Anti-malarial activity

Anti-malarial activity of desferrioxamine has been demonstrated in a range of Plasmodium species under in vitro conditions and more importantly under in vivo conditions in rat [87] and man [88], Desferrioxamine causes reversible effects during early ring stage and late schizont stages of the life cycle. In contrast, irreversible cytocidal effects occur when cultures at the late trophozoite/early schizont stage are exposed to the chelator [89,90]. Primary lesions are associated with the nucleus which is consistent with a perinuclear localization for ribonucleotide reductase [88]. 

Malaria is a worsening problem worldwide. More than 110 million people suffer from infection every year and up to 2 million of these die. A growing number of countries are now affected by drug-resistant strains of the parasites. The introduction of an iron chelator to control such infection is a novel approach, and as chelation is particularly critical at the late trophozoite stage, it may prove possible to limit treatment to relatively short time periods. 

The lipoxygenase family of enzymes catalyse stereospecific oxygenation reactions of fatty-acid substrates. The active site incorporates a non-haem iron centre in as yet an unidentified environment. The active form of the enzyme is the iron(III) state but is converted to iron(II) as the fatty acid is oxidised [91]. Catechol-containing compounds inhibit these enzymes by forming a ternary complex with the iron centre and depending on the substituents on the catechol moiety may even facilitate an internal redox reaction leading to the formation of iron(II) and an inactive form of the enzyme [92,93]. 

5-Lipoxygenase is the first enzyme in a series involved in the conversion of arachidonic acid to the family of leukotrienes. The inhibition of this enzyme therefore decreases leukotriene production without adversely influencing cyclooxygenase-based prostaglandin production [94], 

Leukotrienes have been suggested to be important in a wide range of diseases, including asthma, arthritis and psoriasis and consequently chelators with a highly selective action may prove to possess therapeutic potential. 

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The central. CHOH. group in the cinchona alkaloids seems to be essential to anti-malarial activity Conversion into quinicines [quinatoxines (I) — (VII)] destroys activity and so do such changes as. CHOH. — . CHCl. (cinchona chlorides) or. CHOH. — . CHj. (deoxy-cinchona bases) or. CHOH. — . CO. quina-ketones), or acylation of the hydroxyl group except in the case of quinine ethylcarbonate. 

The effect of change in the spatial relations at C and C is not clear since, as explained above, there is doubt as to the relative activities of the components of the two pairs, quinine and quinidine, and cinchonidine and cinchonine, but epf-C -quinine and epi-C -quinidine are only slightly active or, according to Dirscherl and Thron, inactive. This result supports Neeman s view that for anti-malarial activity the direction of rotation must be the same at C and C but that does not explain the... 

Isonitriles are stable, often naturally occurring, compounds that contain a divalent carbon. An example is axisonitrile-3, which can be isolated from a species of sponge and possesses anti-malarial activity. Write a resonance form for axisonitrile-3 that satisfies the octet rule. Don t forget to include formal charges. 

Replacement of the remaining ether oxygen by basic nitrogen leads to a compound that shows anti-malarial activity. Nitration of aniline derivative 38 leads to substitution para to the alkyl group. (Protonation of the amine under the reaction conditions leads to deactivation of the position para to that group relative to that para to alkyl. The position meta to the protonated amine is less deactivated.)... 

Substituted and aza analogues of febrifugine have been prepared in the search, with a certain amount of success, for a better anti-malarial activity/ toxicity balance <06BMCL1854>. A number of analogues of rutaecarpine, including substituents in and fusion onto ring D were prepared by condensation reactions on iminothio ethers 55... 

F 9- 73. In vitro and in vivo anti-malarial activities of fluoro artemisinin derivatives. 

Finally, gem-difluoromethylene analogs, e.g., 315 and 316, designed to mimic artemisinin, have been prepared by the treatment of the trifluoromethyl derivatives 169 and 173 with 2 equiv of MeLi in THF at —78 °C, and their anti-malarial activity investigated (Scheme 53) <2006JFC637>. 

VII. ANTI MALARIAL ACTIVITIES OF SYNTHETIC ENDOPEROXIDE ANTIMALARIALS... 

Desferrioxamine and several related iron chelators have been demonstrated to inhibit the proliferation of a variety of malignant cell lines [148,149] as well proving inhibitory in acute neonatal leukaemia [150]. In addition desferrioxamine also exhibits in vivo anti-malarial activity in both humans and rats [151,152], Iron chelators have also been used to treat the inflammatory skin disorder, psoriasis, where there is hyperproliferation of keratinocytes and T-lymphocytes [153,154], A general problem still to be overcome with a number of powerful iron chelators is their lack of cell specificity and thus general toxicity for example to bone marrow function [144],... 

Cimanga et al (17) assessed the anti-plasmodial (anti-malarial) activity of three different extracts and four alkaloids from the root back of C. sanguinolenta in vitro against P. falciparum D-6 (chloroquine-sensitive strain), K-1, and W-2 (chloroquine-resistant strains). 

Most QSAR equations will have a contribution from P or from tt or from both. However, there are examples of drugs which have only a slight contribution. For example, a study on antimalarial drugs showed very little relationship between anti-malarial activity and hydrophobic character. This finding lends support to the theory that these drugs are acting in red blood cells, since previous research has shown that the ease with which drugs enter red blood cells is not related to their hydrophobicity. 

Disubstituted primaquine analogues exhibited broader spectrum of anti-malarial activities compounds 59-61 exhibited both blood schizontocidal (P. berghi in mice) and radical curative P.cynomolgi in rhesus monkeys) activities and were also less toxic [26,44,45]. 

Ochna integerrima (Louri) Merr. (stem bark) (I-3,II-3)-Flavanone-chalcones. 1-5-hydroxylophirone B (288) 1-5-hydroxylophirone B l-l-O- -D-glueopyranoside (289) lophirone A (351) lophirone C (344) ealodenone (350) ealodenin A (340). Outer bark good anti-malarial activity, inner barks no antimalarial aetivity. fCaewamatawong et al., 2002[302] lehino et al., 2006[87]. 

The apparent bioactivity of the chalcones in the mixture, coupled with reports that chalcones are known to have anti-plasmodial activity,and that they are available in large quantities, led us to submit them to assays for anti-plasmodial activity the chalcones, flavanones and the homoisoflavanone (Table 5) were found to have redueed but still significant anti-plasmodial activities with IC50 values in the range of 2-20 ig/ml. This is an illustration of the principle that plant extracts and component compounds that are bioactive should be surveyed for anti-malarial activity and for activities against other diseases for which they are not already known. 

Cameron, A., Read, J., Tranter, 1L, et al. (2004) Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity./. Biol. Chem. 279, 31429-31439. 

The 1,2,4-trioxane ring system is the key structural subunit in a number of substances with promising anti-malarial activity, and has been constructed by a number of groups using a photooxygenation approach. Thus the readily available allylic alcohol geraniol reacts with O2 to give a mixture of mono- and... 

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