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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.

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Variation in absorbance of Fe(III)PPIX at 402 nm as a function of complex 6 concentration. Conditions: 40% DMSO, apparent pH 7.5, 0.020 M HEPES buffer, [Complex 6] = 26.98x10−6 M 25°C. Insert: log [(A-Ao) (A∞-A)] vs log [complex 6] (M).
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Fig2: Variation in absorbance of Fe(III)PPIX at 402 nm as a function of complex 6 concentration. Conditions: 40% DMSO, apparent pH 7.5, 0.020 M HEPES buffer, [Complex 6] = 26.98x10−6 M 25°C. Insert: log [(A-Ao) (A∞-A)] vs log [complex 6] (M).

Mentions: Chloroquine and its metal derivatives have shown that they can act through the formation of adducts with ferriprotoporphyrin IX, thus blocking haemozoin formation [15, 16, 38]. Indeed, in previous studies we have indicated that the anti-malarial activity of metal-CQ complexes often correlated with the interaction with haemin and β –haematin inhibition (10,13,14]. Following similar studies to those published previously, the association constant of complexes 1–6 with ferriprotoporphyrin IX (Fe(III)PPIX) were determined (Table 2). This association was followed by spectrophotometric titration at the 402 nm Soret band in aqueous DMSO at pH 5, to the equation for a 1:1 complexation model using nonlinear least squares fitting, strictly following the procedure of Egan et al. [21]. As an example, in Figure 2 is shown the needed concentration of complex 6 to reach the saturation point, and the hypochromism was approximately 70%. The log K value of 5.01 ± 0.01 obtained for CQDP under the present experimental conditions (pH 7.5) is in excellent agreement with the value reports for this method [21], in the case of log K for the studied complexes (1–6) was obtained fitted in a strictly analogous manner, the range of log K values are between 4.05 and 4.87 (Table 2), this indicates that complexes 1–6 interact with haematin comparably that CQDP does, under used conditions. Additionally, it is important of mentioning that these values are in the range of ferroquine, which has demonstrated high anti-malarial activity [5].Figure 2


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)

Variation in absorbance of Fe(III)PPIX at 402 nm as a function of complex 6 concentration. Conditions: 40% DMSO, apparent pH 7.5, 0.020 M HEPES buffer, [Complex 6] = 26.98x10−6 M 25°C. Insert: log [(A-Ao) (A∞-A)] vs log [complex 6] (M).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Variation in absorbance of Fe(III)PPIX at 402 nm as a function of complex 6 concentration. Conditions: 40% DMSO, apparent pH 7.5, 0.020 M HEPES buffer, [Complex 6] = 26.98x10−6 M 25°C. Insert: log [(A-Ao) (A∞-A)] vs log [complex 6] (M).
Mentions: Chloroquine and its metal derivatives have shown that they can act through the formation of adducts with ferriprotoporphyrin IX, thus blocking haemozoin formation [15, 16, 38]. Indeed, in previous studies we have indicated that the anti-malarial activity of metal-CQ complexes often correlated with the interaction with haemin and β –haematin inhibition (10,13,14]. Following similar studies to those published previously, the association constant of complexes 1–6 with ferriprotoporphyrin IX (Fe(III)PPIX) were determined (Table 2). This association was followed by spectrophotometric titration at the 402 nm Soret band in aqueous DMSO at pH 5, to the equation for a 1:1 complexation model using nonlinear least squares fitting, strictly following the procedure of Egan et al. [21]. As an example, in Figure 2 is shown the needed concentration of complex 6 to reach the saturation point, and the hypochromism was approximately 70%. The log K value of 5.01 ± 0.01 obtained for CQDP under the present experimental conditions (pH 7.5) is in excellent agreement with the value reports for this method [21], in the case of log K for the studied complexes (1–6) was obtained fitted in a strictly analogous manner, the range of log K values are between 4.05 and 4.87 (Table 2), this indicates that complexes 1–6 interact with haematin comparably that CQDP does, under used conditions. Additionally, it is important of mentioning that these values are in the range of ferroquine, which has demonstrated high anti-malarial activity [5].Figure 2

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