Antimalarial drugs and their useful therapeutic lives: rational drug design lessons from pleiotropic action of quinolines and artemisinins

Efforts to develop an effective malarial vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Unfortunately, Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to classical antimalarials, necessitating a search for new chemotherapeutics preferably with novel modes of action. Today, rational drug discovery strategy is gaining new impetus as knowledge of malaria parasite biology expands, aided by the parasite genome database and improved bioinformatics tools. Drug development is a laborious, time consuming and costly process, and thus the "useful therapeutic lives" (UTLs) of new drugs should be commensurate with the resources invested in their development. Historical evidence on development and evolution of resistance to classical antimalarial drugs shows that the mode of action of a drug influences its UTL. Drugs that target single and specific targets such as antimalarial antifolates and atovaquone (ATQ) are rendered ineffective within a short time of their clinical use, unlike drugs with pleiotropic action such as chloroquine (CQ) and artemisinins (ART) with long UTLs. Unfortunately, almost all new targets currently being explored for development of novel drugs belong to the "specific target" other than the "multiple target" category, and is plausible that such drugs will have short UTLs. This review relates the pleiotropic action of CQ and ART with their long UTLs, and discusses their relevance in rational drug development strategies. Novel targets with potential to yield drugs with long UTLs are also explored.     

The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs

Malaria, one of the major reemerging parasitic diseases, is caused by protozoal parasites belonging to the genus plasmodia. Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The current line of therapy against malaria is faced with the hurdles of a low or total lack of efficacy due to the evolution of drug-resistant strains of the malarial parasites. Preventive vaccination against malaria is an ideal solution to this problem but is not expected to arrive for at least a decade. Development of antimalarial drugs involving novel mechanisms of action is therefore of imminent importance. Several novel drug candidates of synthetic and natural products origin as well as their combination therapies are currently being evaluated for their efficacy against the drug-resistant strains of the parasites. Various plasmodial targets/pathways, such as the Purine salvage pathway, Pyrimidine biosynthesis pathway as well as the processes in the apicoplast, have been identified and are being utilized for the discovery and development of novel antimalarial therapies. This review provides an overview of the latest developments in terms of drugs, combination therapies and novel plasmodial targets being carried out to counter the menace of drug-resistant malaria.     

Plasmodium falciparum: Multidrug resistance

Malaria is the most lethal and debilitating disease caused by the protozoan parasite Plasmodium worldwide. The most severe forms of disease and the incidence rates of mortality are associated with P. falciparum infections. With the identification of disease source and symptoms, many chemical entities were developed naturally and synthetically for administration as a potential antimalarial drug. The major classes of approved antimalarial drugs that are governed as first‐line treatment in tropical and subtropical areas include quinolines, naphthoquinones, antifolates, 8‐aminoquinolines, and endoperoxides. However, the efficacy of antimalarial drugs has decreased due to ongoing multidrug resistance problem to current drugs. With increasing resistance to the current antimalarial artemisinin and its combination therapies, malaria prophylaxis has declined gradually. New‐generation antimalarial and novel drug target are required to check the incidence of malaria resistance. This review summarizes the emergence of multidrug resistance to known antimalarial and the development of new antimalarial to resolve drug resistance condition. Few essential proteins are also discussed that can be considered as novel drug target against malaria in future.     

Searching for new antimalarial therapeutics amongst known drugs

The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug-like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high-throughput screen of the MicroSource Spectrum and Killer Collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their recently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline, and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.     

Novel rational drug design strategies with potential to revolutionize malaria chemotherapy

Efforts to develop an effective malaria vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to most antimalarial drugs in clinical use. This dire situation is aggravated by reports from Southeast Asia, of the parasite becoming resistant to the "magic bullet" artemisinins, the last line of defense in malaria chemotherapy. Drug development is a laborious and time consuming process, and thus antimalarial drug discovery approaches currently being deployed largely include optimization of therapy with available drugs--including combination therapy and developing analogues of the existing drugs. However, the latter strategy may be hampered by crossresistance, since agents that are closely related chemically may share similar mechanisms of action and/or targets. This may render new drugs ineffective even before they are brought to clinical use. Evaluation of drug-resistance reversers (chemosensitizers) against quinoline-based drugs such as chloroquine and mefloquine is another approach that is being explored. Recently, evaluation of new chemotherapeutic targets is gaining new impetus as knowledge of malaria parasite biology expands. Also, single but hybrid molecules with dual functionality and/or targets have been developed through rational drug design approach, termed as "covalent bitherapy". Since desperate times call for radical measures, this review aims to explore novel rational drug-design strategies potentially capable of revolutionizing malaria therapy. We thus explore malaria apoptosis machinery as a novel drug target, and also discuss the potential of hybrid molecules as well as prodrugs and double prodrugs in malaria chemotherapy.     

吡唑杂合体的抗疟疾活性

疟疾是由按蚊叮咬或输入携带疟原虫血液引起的一类高传染性疾病,其临床症状包括发热、头痛、呕吐等,如不及时治疗可能危及生命。尽管临床上使用的抗疟疾药物对疟疾的防控不可或缺,但随着长期广泛使用甚至滥用,恶性疟原虫对抗疟药物产生了不同程度的耐药性。为克服耐药性,研发新型抗疟疾药物势在必行。吡唑类化合物具有包括抗疟疾在内的多种生物活性,且某些吡唑类药物已广泛用于临床,故这类化合物引起了药物化学家的持续关注。本文将归纳吡唑杂合体在抗疟疾领域的最新研究进展,并讨论此类化合物的构-效关系。     

Targeting protein kinases in the malaria parasite: update of an antimalarial drug target

Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance.     

Preventing antimalarial drug resistance through combinations.

Throughout the tropical world antimalarial drug resistance is increasing, particularly in the potentially lethal malaria parasite Plasmodium falciparum. In some parts of Southeast Asia, parasites which are resistant to chloroquine, pyrimethamine-sulfadoxine, and mefloquine are prevalent. The characteristics of a drug that make it vulnerable to the development of resistance are a long terminal elimination half-life, a shallow concentration-effect relationship, and that one or two base-pair mutations confer a marked reduction in susceptibility. The development of resistance can be delayed or prevented by drug combinations. The artemisinin derivatives are the most potent of all antimalarial drugs. They reduce the infecting parasite biomass by approximately 10 000-fold per asexual life cycle. There are good arguments for combining, de novo, an artemisinin derivative with all newly introduced antimalarial drugs.     

Pharmacodynamics of antimalarial chemotherapy

Malaria chemotherapy is under constant threat from the emergence and spread of multidrug resistance of Plasmodium falciparum. Resistance has been observed to almost all currently used antimalarials. Some drugs are also limited by toxicity. A fundamental component of the strategy for malaria chemotherapy is based on prompt, effective and safe antimalarial drugs. To counter the threat of resistance of P. falciparum to existing monotherapeutic regimens, current malaria treatment is based principally on the artemisinin group of compounds, either as monotherapy or artemisinin-based combination therapies for treatment of both uncomplicated and severe falciparum malaria. Key advantages of artemisinins over the conventional antimalarials include their rapid and potent action, with good tolerability profiles. Their action also covers transmissible gametocytes, resulting in decreased disease transmission. Up to now there has been no prominent report of drug resistance to this group of compounds. Treatment of malaria in pregnant women requires special attention in light of limited treatment options caused by potential teratogenicity coupled with a paucity of safety data for the mother and fetus. Treatment of other malaria species is less problematic and chloroquine is still the drug of choice, although resistance of P. vivax to chloroquine has been reported. Multiple approaches to the identification of new antimalarial targets and promising antimalarial drugs are being pursued in order to cope with drug resistance.     

吡唑杂合体的抗疟疾活性

疟疾是由按蚊叮咬或输入携带疟原虫血液引起的一类高传染性疾病,其临床症状包括发热、头痛、呕吐等,如不及时治疗可能危及生命。尽管临床上使用的抗疟疾药物对疟疾的防控不可或缺,但随着长期广泛使用甚至滥用,恶性疟原虫对抗疟药物产生了不同程度的耐药性。为克服耐药性,研发新型抗疟疾药物势在必行。吡唑类化合物具有包括抗疟疾在内的多种生物活性,且某些吡唑类药物已广泛用于临床,故这类化合物引起了药物化学家的持续关注。本文将归纳吡唑杂合体在抗疟疾领域的最新研究进展,并讨论此类化合物的构-效关系。     

Antimalarial compound identification and design: advances in the patent literature, 2000 – 2003

World patents filed from 2000 to 2003 claiming specific in vitro or in vivo antimalarial activity are examined and compiled in this review in a format that allows comparison across different chemical classes or drug targets. The most over-represented classes include the 1-desoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase inhibitors and novel quinoline or artemisinin analogues. This finding can be linked to important trends in the clinical development of new antimalarial drugs. Patents disclosing novel classes of antimalarial drugs were scarce. This may mean that the target-directed screening effort in malaria has not yet come to fruition, has not been commercially exploited in an appropriate manner, or that next generation compounds in known drug classes are more viable commercial entities.     

Current progress in the chemistry, medicinal chemistry and drug design of artemisinin based antimalarials

This review covers developments in relation to artemisinin-based antimalarial agents. Topics covered include a brief introduction to the history and treatment of malaria, and more recently, drug resistant malaria; the discovery of the naturally occurring novel peroxidic antimalarial artemisinin; artemisinin biosynthesis, metabolism and biotransformations; the diversity of proposed mechanisms of action; pharmacokinetics; the insight into structure-toxicity relationships; the total syntheses and the progress made in the syntheses of its analogs; and, ultimately the contribution of these efforts towards rational drug design in order to access potent, non-toxic antimalarial drugs based on artemisinin.     

Pharmacodynamics of antimalarial chemotherapy

Malaria chemotherapy is under constant threat from the emergence and spread of multidrug resistance of Plasmodium falciparum. Resistance has been observed to almost all currently used antimalarials. Some drugs are also limited by toxicity. A fundamental component of the strategy for malaria chemotherapy is based on prompt, effective and safe antimalarial drugs. To counter the threat of resistance of P. falciparum to existing monotherapeutic regimens, current malaria treatment is based principally on the artemisinin group of compounds, either as monotherapy or artemisinin-based combination therapies for treatment of both uncomplicated and severe falciparum malaria. Key advantages of artemisinins over the conventional antimalarials include their rapid and potent action, with good tolerability profiles. Their action also covers transmissible gametocytes, resulting in decreased disease transmission. Up to now there has been no prominent report of drug resistance to this group of compounds. Treatment of malaria in pregnant women requires special attention in light of limited treatment options caused by potential teratogenicity coupled with a paucity of safety data for the mother and fetus. Treatment of other malaria species is less problematic and chloroquine is still the drug of choice, although resistance of P. vivax to chloroquine has been reported. Multiple approaches to the identification of new antimalarial targets and promising antimalarial drugs are being pursued in order to cope with drug resistance.     

Antimalarial quassinoids: past,present and future

This review is a compilation of the investigations reported to date on the sources, isolation, chemistry and antimalarial activities of natural quassinoids and their synthetic and semisynthetic analogs. It also provides an analysis of the in vitro structure–activity relationship of quassinoids for further evaluation in animal models. The introduction of non-nitrogenous antimalarial drugs has created a new era of malaria chemotherapy to treat Plasmodium falciparum strains that are resistant to existing nitrogenous drugs and the rising incidence of the deadly cerebral malaria. Many antimalarial quassinoids are discovered from simaroubaceous plants that are used traditionally to treat fever and malaria, thereby reiterating the critical role of ethnopharmacology as a rich source of novel drug discovery.     

Recent patent reviews on small molecule-based antimalarial drugs

Malaria is the number one disease in the world responsible for 1-3 million deaths each year. The world wide number of malaria patients is estimated at 400 to 900 million. Approximately one third of the world's population lives in malaria-endemic areas, including Central and South America, Asia, and Africa. Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae are malaria parasites responsible for infecting humans. Mosquitoes that carry malaria parasites have become resistant to insecticides, and the deadliest parasites have become resistant to previously effective antimalarial drugs such as chloroquine, quinine and other clinically used agents. Because of the widespread incidence of malaria in certain parts of the world and because of the increasing parasite resistance to standard anti-malarial agents, there is an urgent need for introducing new effective drugs. This review presents the recent patents that reveal development of novel antimalarial drugs.     

Redox regulation in malaria: current concepts and pharmacotherapeutic implications

Malaria imposes a serious threat to human and becomes more prevalent due to the emergence of drug resistant parasite. Understanding of the underlying mechanism of drug resistance and identification of novel drug targets are key effective processes for the management of malaria. Malaria parasite is highly susceptible to oxidative stress but lives in a pro-oxidant rich environment containing oxygen and iron, which produce a large amount of reactive oxygen species. Management of oxidative stress in malaria parasite is tightly regulated through active redox and antioxidant defense systems. The elevation of oxidative stress as a result of inhibition of any component of this defense system leads to redox imbalance and ultimately parasite death. Therefore, redox system plays an indispensable role for the survival of parasite within the host. Identification of key molecules, which disrupt parasite redox balance by altering key redox reactions and promote oxidative stress in parasites, would be an effective approach to develop novel antimalarial drugs. During the last few decades, contributions by researchers around the globe provide even better understanding of redox biology of malaria parasite. Here, in this review, we are highlighting the knowledge gathered so far regarding the essential redox-active processes and their components in malaria parasite to overcome elevated oxidative insults. We have also given maximum efforts to enlist currently used redox-active antimalarials, their mode of action and pharmacotherapeutic implications.     

Antimalarials in the treatment of schistosomiasis

With just one drug used for individual patient management and community-based morbidity control, the treatment, control, and eventual elimination of schistosomiasis is vulnerable should resistance to praziquantel emerge and spread. The discovery and development of novel chemical entities that exhibit antischistosomal properties, and the repurposing of existing drugs for schistosomiasis is thus of central importance as long as praziquantel remains effective. Here, we discuss the public health relevance of schistosomiasis, which is currently considered a neglected tropical disease. We recapitulate the past and current drug armamentarium against schistosomiasis, including shortcomings and a target product profile of an antischistosomal drug. The central piece of our review is the discovery of the antischistosomal properties of various antimalarial drugs, notably the artemisinins, synthetic trioxolanes, and mefloquine. We summarize findings from preclinical investigations and experiences made thus far from clinical studies. We conclude that a closer collaboration between the malaria and schistosomiasis communities might facilitate the discovery and development of novel antischistosomal drugs, and will foster monitoring and evaluation of the ancillary benefits of antimalarial prophylaxis and treatment against schistosomiasis.     

Combination therapy for malaria: the way forward?

Unless new strategies are deployed to combat malaria, the already enormous health and economic burden related to the disease in tropical countries is bound to worsen. The main obstacle to malaria control is the emergence of drug resistant strains of Plasmodium falciparum. As for HIV/AIDS and tuberculosis, the use of combinations of antimalarial drugs reduces the risk of selecting for resistant mutants of the plasmodial parasites. In large field trials, the combination of an artemisinin derivative and a partner drug with an unrelated mode of action (in this case mefloquine), has shown a remarkable double effect: preventing the emergence and spread of drug resistance, and interrupting the transmission of P. falciparum. This has opened the way for a new approach to the deployment of antimalarial drugs. Coupled with early detection and confirmed diagnosis, this strategy represents the only way forward in the chemotherapy of malaria. Massive economic assistance will be needed to detect and treat adequately the estimated 500 million cases of malaria per year, but without radical action there is no prospect of 'Rolling Back' malaria.     

Advances in molecular targets and chemotherapy of tuberculosis

The need for newer, effective drugs with different modes of action against tuberculosis is great, despite the numerous drugs in clinical use and the development of Bacilli Calmette-Guerin (BCG) vaccine. Three major goals should be considered in the development of new antituberculosis drugs: 1) they should be fast acting to reduce the long duration of treatment, thereby avoiding drug toxicity; 2) they should be active against both sensitive and resistant strains of tubercle bacilli; and 3) they should possess significant activity against dormant bacilli, which represent the stage affecting one-third of the world's tuberculosis patients. This review provides an overview of important current drugs, novel targets for the development of antituberculosis agents and future drug candidates.