1. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents
Adnan A Bekhit, Hayam M A Ashour, Yasser S Abdel Ghany, Alaa El-Din A Bekhit, Azza Baraka Eur J Med Chem. 2008 Mar;43(3):456-63. doi: 10.1016/j.ejmech.2007.03.030. Epub 2007 Apr 14.
Four series of pyrazolyl benzenesulfonamide derivatives have been synthesized. The first series was prepared by cyclization of the intermediate N,N-dimethylaminomethylene-4[3-phenyl-4-(substituted thiosemicarbamoyl hydrazonomethyl)-1H-pyrazol-1-yl]benzenesulfonamide 2a-c with ethyl bromoacetate to afford the corresponding thiazolidinyl derivatives 3a-c. The second series was prepared by cyclization of the key intermediates 2a-c with 4-bromophenacyl bromide giving rise to thiazolinyl derivatives 4a-c. Thiadiazolyl derivatives 5a-c were obtained by heating 2a-c with 2M FeCl(3) solution. Refluxing the intermediates 2a-c in acetic anhydride yielded the corresponding thiadiazolinyl derivatives 6a-c. All the target compounds showed anti-inflammatory activity and three of them 3b, 3c and 4c surpassed that of indomethacin both locally and systemically in the cotton pellet granuloma and rat paw edema bioassay. The active compounds showed selective inhibitory activity towards COX-2 enzyme as revealed by the in vitro enzymatic assay. All the tested compounds proved to have superior gastrointestinal (GI) safety profiles as compared to indomethacin, when tested for their ulcerogenic effects. The acute toxicity study of compounds having promising anti-inflammatory activity (3b, 3c and 4c) indicated that they are well tolerated both orally and parenterally. Antimicrobial activity tests expressed as minimal inhibitory concentrations (MIC), revealed that compounds 3b and 4a showed comparable antibacterial activity to that of ampicillin against Escherichia coli, while compounds 3a, 3c and 4a possessed about half the activity of ampicillin against Staphylococcus aureus. On the other hand, the results showed that all the tested compounds have weak or no antifungal activity against Candida albicans except for compounds 6b and 6c that showed half the activity of the control antifungal drug used (clotrimazole).
2. Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents
Adnan A Bekhit, Tarek Abdel-Aziem Bioorg Med Chem. 2004 Apr 15;12(8):1935-45. doi: 10.1016/j.bmc.2004.01.037.
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.
3. Synthesis and biological evaluation of some hydroxypyrazole derivatives as anti-inflammatory-antimicrobial agents
Adnan A Bekhit, Hamdy M Abdel-Rahman, Aida A Guemei Arch Pharm (Weinheim). 2006 Feb;339(2):81-7. doi: 10.1002/ardp.200500197.
Some hydroxypyrazole derivatives 2-7 were synthesized by cyclocondensation of the keto-ester 1 with hydrazines hydrate or substituted hydrazines followed by reduction and acylation with acetic anhydride or trifluoroacetic anhydride. The newly synthesized compounds were evaluated for their anti-inflammatory, antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compounds N-(4-(5-hydroxy-1-trifluoroacetyl-1H-pyrazol-3-yl)phenyl) trifluoroacetamide 4b, 3-(4-nitrophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ol 5b, and N-(4-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)phenyl)trifluoroacetamide 7b were proved to be the most active anti-inflammatory, antimicrobial agents in the present study with a good safety margin and minimal or no ulcerogenic effect.
