Limits...
Metal-chloroquine derivatives as possible anti-malarial drugs: evaluation of anti-malarial activity and mode of action.

Navarro M, Castro W, Madamet M, Amalvict R, Benoit N, Pradines B - Malar. J. (2014)

Bottom Line: Clearly, a new effective and non-toxic anti-malarial drug is urgently needed.These complexes (1-6) interacted with haem and inhibited β-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents.The high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1-6) could be attributable to their effective interaction with haem and the inhibition of β-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.

View Article: PubMed Central - PubMed

Affiliation: Centro de Química, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela. maribelnava@gmail.com.

ABSTRACT

Background: Malaria still has significant impacts on the world; particularly in Africa, South America and Asia where spread over several millions of people and is one of the major causes of death. When chloroquine diphosphate (CQDP) lost its efficiency as a first-line anti-malarial drug, this was a major setback in the effective control of malaria. Currently, malaria is treated with a combination of two or more drugs with different modes of action to provide an adequate cure rate and delay the development of resistance. Clearly, a new effective and non-toxic anti-malarial drug is urgently needed.

Methods: All metal-chloroquine (CQ) and metal-CQDP complexes were synthesized under N(2) using Schlenk techniques. Their interactions with haematin and the inhibition of β-haematin formation were examined, in both aqueous medium and near water/n-octanol interfaces at pH 5. The anti-malarial activities of these metal- CQ and metal-CQDP complexes were evaluated in vitro against two strains, the CQ-susceptible strain (CQS) 3D7 and the CQ-resistant strain (CQR) W2.

Results: The previously synthesized Au(CQ)(Cl) (1), Au(CQ)(TaTg) (2), Pt(CQDP)(2)Cl(2) (3), Pt(CQDP)(2)I(2) (4), Pd(CQ)(2)Cl(2) (5) and the new one Pd(CQDP)(2)I(2) (6) showed better anti-malarial activity than CQ, against the CQS strain; moreover, complexes 2, 3 and 4 were very active against CQR strain. These complexes (1-6) interacted with haem and inhibited β-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents.

Conclusions: The high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1-6) could be attributable to their effective interaction with haem and the inhibition of β-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.

Show MeSH

Related in: MedlinePlus

Structure of metal-chloroquine and metal chloroquine diphosphate evaluated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4289335&req=5

Fig1: Structure of metal-chloroquine and metal chloroquine diphosphate evaluated.

Mentions: The palladium-chloroquine diphosphate complex was synthesized at room temperature in water. An excess of KI was added to the solution of K2[PdCl4] in order to displace all chloride ligands; subsequently, CQDP was added in a ratio 2:1 with respect to palladium salt, displaced two iodide ligands leads to the new complex(6), which was isolated in good yields as air stable brown solid. Elemental analyses of this complex are in agreement with the molecular formula proposed. The IR spectra of the complexes displayed peaks clearly associated with the presence of the coordinated CQDP. The ESI-MS spectrum of complex displayed a peak of high intensity corresponding to a molecular ion (M - 4H3PO4) at m/z 1000.03. The molar conductivity values obtained for the complex is in the range for 1:4 electrolytes dissolved in DMF [26], corresponding to four phosphates (H2PO4−) of CQDP in the complex. All NMR signals could be unequivocally assigned on the basis of 1D and 2D, Correlation spectroscopy (COSY), Heteronuclear Multiple Quantum Correlation (HMQC) and Heteronuclear Multiple Bond Correlation (HMBC) experiments for both complexes (for complete NMR data see Annex 1; atom numbering for CQDP in Figure 1). The 1H and 31C chemical shift variation of each signal with respect to those of the free ligand (Δδ) was used as a parameter to deduce the mode of bonding of CQDP to the metal. It has been previously shown [9–12, 27] that the largest variations are always observed for the protons and carbons located in the vicinity of the N-atom attached to the metal. The largest shift with respect to the free ligand (CQDP) was observed for NH and H1’ in the 1H NMR spectra and C4 in the 31C NMR spectra (Table 1). All other chloroquine protons and carbons showed smaller displacements, indicating that CQDP is bound to the palladium through the NH atom of the secondary amine, a good donor site in this molecule. Additionally, one signal was observed in the 31P-NMR corresponding to the H2PO4− group of CQDP (see Additional file 1). Based on the experimental data available, the formulation for the new palladium-chloroquine diphosphate compounds corresponds to 16-electron Pd(II) complexes in the usual d8 square planar coordination geometry, of trans configuration due to steric repulsion between the two chloroquine diphosphate ligands.Figure 1


Metal-chloroquine derivatives as possible anti-malarial drugs: evaluation of anti-malarial activity and mode of action.

Navarro M, Castro W, Madamet M, Amalvict R, Benoit N, Pradines B - Malar. J. (2014)

Structure of metal-chloroquine and metal chloroquine diphosphate evaluated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289335&req=5

Fig1: Structure of metal-chloroquine and metal chloroquine diphosphate evaluated.
Mentions: The palladium-chloroquine diphosphate complex was synthesized at room temperature in water. An excess of KI was added to the solution of K2[PdCl4] in order to displace all chloride ligands; subsequently, CQDP was added in a ratio 2:1 with respect to palladium salt, displaced two iodide ligands leads to the new complex(6), which was isolated in good yields as air stable brown solid. Elemental analyses of this complex are in agreement with the molecular formula proposed. The IR spectra of the complexes displayed peaks clearly associated with the presence of the coordinated CQDP. The ESI-MS spectrum of complex displayed a peak of high intensity corresponding to a molecular ion (M - 4H3PO4) at m/z 1000.03. The molar conductivity values obtained for the complex is in the range for 1:4 electrolytes dissolved in DMF [26], corresponding to four phosphates (H2PO4−) of CQDP in the complex. All NMR signals could be unequivocally assigned on the basis of 1D and 2D, Correlation spectroscopy (COSY), Heteronuclear Multiple Quantum Correlation (HMQC) and Heteronuclear Multiple Bond Correlation (HMBC) experiments for both complexes (for complete NMR data see Annex 1; atom numbering for CQDP in Figure 1). The 1H and 31C chemical shift variation of each signal with respect to those of the free ligand (Δδ) was used as a parameter to deduce the mode of bonding of CQDP to the metal. It has been previously shown [9–12, 27] that the largest variations are always observed for the protons and carbons located in the vicinity of the N-atom attached to the metal. The largest shift with respect to the free ligand (CQDP) was observed for NH and H1’ in the 1H NMR spectra and C4 in the 31C NMR spectra (Table 1). All other chloroquine protons and carbons showed smaller displacements, indicating that CQDP is bound to the palladium through the NH atom of the secondary amine, a good donor site in this molecule. Additionally, one signal was observed in the 31P-NMR corresponding to the H2PO4− group of CQDP (see Additional file 1). Based on the experimental data available, the formulation for the new palladium-chloroquine diphosphate compounds corresponds to 16-electron Pd(II) complexes in the usual d8 square planar coordination geometry, of trans configuration due to steric repulsion between the two chloroquine diphosphate ligands.Figure 1

Bottom Line: Clearly, a new effective and non-toxic anti-malarial drug is urgently needed.These complexes (1-6) interacted with haem and inhibited β-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents.The high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1-6) could be attributable to their effective interaction with haem and the inhibition of β-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.

View Article: PubMed Central - PubMed

Affiliation: Centro de Química, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela. maribelnava@gmail.com.

ABSTRACT

Background: Malaria still has significant impacts on the world; particularly in Africa, South America and Asia where spread over several millions of people and is one of the major causes of death. When chloroquine diphosphate (CQDP) lost its efficiency as a first-line anti-malarial drug, this was a major setback in the effective control of malaria. Currently, malaria is treated with a combination of two or more drugs with different modes of action to provide an adequate cure rate and delay the development of resistance. Clearly, a new effective and non-toxic anti-malarial drug is urgently needed.

Methods: All metal-chloroquine (CQ) and metal-CQDP complexes were synthesized under N(2) using Schlenk techniques. Their interactions with haematin and the inhibition of β-haematin formation were examined, in both aqueous medium and near water/n-octanol interfaces at pH 5. The anti-malarial activities of these metal- CQ and metal-CQDP complexes were evaluated in vitro against two strains, the CQ-susceptible strain (CQS) 3D7 and the CQ-resistant strain (CQR) W2.

Results: The previously synthesized Au(CQ)(Cl) (1), Au(CQ)(TaTg) (2), Pt(CQDP)(2)Cl(2) (3), Pt(CQDP)(2)I(2) (4), Pd(CQ)(2)Cl(2) (5) and the new one Pd(CQDP)(2)I(2) (6) showed better anti-malarial activity than CQ, against the CQS strain; moreover, complexes 2, 3 and 4 were very active against CQR strain. These complexes (1-6) interacted with haem and inhibited β-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents.

Conclusions: The high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1-6) could be attributable to their effective interaction with haem and the inhibition of β-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.

Show MeSH
Related in: MedlinePlus