Antimalarial inhibitors

P-Blockers, benzodiazepines, NSAIDs, barbiturates NSAIDs, protease inhibitors, P-blockers, benzodiazepines Antimalarials, NSAIDs, P-blockers, bronchodilators Phosphine oxides, NSAIDs, anticonvulsants Bronchodilators, P-blockers... 

Inhibitors of Folate Metabolism Provide Cancer Chemotherapy Antibacterial Antimalarial Drugs... 

Andrews KT, Walduck A, Kelso MJ, Fairlie DP, Saul A, Parsons PG (2000) Antimalarial effect of histone deacetylation inhibitors and mammalian tumor cytodifferentiating agents. Int J Paarasitol 30 761-768... 

Apicidins - coccidiostats and antimalarial peptides 8 Microsporin A - histone deacetyiase inhibitor 219... 

Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for dihydrofolate reductase activity. Specific dihydrofolate reductase inhibitors have become especially useful as antibacterials, e.g. trimethoprim, and antimalarial drugs, e.g. pyrimethamine. 

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. 

This pro-drug approach provides a paradigm for future antimalarial drug discovery efforts in the sense that this approach can be extended to any protease inhibitor that contains a carbonyl group as the reactive protease inhibitor warhead . Simply masking the carbonyl group within a trioxane or endoperoxide provides a unique and selective mechanism for targeting the malaria parasite by two different mechanisms . ... 

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. 

A considerable number of enzymes occupy a central and crucial role in the activity of drugs. Dihydrofolate reductase, an enzyme involved in purine and amino acid biosynthesis, is the target of antibacterial sulfanilamides, which act both as bacteriostatics and antimalarials. These drugs act on the enzyme in different ways, some being so-called antimetabolites (i.e., reversible enzyme inhibitors). Some diuretics act on carbonic... 

The other major class of antimalarials are the folate synthesis antagonists. There is a considerable difference in the drug sensitivity and affinity of dihydrofolate reductase enzyme (DHFR) between humans and the Plasmodium parasite. The parasite can therefore be eliminated successfully without excessive toxic effects to the human host. DHFR inhibitors block the reaction that transforms deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) at the end of the pyrimidine-synthetic pathway. This reaction, a methylation, requires N °-methylene-tetrahydrofolate as a carbon carrier, which is oxidized to dihydrofolate. If the dihydrofolate cannot then be reduced back to tetrahydrofolate (THF), this essential step in DNA synthesis will come to a standstill. 

A number of antibiotics in addition to the folate antagonists and sulfonamides are modestly active antimalarials. The antibiotics that are bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like organelle, the apicoplast. None of the antibiotics should be used as single agents in the treatment of malaria because their action is much slower than that of standard antimalarials. 

In 1993, the effects of selected topoisomerase II inhibitors, antimalarial agents, DNA binders, naphthoquinones, and various other agents on integrase activity in vitro were investigated [46]. 

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