Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents.
The synthesis of novel series of structurally related 1H-pyrazolyl derivatives is described. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity by two different bioassays namely; cotton pellet-induced granuloma and sponge implantation model of inflammation in rats. In addition, COX-1 and COX-2 inhibitory activities, ulcerogenic effects and acute toxicity were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The combined anti-inflammatory data from local and systemic in vivo animal models showed that compounds 4, 5, 8, 9, 11 and 12a exhibited anti-inflammatory activity comparable to that of indomethacin with no or minimal ulcerogenic effects and high safety margin (LD(50)>500 mg/Kg). In addition, compounds 4, 7, 10, 12a and 12b displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 4 and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory potency and their pronounced antibacterial activities comparable to ampicillin against Gram positive. On the other hand, compound 12a exhibited good selective inhibitory activity against COX-2 enzyme. Therefore, such compound would represent a fruitful matrix for the development of anti-inflammatory-antimicrobial candidates.
Bekhit
Adnan A
AA
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria 21521, Egypt. adnbekhit@hotmail.com
Abdel-Aziem
Tarek
T
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; C031280:pyrazole