Synthesis and biological evaluation of some thiazolylpyrazole derivatives as dual anti-inflammatory antimicrobial agents

• Published in: European journal of medicinal chemistry 2010-12, Vol.45 (12), p.6027-6038
• Main Authors: Bekhit, Adnan A., Fahmy, Hesham T.Y., Rostom, Sherif A.F., Bekhit, Alaa El-Din A.
• Format: Article
• Language: English
• Subjects: Acute toxicity; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; anti-Inflammatory activity; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial activity; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Candida albicans - drug effects; Carrageenan; Catalytic Domain; Cotton Fiber; COX inhibitory activity; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Edema - chemically induced; Edema - drug therapy; Escherichia coli - drug effects; General aspects; Granuloma - chemically induced; Granuloma - drug therapy; Humans; Male; Medical sciences; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Staphylococcus aureus - drug effects; Stereoisomerism; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Thiazolylpyrazoles; Ulcerogenic effect
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.10.001

The synthesis of a novel series of 4-thiazolylpyrazolyl derivatives is described in the present report. All the newly synthesized compounds were examined for their anti-inflammatory activity using cotton pellet-induced granuloma and carrageenan-induced rat paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity were also determined. Furthermore, all compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, Staphylococcus aureus and Candida albicans. A docking pose for compounds 8b, 10a and 10b separately in the active site of the human COX-2 enzyme and DNA-gyrase B was also obtained. The results revealed that compounds 8b, 10a and 10b exhibited good anti-inflammatory activity with no or minimal ulcerogenic effect and good safety margin. Compounds 10a and 10b were found to be the most potent anti-inflammatory agents in the present study. Meanwhile, 10a and 10b displayed higher selective inhibitory activity towards COX-2 compared to indomethacin. Moreover, compounds 10a and 10b exhibited promising antibacterial against both E. coli and S. aureus. Docking studies for 8b, 10a and 10b with COX-2 (PDB ID: 1CX2) and DNA-gyrase B (PDB ID: 1EI1) showed good binding profile. The synthesis of a novel series of 4-thiazolylpyrazolyl derivatives is described. The newly synthesized compounds were examined for their anti-inflammatory activity, inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity. All compounds were evaluated for their in vitro antimicrobial activity against E. coli, S. aureus and C. albicans. A docking pose for compounds 8b, 10a and 10b separately in the active site of the human COX-2 enzyme and DNA-gyrase B was also obtained. The results revealed that compounds 10a and 10b would represent a fruitful matrix for the development of a new class of dual anti-inflammatory antimicrobial agents. [Display omitted]