Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents.

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Bekhit AA, Ashour HM, Abdel Ghany YS, Bekhit Ael-D, Baraka A

Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents.

Eur J Med Chem. 2008 Mar;43(3):456-63. Epub 2007 Apr 14.

PubMed ID

17532544 [ View in PubMed

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Abstract

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).

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Indomethacin	Prostaglandin G/H synthase 2	IC 50 (nM)	2630	N/A	N/A	Details