Plasmodium falciparum antimalarial activity

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126 some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of 11-azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>. 

O Neill PM, Rawe SL, Borsmik K, Miller A, Storr RC, Ward SA, Bray PG Davies J, Ho Oh C, Posner GH. (2005) Enantiomeric 1,2,4-trioxanes display equivalent in vitro antimalarial activity versus Plasmodium falciparum... 

The ozonide (176) was prepared as part of a synthetic study towards the antimalarial natural product artemisinin (177) <92JCS(Pl)325l>. It proved stable enough to allow x-ray crystal structure determination (see Section 4.16.3.1). Other, more complex, polycyclic ozonides were prepared in order to investigate possible antimalarial properties. Compounds were evaluated in vitro for antimalarial activity using a multiresistant strain of Plasmodium falciparum. Most were found to be weakly active although a thousand times less active than artemisinin. 

In effect, antimalarial trojan horse drugs of this type should deliver a double blow to the parasite by exploiting the presence of high concentrations of ferrous ion present in the parasite food vacuole as the trigger for protease inhibitor release. In model studies with prototype 81d, in the presence of ferrous ions, these systems readily degrade to produce the desired chalcone (82b, R = H, in 45% yield from 81d), in tandem with secondary carbon-centred radical 82a (Scheme 29). Furthermore, analogues 81d-f have superior in vitro antimalarial activity to that of arteflene (<25 nM in vitro versus Plasmodium falciparum, arteflene >50 nM). The other product obtained is the diol (82c), a product of two-electron reduction of the endoperoxide bridge. 

G3 factor, 199, 201, 202 mechanisms, 1309, 1310 NMR spectroscopy, 710 OZ 277 drug candidate, 1317, 1319, 1331 Plasmodium falciparum resistance, 608 synthetic, 1282, 1317-31 antimalarial activities, 1332 semi-synthetic artemisinin derivatives, 1313-17, 1332... 

Antimalarial activity. The dried leaf was inactive on Plasmodium falciparum D-6 and W-2, ICjf, greater than 1000 nmols " h Antimycobacterial activity. Essential oil, on agar plate, was active on AntimycO bacterium smegmatis, MIC 0.1 mg/mL 5 Anti-nematodal activity. Water extract of the dried leaf at variable concentrations produced strong activity on Meloidogyne incognita. ... 

A novel approach to the production of antimalarial drugs has been described taking advantage of the in vivo transformation of pteridines by resident enzymes <2005AAC3652>. It was shown that simple precursors such as 2,4-diamino-6-hydroxymethylpterin can be converted into aminopterin or methotrexate, depending upon the precursor chosen, and that the dihydrofolate reductase inhibitors so formed were active against Plasmodium falciparum. 

The in vitro antimalarial activity of 17 and 422-430 against a multiresistant strain of Plasmodium falciparum from Thailand has been studied and the results are given in Table 8 < 1996J(P 1)1101 >. 

Chloroquine destroys schizonts in erythrocytes by interfering with DNA synthesis. The phosphate salts are active orally, whereas the hydrochloride salt is used for intravenous purposes. It accumulates in normal and parasitized erythrocytes. Overdosage has caused reversible corneal damage and permanent retinal damage. In toxic doses, chloroquine causes visual disturbances, hyperexcitability, convulsions, and heart block. It is an antimalarial of choice in all cases except chloroquine-resistant Plasmodium falciparum. In addition, it has a certain degree of effectiveness in amebiasis and in the late stages of rheumatoid arthritis. 

Table 2. Relative In Vitro Antimalarial Activity of 3-Substituted Analogues of Artemisinin against Plasmodium falciparum...

As can be seen in Table 5, neither target 240 (-4%) nor 241 (-16%) displayed substantial antimalarial potency relative to artemisinin (100%) in vitro against the W-2 clone of Plasmodium falciparum, yet the isomeric peroxide 258 was found to possess good antimalarial activity (-60%). The fourfold enhancement in activity of 241 relative to 240 is analogous to the ranking of activities between 10-deoxoartemisinin 108 and artemisinin 1. 

A rapid semiautomated microdilution method for the microbiological assay of the chloroquine has been developed by Desgardins (26). Antimalarial activity of chloroquine may be studied against cultured Plasmodium falciparum, microplates are used to prepare serial dilution of the drug. Parasites obtained from continuous stock cultures are subcultured in the micro-plates for 42 h. Inhibition of uptake of a radio labeled nucleic acid precursor by parasites serves as the indicator of antimicrobial activity. 

Halofantrine (Hf) is a new phenanthrenemethanol antimalarial that shares many physicochemical similarities with cyclosporine and has been the subject of a number of investigations in our laboratory. Hf is orally active, well tolerated, and is finding increasing use in the treatment of malaria associated with multidrug resitant strains of Plasmodium falciparum. However, Hf is extremely lipophilic (log P 8) and poorly water soluble (<10 p,g/mL), and the bioavailability of Hf after oral administration of Hf.HCl tablets is low and variable. 

Key words Plasmodium falciparum, Kinase, Drug, Quantitative structure-activity relationships, Pharmacophore, Docking, Antimalarials... 

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... 

Caridha D, Kathcart AK, Jirage D, Waters NC (2010) Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases. Bioorg Med Chem Lett 20(13) 3863-3867 Geyer JA, Keenan SM, Woodard CL et al (2009) Selective inhibition of Pfinrk, a Plasmodium falciparum CDK, by antimalarial l,3-diaryl-2-propenones. Bioorg Med Chem Lett 19(7) 1982-1985 Jirage D, Chen Y, Caridha D et al (2010) The malarial CDK Pfinrk and its effector PfMATl phosphorylate DNA replication proteins and co-localize in the nucleus. Mol Biochem Parasitol 172(1) 9-18... 

J.K. Baird, and C. Lambros, Effect of membrane filtration of antimalarial drug solutions on in vitro activity against Plasmodium falciparum. Bull WHO 62 439-444, 1984. 

With the Chinese claims validated in 1984 by Klayman and coworkers,94 studies in the early 1980s rapidly addressed two key issues with the advancement of artemisinin as an antimalarial drug. One, how could it be made commercially and if so, what is its mode of action Although the former question was addressed,95,96 the lack in understanding its activity was reported by Gu.97 Here, evidence from prior studies indicated that, while active analogues could be prepared, including dihydroartemisinin and artemether (Figure 3.8), the endoperoxide function was key to this activity.98 In their work, Gu and co-workers postulated that the activity arose from modification of protein synthesis within the malaria parasite, Plasmodium falciparum 1 This was followed by a series of studies that indicated that the activity of artemisinin was attenuated by addition... 

The antimalarial activity of the linear coumarinolignan, grewin (18), was evaluated on cultures of Plasmodium falciparum clones D6 and W2 and it displayed weak antimalarial activity with no discernible cytotoxicity (69). Cleomiscosin A (9) and aquillochin (7), isolated as major constitutents from the heartwood of Acer nikoense, exhibited moderately potent vasorelaxant effects in the rat aorta using nor-epinephrine-stimulated and high K" -depolarized preparations (18). (7 S,8 S)-4 -0-Methyl-cleomiscosin D (29) and cleomiscosin D (11), isolated from Zan-thoxylum avicennae, were found to inhibit superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochlasin B (52). 

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