The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents

Artemisinin derivatives such as artesunate, dihydroartemisinin and artemether are playing an increasing role in the treatment of drug-resistant malaria. They are the most potent antimalarials available, rapidly killing all asexual stages of the parasite Plasmodium falciparum. This review highlights the recent developments in the area of improved second-generation semi-synthetic artemisinin derivatives and fully synthetic antimalarial endoperoxide drugs. In pursuit of synthetic analogues of the artemisinins, one of the major challenges for chemists in this area has been the non-trivial development of techniques for the introduction of the peroxide bridge into candidate drugs. Although chemical research has enabled chemists to incorporate the endoperoxide ‘warhead’ into synthetic analogues of artemisinin, significant drawbacks with many candidates have included comparatively poor antimalarial activity, non-stereoselective syntheses and chemical approaches that are not readily amenable to scale up. However, very recent progress with synthetic 1,2,4-trioxolanes provides a new benchmark for future medicinal chemistry efforts in this area.     

Endoperoxides as potential antimalarial agents

A number of mono- and bicyclic endoperoxides were prepared and tested for antimalarial activity in search of a simplified analogue of the 5-oxygen-substituted 1,2,4-trioxane ring structure of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of P. falciparum. The most active compound in this assay was 2-[((butyloxy)-carbonyl)oxy]-1,1,10-trimethyl-6,9-epidioxy-delta 7-octalin (17a), which showed an IC50 of 100 and 57 ng/mL, respectively. For comparison, qinghaosu exhibits a mean IC50 less than 3.4 ng/mL.     

Recent advances in artemisinin and its derivatives as antimalarial and antitumor agents

Artemisinin, the first and last naturally occurring 1, 2, 4-trioxane originated from Artemisia annua, L. and its derivatives are a potent class of antimalarial drugs. The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and it is high in such areas as well where multidrug-resistance is rampant. Furthermore, artemisinin and many of its analog possess not only antiparasitic effect against Plasmodium falciparum, Schistosoma japonicum and Clonorchis sinensi but also immuno-modulation effects, and antitumor activities. This review covers the chemistry of artemisinin including synthesis of acetal-, non acetal-type C-12 analogs, C-11- and C-13 derivatives from artemisitene, ring-contracted derivatives, dimers, and trimers. Modes of biological action of artemisinin - derived analogs are also reviewed. The main objective of this article is to review the literatures of recent progress taken place in chemistry, mode of biological actions of artemisinin, and its derivatives as antimalarial and antitumor agents during the last three years (1999-2001).     

Synthesis and in vitro studies of novel pyrimidinyl peptidomimetics as potential antimalarial therapeutic agents

A class of new pyrimidinyl peptidomimetic agents (compounds 1-6) were synthesized, and their in vitro antimalarial activities against Plasmodium falciparum were evaluated. The core structure of the new agents consists of a substituted 5-aminopyrimidone ring and a Michael acceptor side chain methyl 2-hydroxymethyl-but-2-enoate. The synthesis of 1-6 featured a Baylis-Hillman reaction of various aldehydes with methyl acrylate catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) and a S(N)2' Mitsunobu reaction under the conditions of diethyl azadicarboxylate (DEAD), triphenylphosphine (Ph(3)P), and various acids. The new compounds exhibited potent in vitro growth inhibitory activity (IC (50) = 10-30 ng/mL) against both chloroquine sensitive (D-6) and chloroquine resistant (W-2) Plasmodium falciparum clones. Compound 6 (IC(50) = 6-8 ng/mL) is the most active compound of the class, the antimalarial efficacy of which is comparable to that of chloroquine. In general, this class of compound exhibited weak to moderate in vitro cytotoxicity against neuronal and macrophage cells with IC (50) in the range of 1-16 microg/mL and showed less toxicity in a colon cell line. Preliminary results indicated that compounds 3 and 6 are active against P. berghei, prolonged the life span of parasite-bearing mice from 6 days for untreated control to 16-24 days for drug-treated animals.     

New semi-synthetic cyclic peptides as potential antifungal and antiprotozoal agents

This patent deals with the synthesis, characterisation and biological activity of a large series of cyclic hexapeptides which display interesting activity against fungi (including Pneumocystis carinii) and protozoa. Novel semisynthetic methods are described and a broad spectrum antifungal activity is expected, as cyclic-hexapeptides are naturally occurring inhibitors of β-glucan synthesis. The antiprotozoal activity is surprising, since these organisms do not have cell walls, and suggests a novel mechanism of action. However, the information on antiprotozoal activity is scant and precludes the evaluation of the potential these new compounds have as antiparasitic drugs.     

Analogues of thiolactomycin as potential antimalarial agents

Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.     

The therapeutic potential of synthetic multivalent carbohydrates

Recent progress has been made in constructing synthetic multivalent carbohydrate ligands targeted at known or probable multivalent carbohydrate ligand receptors. Multivalency can dramatically compensate for the weak affinities of individual carbohydrate ligand moieties. Multivalent branched ligand mimetics have been described bearing multiple mannoside, galactoside, lactoside and Sialyl Lewis X (SLe^x) moieties. New methods for polymeric backbone construction have provided glyco-polymers of defined and controllable size. Promising examples of multivalent ligands giving significant increases in binding potency are being pursued. These types of agents have extensive therapeutic potential in treating infectious diseases or host abnormalities, and also offer exciting potential as drug-conjugate cell-targeting agents.     

The therapeutic potential of synthetic multivalent carbohydrates

Recent progress has been made in constructing synthetic multivalent carbohydrate ligands targeted at known or probable multivalent carbohydrate ligand receptors. Multivalency can dramatically compensate for the weak affinities of individual carbohydrate ligand moieties. Multivalent branched ligand mimetics have been described bearing multiple mannoside, galactoside, lactoside and Sialyl Lewis X (SLe(x)) moieties. New methods for polymeric backbone construction have provided glyco-polymers of defined and controllable size. Promising examples of multivalent ligands giving significant increases in binding potency are being pursued. These types of agents have extensive therapeutic potential in treating infectious diseases or host abnormalities, and also offer exciting potential as drug-conjugate cell-targeting agents.     

The design of semi-synthetic and synthetic glycoconjugate vaccines

Introduction: Glycoconjugate vaccines are among the safest and most efficacious vaccines developed during the last 30 years. They are a potent tool for prevention of life-threatening bacterial infectious diseases like meningitis and pneumonia. The concept of hapten–carrier conjugation is now being extended to other disease areas.

Areas covered: This is an overview of the history and current status of glycoconjugate vaccines. The authors discuss the approaches for their preparation and quality control as well as those variables which might affect their product profile. The authors also look at the potential to develop fully synthetic conjugate vaccines based on the progress of organic chemistry. Additionally, new applications of conjugate vaccines technology in the field of non-infectious diseases are discussed. Through this review, the reader will have an insight regarding the issues and complexities involved in the preparation and characterization of conjugate vaccines, the variables that might affect their immunogenicity and the potential for future applications.

Expert opinion: The immunogenicity of weak T-independent antigens can be increased in quantity and quality by conjugation to protein carriers, which provide T-cell help. Glycoconjugate vaccines are among the safest and most efficacious vaccines developed so far. Various conjugation procedures and carrier proteins can be used. Many variables impact on the immunogenicity of conjugate vaccines and a tight control through physicochemical tests is important to ensure manufacturing and clinical consistency. New and challenging targets for conjugate vaccines are represented by cancer and other non-infectious diseases.     

The design of semi-synthetic and synthetic glycoconjugate vaccines

Introduction: Glycoconjugate vaccines are among the safest and most efficacious vaccines developed during the last 30 years. They are a potent tool for prevention of life-threatening bacterial infectious diseases like meningitis and pneumonia. The concept of hapten-carrier conjugation is now being extended to other disease areas. Areas covered: This is an overview of the history and current status of glycoconjugate vaccines. The authors discuss the approaches for their preparation and quality control as well as those variables which might affect their product profile. The authors also look at the potential to develop fully synthetic conjugate vaccines based on the progress of organic chemistry. Additionally, new applications of conjugate vaccines technology in the field of non-infectious diseases are discussed. Through this review, the reader will have an insight regarding the issues and complexities involved in the preparation and characterization of conjugate vaccines, the variables that might affect their immunogenicity and the potential for future applications. Expert opinion: The immunogenicity of weak T-independent antigens can be increased in quantity and quality by conjugation to protein carriers, which provide T-cell help. Glycoconjugate vaccines are among the safest and most efficacious vaccines developed so far. Various conjugation procedures and carrier proteins can be used. Many variables impact on the immunogenicity of conjugate vaccines and a tight control through physicochemical tests is important to ensure manufacturing and clinical consistency. New and challenging targets for conjugate vaccines are represented by cancer and other non-infectious diseases.     

The therapeutic potential of novel cardiotonic agents

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as β-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca²⁺mobilisation (upstream mechanism). These agents are associated with the risk of Ca²⁺ overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca²⁺ overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca²⁺ ions (central and/or downstream mechanisms). Novel Ca²⁺ sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca²⁺ sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.     

Peptide derivatives of primaquine as potential antimalarial agents

Three peptide derivatives of primaquine were synthesized. The compounds were tested for radical curative antimalarial activity against Plasmodium cynomolgi in rhesus monkeys and blood schizonticidal antimalarial activity against Plasmodium berghei in mice. All three peptide derivatives showed activity against P. cynomolgi greater than that expected for the primaquine content of each prodrug. The toxicity of one of the peptide derivatives was less than that of primaquine in mice.     

The therapeutic potential of novel cardiotonic agents

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as beta-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca(2+) mobilisation (upstream mechanism). These agents are associated with the risk of Ca(2+) overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca(2+) overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca(2+) ions (central and/or downstream mechanisms). Novel Ca(2+) sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca(2+) sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.     

4,5-Disubstituted primaquine analogues as potential antimalarial agents

Three 4,5-disubstituted primaquine analogues were synthesized and evaluated for radical curative activity against Plasmodium cynomolgi in rhesus monkeys. One of the compounds showed moderate activity; however, none of the three compounds were as active as the lead compounds 5-methoxy-4-methylprimaquine and 4-(methoxy-methyl)-5-[m-(trifluoromethyl)phenoxy]primaquine.     

Toxicity of the antimalarial artemisinin and its dervatives

As long as no effective malaria vaccine is available, chemotherapy belongs to the most important weapons fighting malaria. One of the most promising new drug developments is the sesquiterpene artemisinin (ARS) and its derivatives, e.g., artemether, arteether, and sodium artesunate. Large clinical studies and meta-analyses did not show serious side effects, although proper monitoring of adverse effects in developing countries might not be a trivial task. There is a paucity of large-scale clinical trials suitable to detect rare but significant toxicity. Therefore, a final and definitive statement on the safety of artemisinins still cannot be made. In contrast, animal experiments show considerable toxicity upon application of artemisinins. In the present review, the authors give a comprehensive overview on toxicity studies in cell culture and in animals (mice, rats, rabbits, dogs, monkeys) as well as on toxicity reported in human clinical trials. The authors emphasize the current knowledge on neurotoxicity, embryotoxicity, genotoxicity, hemato- and immunotoxicity, cardiotoxicity, nephrotoxicity, and allergic reactions. The lesson learned from animal and human studies is that long-term availability rather than short-term peak concentrations of artemisinins cause toxicity. Rapid elimination of artemisinins after oral intake represents a relatively safe route of administration compared to delayed drug release after intramuscular (i.m.) injection. This explains why considerable toxicities were found in the majority of animal experiments, but not in human studies. In addition, there are drug-related differences, i.e., intramuscular application of artemether or arteether, but not to artesunate, which is safe and gives good profiles after i.m. administration in severe malaria. Although there is no need to increase doses of artemisinins for uncomplicated malaria, this has to be taken into account for cerebellar involvement in severe malaria. It might also be important in determining dose limitations for treatment of other diseases such as cancer.     

The therapeutic potential of agents that inactivate myostatin

Myostatin is a member of the TGF-beta superfamily of secreted growth factors. A lack of functional myostatin or inhibition of the normal myostatin function results in an increased muscling phenotype and, conversely, the systemic administration of myostatin results in muscle wasting. Thus, myostatin is well established as a negative regulator of skeletal muscle mass. Myostatin binds to cell-surface receptors to inhibit both the proliferation and differentiation of myoblasts. Moreover, it functions to regulate both embryonic and post-natal musculature. Thus, potential antagonists to myostatin, whether targeting myostatin synthesis, secretion or receptor binding, show great promise as therapies against muscle-wasting diseases. This review provides an expert opinion on the biology and potential of myostatin antagonists in the treatment of muscle-wasting disorders.     

The therapeutic potential of agents that inactivate myostatin

Myostatin is a member of the TGF-β superfamily of secreted growth factors. A lack of functional myostatin or inhibition of the normal myostatin function results in an increased muscling phenotype and, conversely, the systemic administration of myostatin results in muscle wasting. Thus, myostatin is well established as a negative regulator of skeletal muscle mass. Myostatin binds to cell-surface receptors to inhibit both the proliferation and differentiation of myoblasts. Moreover, it functions to regulate both embryonic and post-natal musculature. Thus, potential antagonists to myostatin, whether targeting myostatin synthesis, secretion or receptor binding, show great promise as therapies against muscle-wasting diseases. This review provides an expert opinion on the biology and potential of myostatin antagonists in the treatment of muscle-wasting disorders.