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A new series of 1,3,5-triaryl-4,5-dihydro-1 H -pyrazole 10a – l was designed and synthesized via cyclization of chalcones 8a – f with 4-amino/methanesulfonylphenylhydrazine hydrochloride 9a – b . All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity, ulcerogenic liability and analgesic activity. All compounds were more COX-2 inhibitors than COX-1. While most compounds showed good anti-inflammatory activity, the trimethoxy derivatives ( 10a , 10b, 10g and 10h ) were the most potent derivatives (ED 50 = 55.78, 53.99, 67.65 and 69.20 μmol/kg respectively) in comparison with celecoxib (ED 50 = 82.15 μmol/kg). Compounds 10a , 10b, 10g and 10h (ulcer index = 2.68, 1.20, 2.63 and 2.66 respectively) showed less ulceration effect than celecoxib (ulcer index = 2.90). Also, Compounds 10a , 10b, 10g and 10h showed analgesic activity higher than celecoxib and comparable to that of ibuprofen. In addition, molecular docking studies were performed for compounds 10a , 10b, 10g and 10h and the results were in agreement with that obtained from the in vitro COX inhibition assays. [ABSTRACT FROM AUTHOR]

• A novel class of trisubstituted pyrazolines as PDE5 inhibitors was discovered. • The compounds were developed inspired by the off-target activity of celecoxib against PDE5. • The developed compounds showed promising selectivity profile. • The developed compounds could increase intracellular cGMP levels in HEK293 cells. Celecoxib, is a selective cyclooxygenase-2 (COX2) inhibitor with a 1,5-diaryl pyrazole scaffold. Celecoxib has a better safety profile compared to other COX2 inhibitors having side effects of systemic hypertension and thromboembolic complications. This may be partly attributed to an off-target activity involving phosphodiesterase 5 (PDE5) inhibition and the potentiation of NO/cGMP signalling allowing coronary vasodilation and aortic relaxation. Inspired by the structure of celecoxib, we synthesized a chemically diverse series of compounds containing a 1,3,5-trisubstituted pyrazoline scaffold to improve PDE5 inhibitory potency, while eliminating COX2 inhibitory activity. SAR studies for PDE5 inhibition revealed an essential role for a carboxylic acid functionality at the 1-phenyl and the importance of the non-planar pyrazoline core over the planar pyrazole with the 5-phenyl moiety tolerating a range of substituents. These modifications led to new PDE5 inhibitors with approximately 20-fold improved potency to inhibit PDE5 and no COX-2 inhibitory activity compared with celecoxib. PDE isozyme profiling of compound 11 revealed a favorable selectivity profile. These results suggest that trisubstituted pyrazolines provide a promising scaffold for further chemical optimization to identify novel PDE5 inhibitors with potential for less side effects compared with available PDE5 inhibitors used for the treatment of penile erectile dysfunction and pulmonary hypertension. [ABSTRACT FROM AUTHOR]