Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites

Iron (Fe) is crucial for cellular proliferation, and Fe chelators have shown activity at preventing the growth of the malarial parasite in cell culture and in animal and human studies. We investigated the anti-malarial activity of novel aroylhydrazone and thiosemicarbazone Fe chelators that show high activity at inhibiting the growth of tumour cells in cell culture [Blood 100 (2002) 666]. Experiments with the chelators were performed using the chloroquine-sensitive, 3D7, and chloroquine-resistant, 7G8, strains of Plasmodium falciparum in vitro. The new ligands were significantly more active in both strains than the Fe chelator in widespread clinical use, desferrioxamine (DFO). The most effective chelators examined were 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone and 2-hydroxy-1-naphthylaldehyde-4-phenyl-3-thiosemicarbazone. The anti-malarial activity correlates with anti-proliferative activity against neoplastic cells demonstrated in a previous study. Our studies suggest that this class of lipophilic chelators may have potential as useful agents for the treatment of malaria.     

Chemical and functional characterization of metal-binding pseudotripeptides with different functionalized N-alkyl residues Dedicated to Professor Dr. Ernst-Gottfried Jaeger on occasion of his 65th birthday

Pseudotripeptide ligands with 4 different N-functionalized glycine residues were qualitatively, semiquantitatively and quantitatively tested for their complexation of the bivalent transition metal ions Zn²⁺, Cu²⁺, Co²⁺, Ni²⁺ and Mn²⁺. The functional side chains have different length and different groups available for complexation. MALDI-MS and ESI-MS were used for more qualitative or semiquantitative estimation of the complex formation tendencies. The found ranking differs by these two methods only for Zn²⁺ and Ni²⁺. For one of the pseudotripeptide ligands, the ligand L1, complex formation with certain transition metal was estimated quantitatively by potentiometric titration. The Zn-complex of that ligand polarizes bound water strongly, resulting in a low pK_a-value. Complexes of pseudotripeptide ligand L1 with certain metal ions were tested for their hydrolytic activity. The pseudo first order rate constants of the hydrolysis of the substrates 4-nitrophenyl acetate and bis(4-nitrophenyl)phosphate were compared to complexes with the same metal ions formed with a very well studied ligand from the literature, the 1,4,7,10-tetraaza cyclododecane (cyclen). The hydrolysis of the phosphate ester occurs very slowly compared to the acetate ester. No correlation exists between the estimated pK_a values of complexes formed from ligand L1 with different metal ions and the phosphate ester hydrolysis. The Ni ions give totally different hydrolytic activities for pseudotripeptide ligand L1 and cyclen. With one exception, the Ni-cyclen complex, all other complexes have only a low or moderate catalytic activity.     

Chemical and functional characterization of metal-binding pseudotripeptides with different functionalized N-alkyl residues Dedicated to Professor Dr. Ernst-Gottfried Jaeger on occasion of his 65th birthday

Summary Pseudotripeptide ligands with 4 different N-functionalized glycine residues were qualitatively, semiquantitatively and quantitatively tested for their complexation of the bivalent transition metal ions Zn²⁺, Cu²⁺, Co²⁺, Ni²⁺ and Mn²⁺. The functional side chains have different length and different groups available for complexation. MALDI-MS and ESI-MS were used for more qualitative or semiquantitative estimation of the complex formation tendencies. The found ranking differs by these two methods only for Zn²⁺ and Ni²⁺. For one of the pseudotripeptide ligands, the ligand L1, complex formation with certain transition metal was estimated quantitatively by potentiometric titration. The Zn-complex of that ligand polarizes bound water strongly, resulting in a low pK _a -value. Complexes of pseudotripeptide ligand L1 with certain metal ions were tested for their hydrolytic activity. The pseudo first order rate constants of the hydrolysis of the substrates 4-nitrophenyl acetate and bis(4-nitrophenyl)phosphate were compared to complexes with the same metal ions formed with a very well studied ligand from the literature, the 1,4,7,10-tetraaza cyclododecane (cyclen). The hydrolysis of the phosphate ester occurs very slowly compared to the acetate ester. No correlation exists between the estimated pK _a values of complexes formed from ligand L1 with different metal ions and the phosphate ester hydrolysis. The Ni ions give totally different hydrolytic activities for pseudotripeptide ligand L1 and cyclen. With one exception, the Ni-cyclen complex, all other complexes have only a low or moderate catalytic activity. Dedicated to Professor Dr. Ernst-Gottfried Jaeger on occasion of his 65th birthday.     

Synthesis of a cross-bridged cyclam derivative for peptide conjugation and 64Cu radiolabeling

The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biological molecules. Previous studies have established that 4,11-bis-(carbo- tert-butoxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (H 2CB-TE2A), a member of the ethylene "cross-bridged" cyclam (CB-cyclam) class of bicyclic tetraaza macrocycles, forms highly kinetically stable complexes with Cu(II) and is less susceptible to in vivo transchelation than its nonbridged analogue, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA). Herein, we report a convenient synthesis of a novel cross-bridged BFC that is structurally analogous to CB-TE2A in that it possesses two coordinating acetate arms, but in addition possesses a third orthogonally protected arm for conjugation to peptides and other targeting agents. Application of this strategy to cross-bridged chelators may also enable the development of even further improved agents for (64)Cu-mediated diagnostic positron emission tomography (PET) imaging as well as for targeted radiotherapeutic applications.     

Synthesis, characterization and kinetic studies of the cis-[RuCl2(cyclen)] complex

We report here the synthesis, characterization and kinetic studies of cis-[RuCl₂(cyclen)]⁺ in aqueous solution, where cyclen is the macrocyclic ligand 1,4,7,10-tetraazacyclododecane. The complex releases one Cl⁻ producing cis-[RuCl(OH)(cyclen)]⁺ in aqueous solution at pH 4.60. The product of this reaction was characterized by Ultraviolet-Visible (UV-Vis) spectrum in comparison to the synthesized cis-[RuCl(OH)(cyclen)](BF₄)·2H₂O. The electrochemical data showed that E_pc of the Ru(III/II) peak increases as the macrocycle ring size decreases and also when the trans conformation is changed to cis. The chloride affinity of Ru(III) depends on the macrocycle ring size since cis-[RuCl₂(cyclam)]⁺ (cyclam=1,4,8,11-tetraazacyclotetradecane) does not release chloride for at least 12 h. The overall effect between cyclam and cyclen reflects the fact that the electron involved in the reduction enters a nonbonding π-d orbital and its energy is affected by the macrocyclic ligand.     

Synthesis,Characterization, Antimicrobial and Antimalarial Activities of Azines Based Schiff Bases and their Pd(II) Complexes

Herein, we report synthesis, characterization, antimicrobial and antimalarial activities of azines Schiff base ligands (L¹−L⁴) and their palladium (II) complexes ( C¹−C⁴ ) of [Pd(L)(OAc)₂] type. The azine ligands (L¹−L⁴) were prepared by condensation of carbonyl compounds with hydrazine hydrate and their complexes by the reaction of palladium acetate with L¹−L⁴ ligands in 1 : 1 molar ratio. The prepared ligands and their complexes were characterized by spectral characterization using ¹H &¹³C-NMR, FT-IR and mass spectral studies, which revealed that the ligands coordinates via azomethine nitrogen and heteroatom or aryl carbon with palladium. Moreover, Schiff bases and their palladium (II) complexes have been screened for their antibacterial (S. aureus, B. subtillis, and S. typhi, P. aeruginosa), antifungal (C. albicans, A. niger, and A. clavatus) and antimalarial (P. falciparum) activities. The Schiff base L⁴ showed good results for antibacterial against S. aureus (MIC, 50 μg/mL) and antimalarial against P. falciparum (IC₅₀, 0.83 μg/mL). The complex C¹ showed best antibacterial activity (MIC, 62.5 μg/mL) against S. typhi and the complex C⁴ exhibited remarkable antimalarial activity (IC₅₀, 0.42 μg/mL) among the tested compounds. Thus, azines based ligands and their Pd complexes can be good antimicrobial and antimalarial agents if explored further.     

Characterization and evaluation of pyrone and tropolone chelators for use in metalloprotein inhibitors

The tetrahedral zinc and cobalt complexes [(Tp^Ph,Me)ZnOH] (Tp^Ph,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) and [(Tp^Ph,Me)CoCl] were combined with 3-hydroxy-2H-pyran-2-one (3,2-pyrone), 3-hydroxy-4H-pyran-4-one (3,4-pyrone), and tropolone to form the corresponding [(Tp^Ph,Me)M(L)] complexes (L = bidentate ligand, M = Zn²⁺, Co²⁺). X-ray crystal structures of these complexes were obtained to determine the mode of binding for each chelator and the coordination geometry of each complex. The complexes [(Tp^Ph,Me)M(3,2-pyrone)] (M = Zn²⁺, Co²⁺) are the first structurally characterized metal complexes with this chelator. These complexes with the various chelators show that the cobalt(II) complexes are generally isostructural with their zinc(II) counterparts. In addition to structural characterization, inhibition data for each ligand against two different zinc(II) metalloproteins, matrix metalloproteinase-3 (MMP-3) and anthrax lethal factor (LF), were obtained. Examination of these chelators in the MMP-3 active site demonstrates the possible mode of inhibition.     

Antimalarial activity of azadipeptide nitriles

Azadipeptide nitriles—novel cysteine protease inhibitors—display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite’s hemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of the compounds was observed. These first generation azadipeptide nitriles represent a promising new class of compounds for antimalarial drug development.     

Synthesis, spectroscopic characterization and biological activity on newly synthesized copper(II) and nickel(II) complexes incorporating bidentate oxygen-nitrogen hydrazone ligands

We report the synthesis of the hydrazone ligands, 1-(phenyl-hydrazono)-propan-2-one (PHP), 1-(p-tolyl-hydrazono)-propan-2-one (THP), 1-[(4-chloro-hydrazono)]-propan-2-one (CHP), and their Ni(II) and Cu(II) metal complexes. The structure of the ligands and their complexes were investigated using elemental analysis, magnetic susceptibility, molar conductance and spectral (IR, UV, and EPR) measurements. IR spectra indicate that the free ligands exist in the hydrazo-ketone rather than azo-enol form in the solid state. Also, the hydrazo-NH exists as hydrogen bonded to the keto-oxygen either as intra or as intermolecular hydrogen bonding. In all the studied complexes, all ligands behave as a neutral bidentate ligands with coordination involving the hydrazone-nitrogen and the keto-oxygen atoms. The magnetic and spectral data indicate a square planar geometry for Cu²⁺ complexes and an octahedral geometry for Ni²⁺ complexes. The ligands and their metal chelates have been screened for their antimicrobial activities using the disc diffusion method against the selected bacteria and fungi. They were found to be more active against Gram-positive than Gram-negative bacteria. It may be concluded that the antimicrobial activity of the compounds is related to cell wall structure of bacteria.Protonation constant of (PHP) ligand and stability constants of its Cu²⁺ and Ni²⁺ complexes were determined by potentiometric titration method in aqueous solution at ionic strength of 0.1 M sodium nitrate. It has been observed that the hydrazone ligand (PHP) titrated here has one protonation constant. The divalent metal ions Cu²⁺ and Ni²⁺ form with (PHP) 1:1 and 1:2 complexes. The insolubility of (THP) and (CHP) ligands in aqueous medium does not permit the determination of their protonation constants and formation constants of the corresponding complexes in aqueous solution.     

New macrobicyclic chelator for the development of ultrastable 64Cu-radiolabeled bioconjugate

Ethylene cross-bridged cyclam with two acetate pendant arms, ECB-TE2A, is known to form the most kinetically stable (64)Cu complexes. However, its usefulness as a bifunctional chelator is limited because of its harsh radiolabeling conditions. Herein, we report new cross-bridged cyclam chelator for the development of ultrastable (64)Cu-radiolabeled bioconjugates. Propylene cross-bridged TE2A (PCB-TE2A) was successfully synthesized in an efficient way. The Cu(II) complex of PCB-TE2A exhibited much higher kinetic stability than ECB-TE2A in acid decomplexation studies, and also showed high resistance to reduction-mediated demetalation. Furthermore, the quantitative radiolabeling of PCB-TE2A with (64)Cu was achieved under milder conditions compared to ECB-TE2A. Biodistribution studies strongly indicate that the (64)Cu complexes of PCB-TE2A cleared out rapidly from the body with minimum decomplexation.     

In vitro efficiency of new acridyl derivatives against Plasmodium falciparum

A series of new 9-substituted acridyl derivatives were synthesized and their in vitro antimalarial activity was evaluated against one chloroquine-sensitive strain (3D7) and three chloroquine-resistant strains [W2 (Indochina), Bre1 (Brazil) and FCR3 (Gambia)] of Plasmodium falciparum. Some compounds inhibit the growth of malarial parasite with IC50 相似文献   

Complexes of salicylaldehyde acylhydrazones: cytotoxicity, QSAR and crystal structure of the sterically hindered t-butyl dimer

A series of acylhydrazones of salicylaldehyde and their transition metal complexes, predominantly copper(II), have been prepared and characterized. The crystal structure of the Cu(II) complex of the sterically hindered t-butyl derivative contains a phenolato bridged dimer with the ligand coordinated as a tridentate moiety. QSAR analyses of the cytotoxicity of the chelators and their Cu(II) complexes reveals that solubility is the dominant factor for activity. Compounds display a maximum with respect to lipophilicity, allowing optimization of the bioactivity for both the ligands and their complexes. Copper complexes are significantly more cytotoxic than the metal-free ligands and complexes of other metals: Cu > Ni > Zn = Mn > Fe = Cr > Cr > Co.     

Factors influencing artemisinin production from shoot cultures of Artemisia annua L.

Artemisinin, an anti-malarial drug isolated from the annual wormwood Artemisia annua L., has a marked activity against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum, and is useful in treatment of cerebral malaria. Shoot cultures of Artemisia annua L. were established on Murashige and Skoog basal medium which contained (per litre) 30 g sucrose, 0.5 mg 6-benzyladenine and 0.05 mg naphthaleneacetic acid. Using an optimized combination of sucrose (30 g/l), nitrate (45 mM), inorganic phosphate (200 mg/l), gibberellic acid (7 mg/l) and the ratio of NH₄ ⁺-N to NO₃ ^–-N of 1:3, artemisinin production reached 26.7 mg/l after 30 days. This procedure provides a potential alternative for production of artemisinin from in vitro tissue cultures.     

Synthesis, characterization and coordination chemistry of dibenzofuran derivatives of 1,4,7,10-tetraazacyclododecane

A 1,4-disubstituted dibenzofuran derivative of 1,4,7,10-tetraazacyclododecane (cyclen), L1, has been prepared by the direct reaction of cyclen and chloroacetyldibenzofuran and the mono-substituted derivative, L2, by reaction of chloroacetyldibenzofuran and 1,4,7-tris(t-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane followed by deprotection with trifluoroacetic acid. The ligands were characterized by ¹H and ¹³C NMR spectroscopy, IR spectroscopy and mass spectrometry. The reaction of the 1,4-disubstituted dibenzofuran cyclen, L1, with Cu(ClO₄)₂·6H₂O in methanol yielded crystals of [CuL1](ClO₄)₂·MeOH·1/2H₂O that were suitable for single crystal structural analysis. The X-ray structure confirmed that the 1,4-disubstituted dibenzofuran cyclen had been formed. The copper(II) coordination sphere in the complex cation, [CuL1]²⁺, is occupied by four nitrogen atoms from the macrocycle and an amide oxygen donor from one dibenzofuran pendant group. As is typical for copper(II)-cyclen complexes, the Cu(II) centre sits above the plane of the macrocycle nitrogen towards the oxygen donor, in this case by 0.5 Å. Fluorescence emission studies indicate that coordination of the macrocycle to either copper(II) or zinc(II) results in a decrease in emission with respect to the emission of the pure ligand.     

Crystal structure and chemical oxidation of the palladium(II) cyclam complex within the cavity of cucurbit[8]uril

Inclusion compound of a macrocyclic cavitand cucurbit[8]uril (C₄₈H₄₈N₃₂O₁₆, CB[8]) with a square-planar palladium(II) complex of a polyamine ligand cyclam, {[Pd(cyclam)]@CB[8]}Cl₂·16?H₂O (1), was synthesized and characterized by X-ray crystallography, elemental analysis, IR, and electrospray ionization (ESI) mass spectrometry. The complex [Pd(cyclam)]²⁺ undergoes chemical oxidation within the CB[8] cavity leading to the formation of the palladium(IV) inclusion compound {trans-[Pd(cyclam)Cl₂]@CB[8]}Cl₂·14H₂O (2). The Pd(II) and Pd(IV) complexes are completely encapsulated within the CB[8] cavity. The cyclam ring in 1 and 2 adopts the most stable configuration (trans-III (S,S,R,R)).     

Solid-state and proton NMR characterization of an iron(II) complex of a tridentate, facially coordinating N,N,O donor ligand

Despite the many enzymes that use 2-His-1-carboxylate facial triads to bind iron(II), there are few crystallographically characterized synthetic iron(II) complexes of tridentate ligands that bind through two imidazoles and one carboxylate. We report ¹H NMR characterization of the equilibrium between one such ligand and aqueous Fe²⁺. The formation of 1:1 and 2:1 complexes is evident, but the 1:1 complex is never the exclusive compound in solution. This behavior has not been reported previously for N,N,O ligand-iron(II) complexes. The 2:1 ligand/iron complex crystallizes from solution, and it has been completely characterized including an X-ray crystal structure.     

Different coordination modes of Hdipic and dipic ligands to nickel(II) ions in a same environment (dipic = 2,6-pyridinedicarboxylate, dipicolinate)

Two new nickel(II) complexes of the composition [Ni(cyclam)(Hdipic)₂] · 2H₂O (1) and [Ni(cyclam)(H₂O)₂][Ni(dipic)₂] · 2.5H₂O (2) (cyclam = 1,4,8,11-tetraazacyclotetradecane) have been prepared and structurally characterized by a combination of analytical, spectroscopic, thermogravimetric, and crystallographic methods. The structure of 1 shows that the central nickel(II) ion is coordinated axially by two monodentate Hdipic ligands. The discrete neutral complex 1 further extends its structure by hydrogen bonding interactions to form a one-dimensional supramolecule. The structure of 2 consists of two independent nickel(II) centers. Water molecules instead of dipic ligands prefer to coordinate to the Ni1 ion forming a divalent cation [Ni(cyclam)(H₂O)₂]²⁺. Two dipic ligands coordinate to the second Ni2 ion forming a divalent anion [Ni(dipic)₂]²⁻. The divalent cations and anions are charge-balanced, resulting in a molecular salt. The divalent cations and anions are interconnected by multiple types of hydrogen bonding interactions.     

N-alkylated cyclen cobalt(III) complexes of 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol DNA alkylating agent as hypoxia-activated prodrugs

A series of cobalt complexes of the potent DNA minor groove alkylator 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol (seco-6-azaCBI-TMI) were prepared from a series of N-substituted cyclen ligands. The final N-substituted complexes carried formal overall charges ranging from +2 to -2 and showed limited improvements in solubility. They showed similar stabilities to that of the complex with the unsubstituted cyclen ligand, and large but variable attenuation of the cytotoxicity of the free alkylator (2-30-fold), compared to 150-fold for the unsubstituted ligand. However, they had oxic/hypoxic ratios (2-22-fold) comparable to that of the unsubstituted cyclen complex (5).     

Chemometric modelling of antimalarial activity of aryltriazolylhydroxamates

We have performed quantitative structure–activity relationship (QSAR) and quantitative activity–activity relationship (QAAR) studies for aryltriazolylhydroxamates having antimalarial activity data against both chloroquine-sensitive (D6 clone) and chloroquine-resistant (W2 clone) strains of Plasmodium falciparum to understand the relationships between the biological activity and molecular properties for the design of new compounds. The QSAR studies were performed using 35 compounds among which 26 molecules were taken using k-means clustering technique in the training set for the derivation of the QSAR models and nine molecules were kept as the test-set compounds to evaluate the predictive ability of the derived models. The chemometric tool used for the analysis was the genetic function approximation. The developed models were analysed in terms of their predictive ability, and comparable results were obtained for cross-validated predictive variance (Q ²) and externally predicted variance (R ² _pred) values (0.761 and 0.829, respectively, for the D6 model, 0.708 and 0.748, respectively, for the W2 model and 0.984 and 0.982, respectively for the QAAR model). The QSAR models suggest that the number of methylene groups (between the triazolyl and hydroxamate moieties) and partially negatively charged surface areas of the molecules are important parameters for the antimalarial activity.     

Metal based drugs: design,synthesis and in-vitro antimicrobial screening of Co(II), Ni(II), Cu(II) and Zn(II) complexes with some new carboxamide derived compounds: crystal structures of N-[ethyl(propan-2-yl)carbamothioyl]thiophene-2-carboxamide and its copper(II) complex

A new series of compounds derived from thiophene-2-carboxamide were synthesized and characterized by IR, ¹H-NMR and ¹³C-NMR, mass spectrometry and elemental analysis. These compounds were further used to prepare their Co(II), Ni(II), Cu(II) and Zn(II) metal complexes. All metal(II) complexes were air and moisture stable. Physical, spectral and analytical data have shown the Ni(II) and Cu(II) complexes to exhibit distorted square-planar and Co(II) and Zn(II) complexes tetrahedral geometries. The ligand (L¹) and its Cu(II) complex were characterized by the single-crystal X-ray diffraction method. All the ligands and their metal(II) complexes were screened for their in-vitro antimicrobial activity. The antibacterial and antifungal bioactivity data showed that the metal(II) complexes were found to be more potent than the parent ligands against one or more bacterial and fungal strains.