A New Series of Hydrazone-Based Anti-Inflammatory Agents Endowed with Selective COX-1 Inhibitory Potency

EFMC-ASMC International Symposium on Advances in Synthetic and Medicinal Chemistry, Zagreb, Hırvatistan, 3 - 07 Eylül 2023, ss.95

Cyclooxygenase-1 (COX-1) has received less attention than cyclooxygenase-2 (COX-2) as a biological target for

the development of selective inhibitors because of the paradigm stating that the constitutively expressed COX-1

serves a homeostatic function in most tissues and it is responsible for the synthesis of prostaglandins, thus

exerting cytoprotective action along with the regulation of platelet activity, gastric and renal functions under

normal physiological conditions. Recent data highlighting the involvement of COX-1 in the pathogenesis of

cancer, inflammation, cardiovascular diseases and pain have changed this paradigm and therefore the

development of selective COX-1 inhibitors has come into prominence.1,2

In an effort to identify selective COX-1 inhibitors, herein, new hydrazone derivatives carrying an indole scaffold

were synthesized. These compounds were subjected to in vitro studies, which were conducted to assess their

inhibitory effects on COX-1 and COX-2 using COX inhibitor screening assay. Compound 2 (Fig. 1) (IC50= 8.90

μM for COX-1; 71.00 μM for COX-2) was found as a selective COX-1 inhibitor in this series as compared to

indomethacin (IC50= 0.12 μM for COX-1; 0.58 μM for COX-2). The in vitro cytotoxic activity of compound 2

towards L929 mouse fibroblast cells was also evaluated. Based on this assay, compound 2 did not exert

cytotoxicity towards L929 cells at its effective concentration. Lipopolysaccharide-induced sepsis model was

used to assess its in vivo anti-inflammatory activity. Compound 2 decreased serum myeloperoxidase (MPO) and

nitric oxide (NO) levels pointing out its anti-inflammatory action. Furthermore, compound 2 diminished serum

aminotransferase (particularly aspartate aminotransferase (AST)) levels.