Polyphenols are plant secondary metabolites which possess many positive effects on human health. Although these beneficial effects could be mediated through an increase in nitric oxide synthase activity, little is known regarding the inhibitory effect of polyphenols on mammal arginase, an enzyme which competes with nitric oxide synthase for their common substrate, L-arginine. The aim of the present study was to determine the potential of a series of polyphenols as mammalian arginase inhibitors and to identify some structure-activity relationships. For this purpose, we first developed a simple and cost-effective colorimetric microplate method using commercially-available mammal bovine liver arginase (b-ARG 1). Among the ten tested polyphenolic compounds [chlorogenic acid, piceatannol, resveratrol, (-)-epicatechin, taxifolin, quercetin, fisetin, caffeic acid, quinic acid, and kaempferol], cholorogenic acid and piceatannol exhibited the highest inhibitory activities (IC = 10.6 and 12.1 µM, respectively) but were however less active as ()-(2-Boronoethyl)-L-cysteine (IC = 3.3 µM), used as reference compound. Enzyme kinetic studies showed that both chlorogenic acid and piceatannol are competitive arginase inhibitors. Structural data identified the importance of the caffeoyl (3,4-dihydroxycinnamoyl)-part and of the catechol function in the inhibitory activity of the tested compounds. These results identified chlorogenic acid and piceatannol as two potential core structures for the design of new arginase inhibitors.

Essential oils or their components are increasingly used to fight bacterial infections. Cinnamaldehyde (CNA), the main constituent of cinnamon bark oil, has demonstrated interesting properties in vitro against various pathogens, including Pseudomonas aeruginosa. In the present study, we investigated the mechanisms and possible therapeutic consequences of P. aeruginosa adaptation to CNA. Exposure of P. aeruginosa PA14 to subinhibitory concentrations of CNA caused a strong albeit transient increase in the expression of operons that encode the efflux systems MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY/OprM. This multipump activation enhanced from 2- to 8-fold the resistance (MIC) of PA14 to various antipseudomonal antibiotics, including meropenem, ceftazidime, tobramycin, and ciprofloxacin. CNA-induced production of pump MexAB-OprM was found to play a major role in the adaption of P. aeruginosa to the electrophilic biocide, through the NalC regulatory pathway. CNA was progressively transformed by bacteria into the less toxic metabolite cinnamic alcohol (CN-OH), via yet undetermined detoxifying mechanisms. In conclusion, the use of cinnamon bark oil or cinnamaldehyde as adjunctive therapy to treat P. aeruginosa infections may potentially have antagonistic effects if combined with antibiotics because of Mex pump activation.

The inhibition of arginase is of substantial interest for the treatment of various diseases of public health interest including cardiovascular diseases. Using an ex vivo experiment on rat aortic rings and an in vitro assay with liver bovine purified arginase, it was demonstrated that several polyphenolic extracts from Cyperus and Carex species possess vasorelaxant properties and mammalian arginase inhibitory capacities. Phytochemical studies performed on these species led to the identification of eight compounds, including monomers, dimers, trimers, and tetramers of resveratrol. The potential of these stilbenes as inhibitors of mammalian arginase was assessed. Five compounds, scirpusin B (5), ε-viniferin (4), cyperusphenol B (6), carexinol A (7), and the new compound virgatanol (1), showed significant inhibition of arginase, with percentage inhibition ranging from 70% to 95% at 100 μg/mL and IC values between 12.2 and 182.1 μM, confirming that these stilbenes may be useful for the development of new pharmaceutical products.

!In an effort to identify novel inhibitors of arginase, a phytochemical study was performed on hempseed cakes (Cannabis sativa L.). It led to the isolation of a new lignanamide, cannabisin I (1), together with seven known lignanamides, cannabisins A, B, C, F, M, 3,3′-demethylgrossamide, grossamide, and two phenylpropanoid amides, N-trans-caffeoyltyramine and N-trans-caffeoyloctopamine, among which was later identified for the first time from C. sativa. Their structures were elucidated by comprehensive analysis of NMR spectroscopy and mass spectrometry data. These compounds were evaluated on mammal arginase (purified liver bovine arginase), showing that N-trans-caffeoyltyramine exhibited the higher activity with an IC 50 value of 20.9 µM, which remains, however, less active than the reference compound S-(2-boronoethyl)-l-cysteine (IC 50 = 4.3 µM). Radical scavenging capacity of these compounds was determined by the ORAC-FL method. All tested cannabisins displayed antioxidant activity close to or better than the reference compounds. N-trans-Caffeoyltyramine has both arginase inhibitory property and antioxidant capacity.

A quantum chemistry guided optimisation (leading to piceatannol analogue 3t) with a good understanding of the catechol binding mode to the bimanganese cluster of arginase.