EFMC-ASMC International Symposium on Advances in Synthetic and Medicinal Chemistry, Zagreb, Croatia, 3 - 07 September 2023, pp.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.