Design and synthesis of new 1,3,4-oxadiazole-1,2,3,4-tetrahydroisoquinoline hybrids as selective COX-2 inhibitors

A series of 1,3,4-oxadiazole tetrahydroisoquinoline hybrids 6a-o was designed and synthesized aiming to search for new and safe anti-inflammatory agents. The compounds were assessed in vitro for their inhibitory effects on the COX-1 and COX-2 isoenzymes. Notably, the tested derivatives 6b, 6k and 6o exhibited high potency on COX-2 with IC₅₀ values 1.72, 0.89 and 1.05 μM, respectively-comparable to that of the reference drug celecoxib (IC₅₀ = 0.82 μM). Fortunately, these three compounds also exhibited moderate selectivity indices (SI = 4.56-16.87) which are higher than that of meloxicam (SI = 2.15) and lower than that of celecoxib (SI = 18.3). This finding is matched with our design of the compounds to search for new NSAIDs that are selective but not specific to COX-2. Accordingly, these derivatives were selected for in vivo anti-inflammatory evaluation using the carrageenan-induced rat paw edema assay where compounds 6k and 6o exhibited superior anti-inflammatory activities at all time intervals compared to reference drug celecoxib. Moreover, a significant reduction in the inflammatory mediators production (PGE-2, TNF-α and IL-6) was observed following treatment with these compounds. Furthermore, all the compounds exhibited a safe gastric profile (UI = 2.33-6.33) compared to indomethacin (UI = 15.33), also compounds 6b and 6k showed close non-significant UI value (UI = 2.33 and 4, respectively) compared to the safe celecoxib (UI = 2.66). Moreover, histopathological investigations showed that oral treatment with the most promising compound 6k revealed mild to moderate lesions in rat paw skin and gastric mucosa. Finally, molecular docking studies were conducted to predict the binding interactions of compounds 6b, 6k and 6o on both COX-1 and COX-2 isoenzymes.

1,2,3,4-tetrahydroisoquinoline; 1,3,4-Oxadiazoles; Anti-inflammatory; COX-2 inhibitors.