Martin Schlitzer

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

Antimalarial Drugs – What is in Use and What is in the Pipeline

Malaria continues to be a potentially fatal threat to almost half of the worlds population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.

Diaryl ester prodrugs of fR900098 with improved in vivo antimalarial activity

The fosmidomycin derivative FR900098 represents an inhibitor of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase with potent antimalarial activity. Prodrugs of FR900098 with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield phosphodiaryl esters. One diaryl ester prodrug demonstrated efficacy in mice infected with the rodent malaria parasite Plasmodium vinckei comparable to i.p. drug administration.

Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity.

FR900098 represents an improved derivative of the new antimalarial drug fosmidomycin and acts through inhibition of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield acyloxyalkyl esters. The most successful compound demonstrated 2-fold increased activity in mice infected with the rodent malaria parasite Plasmodium vinckei.

Structure-activity relationships of novel anti-malarial agents. Part 2: cinnamic acid derivatives.

We have described compound 1 as a lead structure for a novel class of anti-malarial agents. Replacement of the 3-phenylpropionyl moiety of the lead structure 1 by a 4-propoxycinnamic acid residue resulted in a significant improvement in antimalarial activity. Compound 3q represents an important step in the development of lead structure 1 into an anti-malarial drug candidate.

Development of Benzophenone‐Based Farnesyltransferase Inhibitors as Novel Antimalarials

The development of farnesyltransferase inhibitors directed against Plasmodium falciparum is a strategy towards new drugs against malaria. Previously, we described benzophenone‐based farnesyltransferase inhibitors with high in vitro antimalarial activity but no in vivo activity. Through the introduction of a methylpiperazinyl moiety, farnesyltransferase inhibitors with in vivo antimalarial activity were obtained. Subsequently, a structure‐based design approach was chosen to further improve the antimalarial activity of this type of inhibitor. As no crystal structure of the farnesyltransferase of the target organism is available, homology modeling was used to reveal differences between the active sites of the rat/human and the P. falciparum farnesyltransferase. Based on flexible docking data, the piperazinyl moiety was replaced by a N,N,N′‐trimethylethylenediamine moiety. This resulted in an inhibitor with significantly improved in vitro and in vivo antimalarial activity. Furthermore, this inhibitor displayed a notable increase in selectivity towards malaria parasites relative to human cells.

Non-peptidic, non-prenylic inhibitors of the prenyl protein-specific protease Rce1

Several compounds designed as bisubstrate analogues of protein farnesyltransferase inhibited the prenyl protein-specific protease Rce1, qualifying them as lead structures for a novel class of non-peptidic, non-prenylic inhibitors of this protease.

The antimalarial pipeline – An update

There are quite a number of antimalarial compounds in different states of preclinical and clinical development. Among those in advanced stages, combinations of known drugs or new substances from drug classes already used in antimalarial therapy are predominant. More compounds with novel or even unknown mechanism of action are found among those compounds which are in less advanced stages of development.

Design, synthesis and early structure–activity relationship of farnesyltransferase inhibitors which mimic both the peptidic and the prenylic substrate

Inhibition of the farnesylation of ras proteins has been identified as a promising target in tumor therapy. Only a few farnesyltransferase inhibitors are bisubstrate analogues displaying features of both substrates, the farnesylpyrophosphate and the C-terminal CAAX-tetrapeptide sequence of the ras protein. These known bisubstrate analogues consist of an AAX-tripeptide and a farnesyl residue connected through various linkers. We have developed a class of novel compounds that mimic a bisubstrate inhibitor structure and that differ from the known ones by lacking peptidic or farnesylic substructures. Long chain fatty acids and aryl-substituted carboxylic acids were used as farnesyl surrogates. These structures were linked to isoleucine amide, benzoic acid amide, N-substituted aminobenzenesulfonamides and N(alpha)-aryl-substituted methionine derivatives, respectively, which function as AA- or AAX-mimetics.

Studies addressing the importance of charge in the binding of fosmidomycin-like molecules to deoxyxylulosephosphate reductoisomerase.

Fosmidomycin and its homologue FR900098 are inhibitors of 1‐deoxy‐D‐xylulose‐5‐phosphate reductoisomerase, which is part of the mevalonate‐independent isoprenoid biosynthetic pathway. Replacement of the phosphonate moiety by uncharged sulfone or sulfonamide partial structures resulted in complete loss of activity. Dropping one of the two negative charges resulted in a marked decrease in activity. Through occupation of a hydrophobic binding site, some activity could be regained, leading to compounds with micromolar activity against cultured malaria parasites.