Exo- or endo-1H-pyrazole metal coordination modulated by the polyamine chain length in [1 + 1] condensation azamacrocycles. Binuclear complexes with remarkable SOD activity.

The Cu2+ complexes of three [1 + 1] azacyclophane macrocycles having the 1H-pyrazole ring as the spacer and the pentaamine 1,5,8,11,15-pentaazadecane (L1) or hexaamines 1,5,8,12,15,19-hexaazanonadecane (L2) and 1,5,9,13,17,21-hexaazaheneicosane (L3) as bridges show endo- coordination of the pyrazolate bridge giving rise to discrete monomeric species. Previously reported pyrazolacyclophanes evidenced, however, exo-coordination with the formation of dimeric species of 2 : 2, 3 : 2 or even 4 : 2 Cu2+ : L stoichiometry. The complexes have been characterized in solution using potentiometric studies, UV-Vis spectroscopy, paramagnetic NMR, cyclic voltammetry and mass spectrometry. The measurements show that all three ligands have as many protonation steps in water as secondary amines are in the bridge, while they are able to form both mono- and binuclear Cu2+ species. The crystal structures of the complexes [Cu(HL1)Br]Br(1+x)(ClO4)(1-x)·yH2O (1) and [Cu2(H-1L2)Cl(ClO4)](ClO4)·H2O·C2H5OH (2) have been solved by X-ray diffraction studies. In 1 the metal ion lies at one side of the macrocyclic cavity being coordinated by one nitrogen of the pyrazolate moiety and the three consecutive nitrogen atoms of the polyamine bridge. The other nitrogen of the pyrazole ring is hydrogen-bonded to an amine group. In 2 the two metal ions are interconnected by a pyrazolate bis(monodentate) moiety and complete their coordination spheres with three amines and either a bromide or a perchlorate anion, which occupy the axial positions of distorted square pyramid geometries. Paramagnetic NMR studies of the binuclear complexes confirm the coordination pattern observed in the crystal structures. Cyclic voltamperommetry data show potentials within the adequate range to exhibit superoxide dismutase (SOD) activity. The IC50 values calculated by McCord-Fridovich enzymatic assays show that the binuclear Cu2+ complexes of L2 and L3 have SOD activities that rank amongst the highest ones reported so far.

Selective recognition of neurotransmitters in aqueous solution by hydroxyphenyl aza-scorpiand ligands.

The synthesis, acid-base behaviour and anion recognition of neurotransmitters (dopamine, tyramine and serotonin) in aqueous solution of different aza-scorpiand ligands functionalized with hydroxyphenyl and phenyl moieties (L1-L3 and L4, respectively) have been studied by potentiometry, NMR, UV-Vis and fluorescence spectroscopy and isothermal titration calorimetry (ITC). The analysis of the potentiometric results shows the selective recognition of serotonin at physiological pH (Keff = 8.64 × 104) by L1. This selectivity has an entropic origin probably coming from a fine pre-organization of the interacting partners. Thus, the complementarity of the receptor and the substrate allows the reciprocal formation of hydrogen bonds, π-π and cation-π interactions, stabilizing the receptors and slowing the rate of oxidative degradation, and satisfactory results are obtained at acidic and neutral pH values. NMR and molecular dynamics studies reveal the rotation blockage in the neurotransmitter side chain once complexed with L1.

The Bioactivity of Xylene, Pyridine, and Pyrazole Aza Macrocycles against Three Representative Leishmania Species.

Due to the urgent need for finding effective and free of secondary effect treatments for every clinical form of Leishmaniasis, a series of synthetic xylene, pyridine and, pyrazole azamacrocycles were tested against three Leishmania species. A total of 14 compounds were tested against J774.2 macrophage cells which were models for host cells, and against promastigote and amastigote forms of each studied Leishmania parasite. Amongst these polyamines, one proved effective against L. donovani, another one for L. braziliensis and L. infantum, and another one was selective solely for L. infantum. These compounds showed leishmanicidal activity and reduced parasite infectivity and dividing ability. Action mechanism studies gave a hint that compounds were active against Leishmania due to their ability to alter parasite metabolic pathways and reduce (except Py33333) parasitic Fe-SOD activity.

Heterocyclic Diamines with Leishmanicidal Activity.

Leishmaniasis is one of the world's most neglected diseases with a worldwide prevalence of 12 million people. There are no effective human vaccines for its prevention, and outdated drugs hamper treatment. Therefore, research aimed at developing new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, here, we present 10 new compounds made up by linking alkylated ethylenediamine units to pyridine or quinoline heterocycles with promising in vitro and in vivo efficacy against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani, and Leishmania braziliensis species. Three compounds (2, 4, and 5) showed a selectivity index much higher in the amastigote form than the reference drug glucantime. These three derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing alterations in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy due to their effectiveness and their ready synthesis.

Ditopic Aza-Scorpiand Ligands Interact Selectively with ds-RNA and Modulate the Interaction upon Formation of Zn2+ Complexes.

Nucleic acids are essential biomolecules in living systems and represent one of the main targets of chemists, biophysics, biologists, and nanotechnologists. New small molecules are continuously developed to target the duplex (ds) structure of DNA and, most recently, RNA to be used as therapeutics and/or biological tools. Stimuli-triggered systems can promote and hamper the interaction to biomolecules through external stimuli such as light and metal coordination. In this work, we report on the interaction with ds-DNA and ds-RNA of two aza-macrocycles able to coordinate Zn2+ metal ions and form binuclear complexes. The interaction of the aza-macrocycles and the Zn2+ metal complexes with duplex DNA and RNA was studied using UV thermal and fluorescence indicator displacement assays in combination with theoretical studies. Both ligands show a high affinity for ds-DNA/RNA and selectivity for ds-RNA. The ability to interact with these duplexes is blocked upon Zn2+ coordination, which was confirmed by the low variation in the melting temperature and poor displacement of the fluorescent dye from the ds-DNA/RNA. Cell viability assays show a decrease in the cytotoxicity of the metal complexes in comparison with the free ligands, which can be associated with the observed binding to the nucleic acids.

A Metal-Based Receptor for Selective Coordination and Fluorescent Sensing of Chloride.

A scorpionate Zn2+ complex, constituted by a macrocyclic pyridinophane core attached to a pendant arm containing a fluorescent pyridyl-oxadiazole-phenyl unit (PyPD), has been shown to selectively recognize chloride anions, giving rise to changes in fluorescence emission that are clearly visible under a 365 nm UV lamp. This recognition event has been studied by means of absorption, fluorescence, and NMR spectroscopy, and it involves the intramolecular displacement of the PyPD unit by chloride anions. Moreover, since the chromophore is not removed from the system after the recognition event, the fluorescence can readily be restored by elimination of the bound chloride anion.

About the relevance of anion-π interactions in water.

Anion-π interactions are emerging as exotic features with potential applications in chemistry. In the last years, their relevance in living systems has been outlined, and so far there is no concluding significant evidence recognized about the participation of anion-π interactions in water because anion-π sensors contain large aromatic hydrophobic surfaces with limited solubility. By transforming a neutral heterocycle (for example quinoline) into its corresponding salt (quinolinium), we have been able to overcome these solubility issues, and new cationic water-soluble fluorophores have been prepared. Herein, we used N-alkylated heterocycles as π-acidic surfaces to shed light on the nature of anion-π in water by the direct measurement of the fluorescence and UV/Vis spectra in combination with DFT and X-ray analyses.

Inhibitory Effect of Azamacrocyclic Ligands on Polyphenol Oxidase in Model and Food Systems.

Enzymatic browning is one of the main problems faced by the food industry due to the enzyme polyphenol oxidase (PPO) provoking an undesirable color change in the presence of oxygen. Here, we report the evaluation of 10 different azamacrocyclic compounds with diverse morphologies as potential inhibitors against the activity of PPO, both in model and real systems. An initial screening of 10 ligands shows that all azamacrocyclic compounds inhibit to some extent the enzymatic browning, but the molecular structure plays a crucial role on the power of inhibition. Kinetic studies of the most active ligand (L2) reveal a S-parabolic I-parabolic noncompetitive inhibition mechanism and a remarkable inhibition at micromolar concentration (IC50 = 10 µM). Furthermore, L2 action has been proven on apple juice to significantly reduce the enzymatic browning.

Hybrid GMP-polyamine hydrogels as new biocompatible materials for drug encapsulation.

Here we present the preparation and characterization of new biocompatible materials for drug encapsulation. These new gels are based on positively charged [1+1] 1H-pyrazole-based azamacrocycles which minimise the electrostatic repulsions between the negatively charged GMP molecules. Rheological measurements confirm the electroneutral hydrogel structure as the most stable for all the GMP-polyamine systems. Nuclear magnetic resonance (NMR) was employed to investigate the kinetics of the hydrogel formation and cryo-scanning electron microscopy (cryo-SEM) was used to obtain information about the hydrogel morphology, which exhibited a non-homogeneous structure with a high degree of cross-linking. It is possible to introduce isoniazid, which is the most employed antibiotic for tuberculosis treatment, into the hydrogels without disrupting the hydrogel structure at appropriate concentrations for oral administration.

Influence of the chain length and metal : ligand ratio on the self-organization processes of Cu2+ complexes of [1 + 1] 1H-pyrazole azamacrocycles.

Three new [1 + 1] macrocycles formed by the reaction of 1H-3,5-bis(chloromethyl)pyrazole with the tosylated amines 1,4,7,10-tetraazadecane (L1), 1,4,8,11-tetraazaundecane (L2) and 1,5,10,14-tetraazatetradecane (L3) are described. Potentiometric studies and HR-ESI-Mass spectrometry show the formation of dimeric binuclear Cu2+ complexes whose organization depends on the type of hydrocarbon chains connecting the amine groups. Furthermore, trinuclear or/and tetranuclear complexes are formed depending also on the length of the polyaminic bridge and on the sequence of the hydrocarbon chains. The crystal structures of the [2 + 2] [Cu2(H(H-1L2))2](ClO4)4·4H2O (1) and [Cu2(H-1L2)2](ClO4)2 (2) complexes show in both of them two macrocycles self-assembled by the metal ions which interconnect their pyrazolate fragments that behave as bis(monodentate) ligands. While in 1 one central amine of each macrocycle binds to the axial position of a distorted square-pyramid and the other ones remain protonated, in 2 all the amine groups are involved in the coordination giving rise to a strongly distorted octahedral geometry. Paramagnetic 1H NMR measurements support that these structures also form in solution. Interestingly, tetranuclear complexes [Cu4(H-1L4)2(OH)2.08](ClO4)2.92Br0.54Cl0.46 (3) and [Pd2.39Cu1.61(H-1L4)2(OH)2](ClO4)2Cl1.33Br0.67·2.87H2O (4) have been isolated for the macrocycle containing the 1,5,9,13-tetraamine chain (L4). 3 has two binucleating units, one of them formed by the pyrazolate moieties and their neighbouring secondary amines and the other by the two central amines of both macrocycles. This latter Cu2+ coordination site is completed by two hydroxide anions as bridging ligands. 4 was obtained from a solution prepared to achieve full formation of the dimeric cage [Cu2(H-1(HL4))2]4+ by addition of K2PdCl4. The Pd2+ ion due to its softer acidic characteristics displaces the Cu2+ ions from the pyrazolate site. UV-vis spectroscopy suggests that the exchange is completed at room temperature after one hour.

Homo- and Heterobinuclear Cu2+ and Zn2+ Complexes of Ditopic Aza Scorpiand Ligands as Superoxide Dismutase Mimics.

Two polytopic aza-scorpiand-like ligands, 6-[7-(diaminoethyl)-3,7-diazaheptyl]-3,6,9-triaza-1-(2,6-pyridina)cyclodecaphane (L1) and 6-[6'-[3,6,9-triaza-1-(2,6-pyridina)cyclodecaphan-6-yl]-3-azahexyl]-3,6,9-triaza-1-(2,6-pyridina)cyclodecaphane (L2), have been synthesized. The acid-base behavior and Cu2+, Zn2+, and Cu2+/Zn2+ mixed coordination have been analyzed by potentiometry, cyclic voltammetry, and UV-vis spectroscopy. The resolution of the crystal structures of [Cu2L2Cl2](ClO4)2·1.67H2O (1), [Cu2HL2Br2](ClO4)3·1.5H2O (2), and [CuZnL2Cl2](ClO4)2·1.64H2O (3) shows, in agreement with the solution data, the formation of homobinuclear Cu2+/Cu2+ and heterobinuclear Cu2+/Zn2+ complexes. The metal ions are coordinated within the two macrocyclic cavities of the ligand with the involvement of a secondary amino group of the bridge in the case of 1 and 3. Energy-dispersive X-ray spectroscopy confirms the 1:1 Cu2+/Zn2+ stoichiometry of 3. The superoxide dismutase (SOD) activities of the Cu2+/Cu2+ and Cu2+/Zn2+ complexes of L1 and L2 have been evaluated using nitro blue tetrazolium assays at pH 7.4. The IC50 and kcat values obtained for the [Cu2L1]4+ complex rank among the best values reported in the literature for Cu-SOD mimics. Interestingly, the binuclear Cu2+ complexes of L1 and L2 have low toxicity in cultures of mammalian cell lines and show significant antioxidant activity in a copper-dependent SOD (SOD1)-defective yeast model. The results are rationalized by taking into account the binding modes of the Cu2+ ions in the different complexes.

Molecular Rearrangement of an Aza-Scorpiand Macrocycle Induced by pH: A Computational Study.

Rearrangements and their control are a hot topic in supramolecular chemistry due to the possibilities that these phenomena open in the design of synthetic receptors and molecular machines. Macrocycle aza-scorpiands constitute an interesting system that can reorganize their spatial structure depending on pH variations or the presence of metal cations. In this study, the relative stabilities of these conformations were predicted computationally by semi-empirical and density functional theory approximations, and the reorganization from closed to open conformations was simulated by using the Monte Carlo multiple minimum method.

Synthesis, Characterization, and Cu(2+) Coordination Studies of a 3-Hydroxy-4-pyridinone Aza Scorpiand Derivative.

The synthesis, acid-base behavior, and Cu(2+) coordination chemistry of a new ligand (L1) consisting of an azamacrocyclic core appended with a lateral chain containing a 3-hydroxy-2-methyl-4(1H)-pyridinone group have been studied by potentiometry, cyclic voltammetry, and NMR and UV-vis spectroscopy. UV-vis and NMR studies showed that phenolate group was protonated at the highest pH values [log K = 9.72(1)]. Potentiometric studies point out the formation of Cu(2+) complexes of 1:2, 2:2, 4:3, 1:1, and 2:1 Cu(2+)/L1 stoichiometries. UV-vis analysis and electrochemical studies evidence the implication of the pyridinone moieties in the metal coordination of the 1:2 Cu(2+)/L1 complexes. L1 shows a stronger chelating ability than the reference chelating ligand deferiprone. While L1 shows no cytotoxicity in HeLa and ARPE-19 human cell lines (3.1-25.0 µg/mL), it has significant antioxidant activity, as denoted by TEAC assays at physiological pH. The addition of Cu(2+) diminishes the antioxidant activity because of its coordination to the pyridinone moiety phenolic group.

Oxidative stress protection by manganese complexes of tail-tied aza-scorpiand ligands.

The Mn2+ coordination chemistry of double scorpiand ligands in which two polyazacyclophane macrocycles have been connected by pyridine, phenanthroline and bipyridine spacers has been studied by potentiometry, paramagnetic NMR and electrochemistry. All ligands show high stability with Mn2+ and the complexes were formed in a wide pH range. DFT calculations support the structures and coordination geometries derived from the study. A remarkable antioxidant activity was evidenced for these systems by the McCord-Fridovich assay and in Escherichiacoli sodAsodB deficient bacterial cells. The three systems were tested as anti-inflammatory drugs in human macrophages measuring the accumulation of cytokines upon lipopolysaccharide (LPS) pro-inflammatory effect. All complexes showed anti-inflammatory effect, being [Mn2L1]4+ the most efficient one.

Trapping a Highly Reactive Nonheme Iron Intermediate That Oxygenates Strong C-H Bonds with Stereoretention.

An unprecedentedly reactive iron species (2) has been generated by reaction of excess peracetic acid with a mononuclear iron complex [Fe(II)(CF3SO3)2(PyNMe3)] (1) at cryogenic temperatures, and characterized spectroscopically. Compound 2 is kinetically competent for breaking strong C-H bonds of alkanes (BDE ≈ 100 kcal·mol(-1)) through a hydrogen-atom transfer mechanism, and the transformations proceed with stereoretention and regioselectively, responding to bond strength, as well as to steric and polar effects. Bimolecular reaction rates are at least an order of magnitude faster than those of the most reactive synthetic high-valent nonheme oxoiron species described to date. EPR studies in tandem with kinetic analysis show that the 490 nm chromophore of 2 is associated with two S = 1/2 species in rapid equilibrium. The minor component 2a (∼5% iron) has g-values at 2.20, 2.19, and 1.99 characteristic of a low-spin iron(III) center, and it is assigned as [Fe(III)(OOAc)(PyNMe3)](2+), also by comparison with the EPR parameters of the structurally characterized hydroxamate analogue [Fe(III)(tBuCON(H)O)(PyNMe3)](2+) (4). The major component 2b (∼40% iron, g-values = 2.07, 2.01, 1.95) has unusual EPR parameters, and it is proposed to be [Fe(V)(O)(OAc)(PyNMe3)](2+), where the O-O bond in 2a has been broken. Consistent with this assignment, 2b undergoes exchange of its acetate ligand with CD3CO2D and very rapidly reacts with olefins to produce the corresponding cis-1,2-hydroxoacetate product. Therefore, this work constitutes the first example where a synthetic nonheme iron species responsible for stereospecific and site selective C-H hydroxylation is spectroscopically trapped, and its catalytic reactivity against C-H bonds can be directly interrogated by kinetic methods. The accumulated evidence indicates that 2 consists mainly of an extraordinarily reactive [Fe(V)(O)(OAc)(PyNMe3)](2+) (2b) species capable of hydroxylating unactivated alkyl C-H bonds with stereoretention in a rapid and site-selective manner, and that exists in fast equilibrium with its [Fe(III)(OOAc)(PyNMe3)](2+) precursor.

Quantification of CH-π Interactions Using Calix[4]pyrrole Receptors as Model Systems.

We describe the use of two series of aryl-extended calix[4]pyrrole receptors bearing two and four electronically tunable phenyl groups, respectively, in their meso-positions as model systems for the quantification of CH-π interactions in solution. The "four-wall" and the "two-wall" receptors formed thermodynamically stable 1:1 complexes in acetonitrile solution with both trimethylamine N-oxide and trimethylphosphine P-oxide as guests. The complexes were mainly stabilized by the formation of four convergent hydrogen bonds between the oxygen atom of the guests and the pyrrole NHs of the host. In general, the N-oxide produced thermodynamically more stable hydrogen bonding interactions than the P-oxide. Upon guest binding, the receptors adopted the cone conformation and the methyl groups of the included guests engaged in CH-π interactions with the aromatic walls. We show that the modification of the electronic properties of the aromatic surfaces, in any of the receptor series, did not have a significant impact in the measured binding affinities for a given guest. However, the larger binding affinities determined for the "four-wall" receptors in comparison to the "two-wall" counterparts supported the importance of CH-π interactions on guest complexation. The strength of the CH-π interactions present in the inclusion complexes was quantified employing the octamethyl calix[4]pyrrole as reference. We determined an average magnitude of ~1 kcal·mol(-1) for each CH-π interaction. The CH-π interactions featured a reduced electrostatic nature and thus dispersion forces were assigned as main contributors of their strength.

Equilibrium, kinetic, and computational studies on the formation of Cu2+ and Zn2+ complexes with an indazole-containing azamacrocyclic scorpiand: evidence for metal-induced tautomerism.

Cu(2+) and Zn(2+) coordination chemistry of a new member of the family of scorpiand-like macrocyclic ligands derived from tris(2-aminoethyl)amine (tren) is reported. The new ligand (L1) contains in its pendant arm not only the amine group derived from tren but also a 6-indazole ring. Potentiometric studies allow the determination of four protonation constants. UV-vis and fluorescence data support that the last protonation step occurs on the indazole group. Equilibrium measurements in the presence of Cu(2+) and Zn(2+) reveal the formation of stable [ML1](2+), [MHL1](3+), and [ML1(OH)](+) complexes. Kinetic studies on the acid-promoted decomposition of the metal complexes were carried out using both absorbance and fluorescence detection. For Zn(2+), both types of detection led to the same results. The experiments suggest that [ZnL1](2+) protonates upon addition of an acid excess to form [ZnHL1](3+) within the mixing time of the stopped-flow instrument, which then decomposes with a first-order dependence on the acid concentration. The kinetic behavior is more complex in the case of Cu(2+). Both [CuL1](2+) and [CuHL1](3+) show similar absorption spectra and convert within the mixing time to a new intermediate species with a band at 750 nm, the process being reverted by addition of base. The intermediate then decomposes with a second-order dependence on the acid concentration. However, kinetic experiments with fluorescence detection showed the existence of an additional faster step. With the help of DFT calculations, an interpretation is proposed in which protonation of [CuL1](2+) to form [CuHL1](3+) would involve dissociation of the tren-based NH group in the pendant arm and coordination of a 2H-indazole group. Further protonation would lead to dissociation of coordinated indazole, which then will convert to the more stable 1H tautomer in a process signaled by fluorescence changes that would not be affecting to the d-d spectrum of the complex.

A thermodynamic insight into the recognition of hydrophilic and hydrophobic amino acids in pure water by aza-scorpiand type receptors.

Interactions of different hydrophilic (His, Asp, Glu,) and hydrophobic (Ala, Phe, Tyr, Trp) amino acids in water with a scorpiand aza-macrocycle (L1) containing a pyridine group in the ring and its derivative (L2) bearing a naphthalene group in the tail have been analysed by potentiometric and calorimetric measurements. Theoretical calculations corroborate that major attractive forces that hold the adduct together are hydrogen bonds and salt-bridges, even though other interactions such as π-stacking or NH(+)⋯π may contribute in the case of hydrophobic amino acids and L2. Calorimetric measurements indicate that the interactions between L1 and the different amino acids are principally driven by entropy, often associated with solvation/desolvation processes.

Homo- and heterobinuclear Cu²âº and Zn²âº complexes of abiotic cyclic hexaazapyridinocyclophanes as SOD mimics.

The new receptor 3,7,11,15,19,23-hexaaza-1(2,6)-pyridinacyclotetracosaphane (L1) containing a complete sequence of propylenic chains has been synthesised. The acid-base behaviour and Cu²âº and Zn²âº coordination have been analysed by potentiometric measurements in 0.15 M NaClO4 for L1 and for the related compounds 3,7,11,14,18,22-hexaaza-1(2,6)-pyridinacyclotricosaphane (L2), 3,7,10,13,16,20-hexaaza-1(2,6)-pyridinacycloheneicosaphane (L3) and 3,7,10,12,15,19-hexaaza-1(2,6)-pyridinacycloicosaphane (L4). The crystal structure of [(CuH4L2)(H2O)(ClO4)](ClO4)5·3H2O shows an interesting combination of a metal ion coordinated by the pyridine nitrogen atom and the adjacent amine groups of the chain, and a perchlorate anion sitting at the middle of the site defined by the remaining four protonated ammonium groups of L1. Paramagnetic NMR data suggest that imidazole coordinates to the Cu²âº ions as a bridging ligand in a wide pH range. SOD activity for Cu²âº-Cu²âº and Cu²âº-Zn²âº complexes with L1-L4 have been measured by NBT assays at pH 7.4, obtaining some of the lowest values so far reported for SOD mimics. SOD activity has also been checked by chemiluminescence assays using polymorphonuclear leukocytes (PMNLs).

In vitro activity of scorpiand-like azamacrocycle derivatives in promastigotes and intracellular amastigotes of Leishmania infantum and Leishmania braziliensis.

The activity of a family scorpiand-like azamacrocycles against Leishmania infantum and Leishmania braziliensis was studied using promastigotes, axenic and intracellular amastigotes forms. All the compounds are more active and less toxic than meglumine antimoniate (Glucantime). Moreover, the data on infection rates and amastigotes showed that compounds P2Py, PN and P3Py are the most active against both species of Leishmania. On the other hand, studies on the inhibitory effect of these compounds on SOD enzymes showed that while the inhibition of the Fe-SOD enzyme of the promastigote forms of the parasites is remarkable, the inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli is negligible. The ultrastructural alterations observed in treated promastigote forms confirmed that the compounds having the highest activity were those causing the largest cell damage. The modifications observed by (1)H NMR, and the amounts of catabolites excreted by the parasites after treatment with the compounds, suggested that the catabolic mechanism could depend on the structure of the side chains linked to the aza-scorpiand macrocycles.