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• Hybrids from tetrahydro-1H-pyrazolo[3,4- b quinolines were designed and prepared. • The compounds were tested for their dual activity as AChE / COX-2 inhibitors. • All compounds showed activities comparable to or significantly higher than tacrine. • Most of the compounds showed activities comparable to celecoxib. • All compounds showed a safe hepatic profile via hepatotoxicity testing. New tetrahydro-1 H -pyrazolo[3,4- b quinoline derivatives were designed, synthesized and characterized as dual anticholinestrase and cyclooxygenase-2 inhibitors. The in vitro and in vivo anti-cholinesterase evaluation exhibited promising activities with lower hepatotoxicity for many candidates compared to tacrine as a reference. Furthermore, their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay demonstrated superior activity to celecoxib with higher selectivity indices for some compounds. In addition, some candidates showed extended anti-inflammatory activity by inhibiting COX-2 protein induction. Besides, in silico docking experiments of the active compounds against h AChE rationalized the observed in vitro AChE inhibitory activity. In conclusion, this work provides an extension of the chemical space of tetrahydro-1 H -pyrazolo[3,4- b quinoline chemotype for the anticholinestrase and anti-inflammatory activity. This would aid to minimize the possible neuroinflammation linked to the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]