Antimalarial agents compounds

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Acridine dyes such as the antimalarial agent quinacrine (Atabrine) shown next are large planar aromatic compounds that intercalate or sandwich themselves between the stacked bases of the helix. 

Dwivedi et al. used a thin-layer chromatographic densitometric and ultraviolet spectrophotometric methods for the simultaneous determination of primaquine and a new antimalarial agent, CDRI compound number 80/53 [68]. The new antimalari-al agent, compound 80/53 is unstable in acidic conditions where it is converted into primaquine. To conduct stability studies of this compound, thin-layer chromatography densitometric and ultraviolet spectrophotometric determination methods were developed. These methods are also suitable of the determination of compound 80/53 or primaquine in bulk and pharmaceutical dosage forms. 

Moore and Hemmens [119] studied the photosensitization of primaquine and other antimalarial agents. The drugs were tested for in vitro photosensitizing capability by irradiation with 365 nm ultraviolet light in aqueous solutions. The ability of these compounds to photosensitize the oxidation of 2,5-dimethylfuran, histidine, trypotophan, or xanthine, and to initiate the free radical polymerization of acrylamide was examined in the pH range 2 12. Primaquine does not have significant photochemical activity in aqueous solution. 

Brown algae of the family Dictyotaceae yielded diterpenes of the dolabellane, xenicane, crenulide as well as extended germacrane and hydroazulenoid types. Some of these compounds were identified as capable of demonstrating appreciable selectivity as antimalarial agents... 

Artemisinin compounds clear parasites from the blood more rapidly than any other antimalarial agent, by a unique pharmacodynamic action. They are concentrated in parasitized erythrocytes, and structure-activity relations (see Chapter 2) suggest that their endoperoxide bridge is essential for the antimalarial effect. A critical step in the mechanism of action seems to be a hemin-catalyzed reduction of the peroxide moiety, which results in free radicals and reactive aldehydes that subsequently kill the malaria parasites. The hemin-rich internal environment of the parasites is assumed to be responsible for the selective toxicity of artemisinin toward these organisms. 

Shiekhattar R, Mermelstein F, Fisher RP et al (1995) Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature 374(6519) 283-287 Waters NC, Woodard CL, Prigge ST (2000) Cyclin H activation and drug susceptibility of the Pfinrk cyclin dependent protein kinase from Plasmodium falciparum. Mol Biochem Parasitol 107(l) 45-55 Xiao Z, Waters NC, Woodard CL et al (2001) Design and synthesis of Pfinrk inhibitors as potential antimalarial agents. Bioorg Med Chem Lett ll(21) 2875-2878 Woodard CL, Li Z, Kathcart AKet al (2003) Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases. J Med Chem 46(18) 3877-3882... 

Theoretical calculations dealing with 1,2-dioxocins are related to the remarkable antimalarial activity showed by both natural and synthetic compounds containing the eight-membered ring. Thus, two reports propose quick in silico discovery of new candidates as possible antimalarial agents and a third report gives a contribution to clarify the mechanism of action of antimalarial agents. Of which, only one utilizes theoretical calculations to determine the... 

The compounds were tested against P. falciparum (3D7) and showed good antimalarial activity (Fig. 18). In particular, compounds 136 showed much better potency than chloroquine, a known antimalarial agent (MIC = 0.39 pg/mL). 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

Quinoline is used as an intermediate in the production of quinoline-related compounds (e.g., 8-hydro-xyquinoline). It is a solvent for resins and terpenes, and is used in the production of paint. Quinoline is also an antimalarial agent. Sources of quinoline include petroleum and coal processing, wood preservation and the use of shale oil. 

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