Cinnamide Derivatives as Mammalian Arginase Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

Abstract

Arginases are enzymes that are involved in many human diseases and have been targeted for new treatments. Here a series of cinnamides was designed, synthesized and evaluated in vitro and in silico for their inhibitory activity against mammalian arginase. Using a microassay on purified liver bovine arginase (b-ARG I), (E)-N-(2-phenylethyl)-3,4-dihydroxycinnamide, also named caffeic acid phenylamide (CAPA), was shown to be slightly more active than our natural reference inhibitor, chlorogenic acid (IC50 = 6.9 ± 1.3 and 10.6 ± 1.6 µM, respectively) but it remained less active that the synthetic reference inhibitor Nω-hydroxy-nor-l-arginine nor-NOHA (IC50 = 1.7 ± 0.2 µM). Enzyme kinetic studies showed that CAPA was a competitive inhibitor of arginase with Ki = 5.5 ± 1 µM. Whereas the activity of nor-NOHA was retained (IC50 = 5.7 ± 0.6 µM) using a human recombinant arginase I (h-ARG I), CAPA showed poorer activity (IC50 = 60.3 ± 7.8 µM). However, our study revealed that the cinnamoyl moiety and catechol function were important for inhibitory activity. Docking results on h-ARG I demonstrated that the caffeoyl moiety could penetrate into the active-site pocket of the enzyme, and the catechol function might interact with the cofactor Mn2+ and several crucial amino acid residues involved in the hydrolysis mechanism of arginase. The results of this study suggest that 3,4-dihydroxycinnamides are worth being considered as potential mammalian arginase inhibitors, and could be useful for further research on the development of new arginase inhibitors.

Inhibitory Effect on Arginase and Total Phenolic Content Determination of Extracts from Different parts of Melastoma malabathricum L.

“…6 It contains some phenolic compound such as quercetin, 6 epicathecin, epicathecin galat, kaempferol 6,26 which is suspected as responsible compound for inhibitor of mamalia arginase 1 also cinnamic acid derivate 27 which can be also responsible for the inhibitory effect on arginase. 28 These compound worked synergistically in the extract and showed higher arginase inhibitory effect on arginase than other Part extract of the plant. In other study, flavonol and epicatechin from Cocoa showed inhibition of arginase in HUVEC, 29 Flavanone from Scutellaria indica showed inhibition of arginase in mice kidney lisate.…”

Phenolic Compounds as Arginase Inhibitors: New Insights Regarding Endothelial Dysfunction Treatment

“…However, many of these prototypes have an unfavourable toxicological profile, with high potency (subnanomolar range), especially in relation to hepatocytes, which results in them being decharacterised as new inhibitors unless such obstacles are improved by means of structural, molecular, or pharmacotechnical modifications (prodrug and vector-based dosage forms). Furthermore, another issue to be addressed is the inappropriate (oral) pharmacokinetic profile presented by most of the available inhibitors, since in most cases these are substances whose structures are based on amino acids, which easily lose stability (very short half-life) and potency at physiological pH [121].…”

Arginase Inhibitory, Antioxidant Activity, Total Phenolic Content and Total Flavonoid Content of Ethyl Acetate Extract of Caesalpiniaturtuosa Roxb Stem Bark

“…NO is a crucial vasoconstrictor. 9 Besides, excess of ornithine causes vascular structural problems and neural toxicity. 7 Also related to abnormal arginase activity, previous study showed that urea at certain concentrations can induce reactive oxygen species (ROS) production which further cause activation of pro-inflammatory pathways, and inactivation of the anti-atherosclerosis.…”

“…Inhibiting arginase activity has proven to be beneficially useful in various illness such as hypertension, erectile dysfunction, diabetic renal injury, myocardial ischemiareperfusion injury. 9 Arginase inhibitor is compounds that interact with arginase which reduce the activity of this enzyme and increase the availability of L-arginine as substrate for NOS resulting in NO balancing. First generation of arginase inhibitor is N-hydroxy-l-arginine (NOHA) and N-hydroxy-nor-l-arginine (nor-NOHA), characterized by N-hydroxy-guanidinium side chains.…”