial Agents,Antibiotic,Antimycobacterial Agents,Bacteriocidal Agents,Bacteriocides,Agent, Anti-Bacterial,Agent, Anti-Mycobacterial,Agent, Antibacterial,Agent, Antimycobacterial,Agent, Bacteriocidal,Agents, Anti-Bacterial,Agents, Anti-Mycobacterial,Agents, Antibacterial,Agents, Antimycobacterial,Agents, Bacteriocidal,Anti Bacterial Agent,Anti Bacterial Agents,Anti Bacterial Compound,Anti Bacterial Compounds,Anti Mycobacterial Agent,Anti Mycobacterial Agents,Compound, Anti-Bacterial,Compounds, Anti-Bacterial
D000983 Antipyrine An analgesic and antipyretic that has been given by mouth and as ear drops. Antipyrine is often used in testing the effects of other drugs or diseases on drug-metabolizing enzymes in the liver. (From Martindale, The Extra Pharmacopoeia, 30th ed, p29) Phenazone,Anodynin,Pyramidone
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013830 Thiadiazoles Heterocyclic compounds composed of a five-membered heterocyclic ring which contains one sulfur and two nitrogen atoms. Thiadiazole
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs

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