Novel N -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 N -methylsulfonylindole derivatives 3a&b , 4a–e, and 5a–e were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds 4b , 4e and 5d had selective antibacterial activity against the Gram-negative bacteria, Salmonella enterica and/or E. coli . The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. In vitro anti-inflammatory activity was estimated. Compounds 4d , 4e , 5b , and 5d 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 5d , 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 4e and 5d . Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.

Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies

“…The inhibitory activities of the test compounds against COX-1 and COX-2 enzymes were determined by enzyme immune assay (EIA) kits (Cayman Chemical, Ann Arbour, MI, USA) using COX-1 (ovine) and COX-2 (human recombinant) according to reported methods 63 – 65 . The inhibitory activity was measured and reported as IC 50 value (µM).…”

“…The ability of the test compounds to inhibit the 5-LOX enzyme was evaluated using the Human Lipoxygenase Inhibitor screening assay (EIA) kit (Cayman Chemical). The IC 50 values were measured in µM according to the manufacturer’s instructions and reported method 63 – 65 . Data are expressed as IC 50 ± SEM for triplicate studies.…”

Coumarin-chalcone hybrid LM-021 and indole derivative NC009-1 targeting inflammation and oxidative stress to protect BE(2)-M17 cells against α-synuclein toxicity

“…The underlying mechanisms for anti-inflammatory properties of NC009-1 remain to be determined. However, we propose that it may have COX-inhibiting activity as the other indole derivatives have shown [ 40 , 41 ]. Since NC009-1 has chemical chaperone activity as shown by thioflavin T assay in the present study and also activate chaperone HSPB1 in our previous study [ 23 ], its chaperone activity may reduce α-synuclein aggregation to diminish microglia activation.…”

Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof

“…Dual inhibition of COX-1/COX-2 upregulates 5-LOX pathway, so it increases LTs synthesis 33 . Consequently, simultaneous inhibition of COX-2 and 5-LOX enzymes could decrease the side effects of anti-inflammatory candidates 34 , 35 . On the other hand, 1,5-diarylpyrazole was a major pharmacophore in various selective COX-2 inhibitors like celecoxib I .…”