Novel click modifiable thioquinazolinones as anti-inflammatory agents: Design, synthesis, biological evaluation and...

Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC₅₀ (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC₅₀ 0.05 μM), diclofenac (IC₅₀ 0.8 μM) and indomethacin (IC₅₀ 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC₅₀ (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC₅₀ 2.41 μM) and Meclofenamate sodium (IC₅₀ 5.64 μM) as positive controls. These compounds were further challenged by PMA-induced THP-1 differentiation assay where compounds 2c and 3j inhibited monocyte to macrophage differentiation efficiently with IC₅₀ values of 4.78 μM and 5.63 μM, respectively, compared to that of diclofenac sodium (4.86 μM). On the other hand, 3h demonstrated a significantly increased potency compared to diclofenac in this assay (IC₅₀ = 0.13 μM). The same compounds exhibited significant in vivo anti-inflammatory effect as indicated by the formalin-induced rat-paw edema test. Docking experiments of compounds 2c, 3b, 3h, 3j, and 3k into COX-2 binding pocket have been conducted, where strong binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration, Molsoft and Pre-ADMET software products.