4-Methylcoumarin Derivatives Inhibit Human Neutrophil Oxidative Metabolism and Elastase Activity

Abstract

Increased neutrophil activation significantly contributes to the tissue damage in inflammatory illnesses; this phenomenon has motivated the search for new compounds to modulate their effector functions. Coumarins are natural products that are widely consumed in the human diet. We have evaluated the antioxidant and immunomodulator potential of five 4-methylcoumarin derivatives. We found that the 4-methylcoumarin derivatives inhibited the generation of reactive oxygen species by human neutrophils triggered by serum-opsonized zymosan or phorbol-12-myristate-13-acetate; this inhibition occurred in a concentration-dependent manner, as revealed by lucigenin-and luminol-enhanced chemiluminescence assays. Cytotoxicity did not mediate this inhibitory effect. The 7,8-dihydroxy-4-methylcoumarin suppressed the neutrophil oxidative metabolism more effectively than the 6,7-and 5,7-dihydroxy-4-methylcoumarins, but the 5,7-and 7,8-diacetoxy-4-methylcoumarins were less effective than their hydroxylated counterparts. An analysis of the biochemical pathways suggested that the 6,7-and 7,8-dihydroxy-4-methylcoumarins inhibit the protein kinase C-mediated signaling pathway, but 5,7-dihydroxy-4-methylcoumarin, as well as 5,7-and 7,8-diacetoxy-4-methylcoumarins do not significantly interfere in this pathway of the activation of the human neutrophil oxidative metabolism. The 4-methylcoumarin derivatives bearing the catechol group suppressed the elastase and myeloperoxidase activity and reduced the 1,1-diphenyl-2-picrylhydrazyl free radical the most strongly. Interestingly, the 5,7-dihydroxy-4-methylcoumarin scavenged hypochlorous acid more effectively than the o-dihydroxy-substituted 4-methylcoumarin derivatives, and the diacetoxylated 4-methylcoumarin derivatives scavenged hypochlorous acid as effectively as the 7,8-dihydroxy-4-methylcoumarin. The significant influence of small structural modifications in the inhibitory potential of 4-methylcoumarin derivatives on the effector functions of neutrophil makes them interesting candidates to develop new drugs for the treatment of inflammatory diseases mediated by increased neutrophil activation.KEY WORDS: antioxidant chemiluminescence elastase hypochlorous acid immunomodulation 4-methylcoumarin myeloperoxidase neutrophil protein kinase C

Screening and evaluation of cytotoxicity and antiviral effects of secondary metabolites from water extracts of Bersama abyssinica against SARS-CoV-2 Delta

“…The presence of 2,4-di-tert-butylphenol in water extract could have contributed to activity against SARS-CoV-2, which is reported by other studies [ 45 , 46 ] and presence of 7,8-Dihydroxy-4-methylcoumarin and 2,3, 6-trimethoxyflavone in the same extract have increased activity against SARS-CoV-2, which was reported to have antioxidant properties [ 47 , 48 ], enhancing viral inhibition. In addition, 4-formyl-2-methoxyphenyl propionate was also identified in water extract which has various pharmacological uses including anticardiovasular, antioxidant and anti-inflammatory [ 49 ] that would have enhanced inhibition in SARS-CoV-2 B1.…”

4-methylesculetin, a coumarin derivative, ameliorates dextran sulfate sodium-induced intestinal inflammation

“…Since MPO activity is directly proportional to neutrophils migration and it is also responsible for the reduction in the antioxidant defenses of the intestinal epithelia [31], the inhibition of MPO activity accompanied by GSH maintenance in treated animals, confirms the intestinal antioxidant and anti-inflammatory effects of 4-methylesculetin. Besides, 4-ME is the most potent inhibitory compound on the neutrophils oxidase metabolism, inhibiting MPO and elastase enzymes activities and acting as HOCl scavenger [32].…”

Screening and Evaluation of Cytotoxicity and Antiviral Effects of Secondary Metabolites from Water Extracts of Bersama abyssinica against SARS-CoV-2 Delta

“…The water extract of B. abyssinica yielded polyphenols especially the coumarin and avonoids which are reported to have high antiviral activity against Corona virus [26]. High antiviral activity from water extract could be due to presence of 2,4-di-tert-butylphenol that is well studied with antiviral activity [27,28] and strong antioxidant properties of 7,8-Dihydroxy-4-methylcoumarin and 2,3, 6-trimethoxy avone [29,30], enhancing viral inhibition. In addition, 4-formyl-2-methoxyphenyl propionate identi ed in water extract has various pharmacological uses including anticardiovasular and anti-in ammatory [31] that would enhance inhibition in SARS-CoV-2…”