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• A variety of tri-substituted pyrazole derivatives 3 - 15 were synthesized and evaluated for their anti-inflammatory, analgesic, antipyretic and ulcerogenic properties. • Some of the tested conjugates showed promising biological observations comparable to standard reference celecoxib, in addition, to their safety margin for gastric mucosa when evaluated for their ulcer-producing activity. • The most potent derivatives 3a, 3b, 6, 8 and 11 were assayed for their COX-2, TNF-α, PGE2 and IL1β levels in rat paws using the carrageenan inflammation model with the ELISA kit. • Compound 8 possesses the best promising anti-inflammatory observations, antipyretic effect and long-lasting analgesic activity without ulcerogenic potential in addition to showing mutual inhibitory effects on all tested enzymes. • A molecular docking study was introduced to recognize the binding interactions of the most potent candidates into active sites of COX-2 and TNF-α. • Compound 8 has the best binding interaction scores with both targeted enzymes that supported its obtained bio-observations and proves that it has the potential to be developed into an anti-inflammatory drug. Starting from the precursors 3-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1) and 3-(4-bromophenyl)-1-ethyl-1 H -pyrazole-4-carbaldehyde (2), a variety of trisubstituted pyrazole derivatives 3 - 15 were synthesized and evaluated for their anti-inflammatory, analgesic, antipyretic and ulcerogenic properties. Derivatives 3a, 3b, 6, 8 and 11 showed promising anti-inflammatory observations with potencies of 99.5, 100.3, 92.4, 77.1 and 103.1, respectively, compared with celecoxib the used standard reference, they also exhibited a promising onset action of analgesic with efficiency superior to the used reference drug, in addition to their antipyretic effect and safety margin for gastric mucosa compared with the reference drugs. Based on the obtained observations, derivatives 3a, 3b, 6, 8 and 11 were assayed for their COX-2, TNF- α , PGE2 and IL1 β levels in rat paws using the carrageenan inflammation model with the ELISA kit. Compound 8 has the best promising anti-inflammatory observations, antipyretic effect and long-lasting analgesic activity without ulcerogenic potential in addition to showing mutual inhibitory effects on all tested enzymes. Furthermore, a molecular docking study was introduced to recognize the binding interactions of the most potent candidates 3a, 3b, 6, 8 and 11 into the active sites of COX-2 and TNF- α. Compound 8 has the best binding interaction scores with both targeted enzymes that supported its obtained bio-observations and prove that it has the potential to be developed into an anti-inflammatory drug. [Display omitted] [ABSTRACT FROM AUTHOR]