Recent Advances in Antimalarial Drug Development

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.
Medicinal Research Reviews (Impact Factor: 8.13). 05/2007; 27(1):65-107. DOI: 10.1002/med.20062
Source: PubMed

ABSTRACT Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development.

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    ABSTRACT: For antimalarial 8-aminoquinoline (8-AQ) drugs, the ionization potential (the energy required to remove an electron) of their putative metabolites has been proposed to be correlated in part to their hemotoxicity potential. NPC1161 is a developmental candidate as an 8-AQ antimalarial drug. In this work, the ionization potentials (IPs) of the S-NPC1161 (NPC1161a) hydroxylated derivatives, which are possible metabolites derived from action of endogenous cytochrome P450 (CYP450) enzymes, were calculated at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water. The derivative hydroxylated at N1' (the 8-amino) was found to have the smallest IP of ~430 kJ/mol, predicting that it would be the most hemotoxic. The calculated IPs of those derivatives hydroxylated at the C-2 and the C-7 positions were ~475 and ~478 kJ/mol, respectively, while the calculated IPs of those hydroxylated at all other possible positions were between 480-490 kJ/mol. The homolytic bond dissociation energies (HBDEs) of all C-H/N-H bonds in NPC1161a were also calculated. The smaller HBDEs of the C-H/N-H bonds on the 8-amino side chain suggest these positions are more easily hydroxylated compared to other sites. Molecular orbital analysis implied that the N1' position would be the most reactive center when NPC1161 approaches the heme in CYP450.
    The Journal of Physical Chemistry A 06/2014; 118(29). DOI:10.1021/jp502612t · 2.78 Impact Factor
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    ABSTRACT: A one-pot, two-step synthesis of α-O-, S-, and N-substituted 4-methylquinoline derivatives through Cu-catalyzed aerobic oxidations of N-hydroxyaminoallenes with alcohols, thiols, and amines is described. This reaction sequence involves an initial oxidation of N-hydroxyaminoallenes with NuH (Nu=OH, OR, NHR, and SR) to form 3-substituted 2-en-1-ones, followed by Brønsted acid catalyzed intramolecular cyclizations of the resulting products. Our mechanistic analysis suggests that the reactions proceed through a radical-type mechanism rather than a typical nitrone-intermediate route. The utility of this new Cu-catalyzed reaction is shown by its applicability to the synthesis of several 2-amino-4-methylquinoline derivatives, which are known to be key precursors to several bioactive molecules.
    Chemistry - A European Journal 02/2015; 21(12). DOI:10.1002/chem.201406317 · 5.70 Impact Factor
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    ABSTRACT: Dispersive liquid-liquid microextraction (DLLME) followed by UV-Vis spectrophotometry was applied for extraction/preconcentration and determination of trace levels of quinine (QN). Chloroform and methanol were chosen as the extraction solvent and the disperser solvent, respectively. A central composite design (CCD) was applied to optimize the effective parameters of DLLME including volume of extraction solvent, pH, and salt concentration. The optimal conditions were obtained as 160 mu L for the volume of extraction solvent, 9.88 for pH, and 2.2% (w/v) for salt concentration. The linear dynamic range (LDR) was 25-700 mu g L-1 with a correlation coefficient of 0.994. The limit of detection (LOD) and relative standard deviation (RSD) were 14.71 mu g L-1 and 1.13%, respectively. The method was successfully applied for the determination of QN in real samples and satisfactory relative recoveries (101.51-108.02%) were obtained.
    Analytical methods 01/2013; 5(19). DOI:10.1039/c3ay40478a · 1.94 Impact Factor