Cinnamides Target Leishmania amazonensis Arginase Selectively

Abstract

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3–17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors.

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

“…In particular, the interaction with Asp141 was also found in complexes of LaARG with quercetin, quercitrin and isoquercitrin, where the two hydroxyls in catechol group of the flavonoids formed a hydrogen bond with Asp141 [18]. Moreover, in a study of cinnamide inhibitors evaluated in LaARG, it was observed that some of these inhibitors share Van der Waals interactions with the same residues as compound 1 and 2 (His139, Val149, and His154), as well as electrostatic interactions with Asp245 and Glu288 [20]. Furthermore, several of these Van der Waals interactions were also found with chalcone inhibitors in L. infantum [22].…”

“…On the other hand, biological activity and cytotoxicity studies indicated that both LmARG inhibitors had leishmanicidal activity being compound 1 as active as the reference drug Glucantime (32 and 35 µM, respectively) and more selective against the amastigote stage of the parasite than the three reference drugs used for the treatment of leishmaniasis (Table 3). In the same context, several cinnamides derivatives were reported as LaARG inhibitors and tested against L. amazonensis promastigotes, but only caffeic acid phenylamide (CAPA) showed biological activity with an IC 50 of 82.56 µM, however, no data over its effect against mammalian cell lines are available [20].…”

“…On the other hand, arginase-knockout mutants from L. mexicana, L. amazonensis and L. major demonstrated the importance of this enzyme since its absence made parasites auxotrophic to polyamines [13,16,17]. Actually, there are several arginase inhibitors reported in different Leishmania species, in the case of L. amazonensis (LaARG), [1,2,4]triazolo [1,5-a]pyrimidine derivatives [17], flavanols [18,19], and cinnamide derivatives [20] had been reported, with the best compounds showing a mixed type inhibition and a I 50 in the micromolar range. In L. infantum (LiARG), natural phenolic derivatives [21] and chalcone derivatives [22] have been reported as enzyme inhibitors.…”

Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides

“…A variety of phenolic acid derivatives (e.g., cinnamic acid) and the related natural dihydroxycinnamic compounds (e.g., catechol-containing caffeic, chlorogenic, or rosmarinic acids) revealed the antileishmanial and/or antiplasmodial potency [ 15 , 16 ]. Hence, rosmarinic acid analogues and new caffeic acid-derivative amides were synthesized and tested to target human and L. amazonesis arginases, respectively [ 17 , 18 ]. In an attempt to determine the potential arginase-inhibitor binding modes, the computer-aided structure-based protocol was applied indicating that cinnamoyl or 3,4-hydroxycinnamoyl motifs are crucial for the mechanism of arginase inhibition.…”

Selene-Ethylenelacticamides and N-Aryl-Propanamides as Broad-Spectrum Leishmanicidal Agents

“…The following supporting information can be downloaded at: , Sections S1–S7; Figures S1–S72; Tables S1–S8. References [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ] are cited in the Supplementary Materials.…”