Design and Synthesis of Aza-/Oxa Heterocycle-Based Conjugates as Novel Anti-Inflammatory Agents Targeting Cyclooxygenase‑2

A library
of hybrid molecules was procured by the combination of
triazine–indole adduct with morpholine/piperidine/pyrrolidine
and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound 6 having an IC50 value of 20 nM for COX-2 and 3000
nM for COX-1. The significant reduction in the formation of prostaglandin
E2 in the lipopolysaccharide-treated (COX-2-activated)
human whole blood, almost no change in the production of thromboxane
B2 in the calcium ionophore-treated (COX-1-activated) sample
of human whole blood, and the mechanistic studies on Swiss albino
mice ensured that compound 6 is selective for COX-2.
The association constant (Ka) of compound 6 with COX-2 was found to be of the order of 0.48 × 106 M–1. The diffusion spectroscopy experiments
and relaxation time (T1) calculations
of compound 6 in the presence of COX-2 assisted in identifying
the site-specific interactions of 6 with the enzyme,
and these results fall into nice correlation with the theoretical
data obtained from molecular docking and quantitative structure–activity
relationship studies. With maximum tolerable dose >2000 mg kg–1, compound 6 made 68 and 32% reduction
in formalin-induced analgesia and carrageenan-induced inflammation
in Swiss albino mice.