Synthesis, characterization and antimalaria studies of some mono carbonyl curcumin analogs and their aryl hydrazone derivatives
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Date
2016
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Obafemi Awolowo University
Abstract
The study synthesized mono carbonyl analogs of curcumin, the aryl hydrazone derivatives of the mono carbonyl curcumin analogs and a 2,4-dinitrophenyl pyrazolone derivative of curcumin itself. The synthesized compounds were then characterized, docked with plasmepsin II, and the acute toxicity of the synthesized compounds as well as the percentage chemosuppression of the rodent strain of malaria parasite (Plasmodium berghei) NK65(CS) were determined. This was with a view to establishing the compounds suitable for a curative assay and discovering new potent and relatively non-toxic synthetic analogs of curcumin that could be used to combat Plasmodium falciparum which is the malaria causal organism in man.
The monocarbonyl curcumins were synthesized by a simple Claisen-Schmidt condensation reaction by reacting two molar equivalents of a substituted benzaldehyde with a molar equivalent of acetone in acidic/basic conditions to yield compounds 1a-7a. The monocarbonyl curcumins were then reacted with a molar equivalent of 2,4-dinitrophenyl hydrazine with stirring in ethanol (at room temperature) under acid catalysis for 18 hrs to yield the corresponding DNP hydrazone1b-7b. Compound 3a was reacted with 4-nitro phenylhydrazine under the same conditions as DNP which resulted into a pyrazoline, 3c. Curcumin was also reacted with DNP under the same condition to yield a pyrazolone, 11e. The synthesized compounds were then characterized using spectroscopic techniques such as UV-Visible, IR, 1H and 13C NMR spectroscopy. The synthesized compounds were docked with plasmepsin II, one of the enzymes used by the parasite to digest haemoglobin, using flexX, a part of the LeadIT tools to estimate the binding affinity of the compounds for the protein as a function of antimalarial activity. All the synthesized compounds were tested in-vivo using a four day chemosuppressive assay for their antimalarial activity. The test animals were monitored afterwards for 24 days to assess the long term effect of the drug on the test models and to estimate the survival index (SI) of the test models with respect to the test compounds. The compounds were administered using a lipid based drug delivery system (cotton seed oil was used as the vehicle for the compounds administered orally).
The binding energies computed for the compounds ranged from -19.29 to -35.96 kJ/mol. Chloroquine was used as a control molecule and all the compounds had binding affinity greater than that of chloroquine (-17.02 kJ/mol). Some of the compounds docked had high affinity for the plasmepsin II. Compounds 1b, 4b, 5b, 6a, 6b, 7b and 10b had binding energies ranging from -25 to -36 kJ/mol. Among the compounds listed, only compound 6a was a monocarbonyl curcumin analog of curcumin. Compounds 1a (83.72 % chemosuppression at 200 mg/kg and SI of 68.75 %), 2b (81.93% chemosuppression at 200 mg/kg and SI of 50 %), 3a (58.62 % chemosuppression at 200 mg/kg and SI of 100 %), 5a (66.59 % chemosuppression at 100 mg/kg and SI of 68.75 %), 6a (71.2 % chemosuppression at 50 mg/kg and SI of 46.15 %) and 11e (74.09 % chemosuppression at 50 mg/kg and SI of 54.55 %)were the compounds that had the best combination of survival index and chemosuppression profiles.
This study concluded that the compounds 1a, 2b, 3a, 5a, 6a and 11e had high chemosuppression compared to curcumin which was comparable to chloroquine and could therefore be selected for a curative in-vivo assay.
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xxiv, 208p
Keywords
Antimalaria, Chemosuppression, Carbonyl curcumin, Aryl hydrazone derivatives, Mono carbonyl curcumin, Malaria parasite, chemosuppression
Citation
Fadare, O.A. (2016). Synthesis, characterization and antimalaria studies of some mono carbonyl curcumin analogs and their aryl hydrazone derivatives. Obafemi Awolowo University