Novel <i>N</i> -methylsulfonyl-indole derivatives: biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardio vascular risks

Abstract

Three novel series of <i>N</i>-methylsulfonylindole derivatives <b>3a&b</b>, <b>4a-e,</b> and <b>5a-e</b> were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds <b>4b</b>, <b>4e</b> and <b>5d</b> had selective antibacterial activity against the Gram-negative bacteria, <i>Salmonella enterica and/or E. coli</i>. The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. <i>In vitro</i> anti-inflammatory activity was estimated. Compounds <b>4d</b>, <b>4e</b>, <b>5b</b>, and <b>5d</b> showed the highest anti-inflammatory activity. The COX-1, COX-2 and 5-LOX inhibitory activities were measured using enzyme immune assay (EIA) kits. Due to the dual COX-2/5-LOX inhibitory activity of compound <b>5d</b>, its cardiovascular profile was determined by measuring cardiac biomarkers (LDH, CK-MB, and Tn-I). Besides, the histopathological study of the heart muscle and stomach were examined for the most active COX-2 inhibitors <b>4e</b> and <b>5d</b>. Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.