To semiquantitatively estimate the contribution of each energy component to the docking score,

a cross-correlation matrix of the values shown in Table 2 was calculated (Table 3). The hydrogen bonding and steric energy components, as well as the molecular weights and numbers of free atom–atom bond torsions (entropic contribution), are related to the docking score energies. Consequently, those features should be ABT-888 cost considered carefully in the design of new lead compounds. Knowledge of the biology of the host-parasite relationship is central to establishing a paradigm to treat leishmaniasis. PA synthesis is a metabolic pathway that has been explored for drug development against Trypanosoma and Leishmania ( Colotti & Ilari, 2011). The inhibition of PA synthesis can cause oxidative stress in parasite cells, due to a deficiency in trypanothione production ( Colotti & Ilari,

2011). Arginase from Leishmania is the first enzyme in the PA pathway, and blocking it can lead to oxidative stress and promote infection control. In a study of 105 PLX-4720 natural compounds, the leishmanicidal activity of the flavonoids fisetin, quercetin, luteolin and 7,8-dihydroxyflavone showed high potency against the amastigotes of L. (L.) donovani ( Tasdemir et al., 2006). These four compounds also showed potential as inhibitors of ARG-L. Fisetin is a flavonoid present in strawberries; quercetin is abundant in onions and broccoli, from and luteolin can be found

in celery, green pepper, parsley and chamomile tea (Shimoi et al., 1998). In this study, we observed that fisetin is a flavonoid that possesses a high potency in arginase inhibition. Fisetin was the most potent arginase inhibitor, with four and ten times higher potency than quercetin and luteolin, respectively. Comparing the structures of these flavonoids revealed that the hydroxyl group at position 3 contributed significantly to the inhibitory activity of arginase, while the hydroxyl at position 5 did not. In the absence of a catechol group on the galangin, arginase inhibition declined sharply, suggesting that the catechol group is important for inhibition activity. The absence of a hydroxyl group at position 3 and catechol on the apigenin inhibited only 6% of ARG-L at 125 μM. C-glycosylation on the isoorientin (luteolin-6-C-glucoside) and the orientin (luteolin-8-C-glucoside) did not enhance arginase inhibition. In contrast, the 7,8-dihydroxyflavone showed an IC50 of 12 μM when the hydroxyl at position 3 and the catechol group were absent. These data indicate that position 8 enhanced the inhibition activity of this compound. The inhibition of ARG-L increased due to the hydroxylation of the phenyl group of molecules hydroxylated at positions 3, 5, and 7, such as in galangin (IC50 100 μM), kaempferol (IC50 50 μM) and quercetin (IC50 4.3 μM).