recent advances in antimalarial drugs: structures, mechanisms of … · 2017-10-27 · ) and...

Recent advances in antimalarial drugs: structures, mechanisms of action

and clinical trials

J.-P. Jourdan1, J. Schneider

1, A. Dassonville-Klimpt1, P. Sonnet

1. 1 LG2A, UMR-CNRS 7378, UFR de Pharmacie, Université de Picardie Jules Verne, 1 rue des Louvels, 80 037 Amiens,

France.

Malaria, caused by protozoa of the genus Plasmodium, is transmitted to humans through bites from female Anopheles

mosquitoes. Among the five pathogenic species, P. falciparum and P. vivax are responsible for more than 95 % of malaria

cases in the world. P. falciparum is the most dangerous and is prevalent in tropical zones of Africa, Latin America and

Asia. According to the World Health Organization (WHO), about 100 tropical and sub-tropical countries are endemic and

3.3 billion people are exposed to malarial infections. Approximately, 429.000 people died of malaria in 2015. During the

last 50 years, two principal classes of antimalarial drugs were developed such as antifolates (pyrimethamine, trimethoprim,

sulfadoxine) and quinoline-containing drugs (quinine, mefloquine, chloroquine and primaquine). Antimalarial agents such

as antibiotics (doxycycline), arylaminoalcohol compounds (lumefantrine), hydroxynaphtoquinone derivatives

(atovaquone) and artemisinin (active principle of Artemesia annua) have been introduced during this period. The

extremely fast development of P. falciparum resistance phenomena to antimalarial drugs, particularly to chloroquine but

even with the most recent ones, urges the development of new molecules. Important efforts have been realized to

understand the molecular mechanisms for drug action and resistance and to find new antimalarial compounds. In this

paper, we propose to review the: i) antimalarial molecule drugs currently available, ii) new therapeutic approaches and

drug strategies developed and iii) recent drug candidates involved in clinical trials.

Keywords: malaria, antimalarial drugs, drug development, clinical trials.

1. Introduction

Malaria causes 212 million of infected cases, in 2015, localized in 91 endemic countries [1]. The mortality of this

infectious disease is about 429,000 persons of which 300,000 children under 5 years. Pregnant women and children are

the most sensitive people to malaria. Malaria has also a severe socioeconomic impact in countries where it is endemic

because of the persistent and disabling symptoms of the disease. The emergence of parasite resistances is the major

reason why malaria remains a major worldwide public health problem and requires new innovative solutions.

Plasmodium genus is divided in 5 species responsible of human disease: P. vivax, P. ovale, P. malariae, P.

falciparum and P. knowlesi. P. falciparum and P. knowlesi are species inducing severe forms of malaria. Regarding P.

falciparum, the phenomenon of multidrug resistance is widespread. The parasitic cycle is partitioned in two stages: i) a

sexual stage in the female Anopheles mosquito (vector), ii) an asexual stage in the human (host) [2]. The sexual stage

begins in the Anopheles mosquito with the gametes fusion to form the human infesting form (sporozoite). When

humans are infected by mosquito bite, the asexual stage occurs and sporozoites invade liver through the blood stream

and start replicating to become schizonts. Liver stage is asymptomatic. For P. vivax and P. ovale strains, some

sporozoites turn into hypnozoites. These latent forms remain in the liver and are responsible of relapses months or even

years after the primary infection. The erythrocytic stage occurs after liver cells burst releasing merozoites that maturate

in ring forms then blood schizonts via a trophozoite stage. This phase is symptomatic and can lead to death.

Antimalarial strategies are based on the parasitic cycle. The preventive measures concern transmission and sexual

stage (pyrethroid as insecticide against the Anopheles mosquito) while prophylactic or curative treatments target the

liver or erythrocytic human stages. The development of erythrocytic stage drugs is the best way to control symptoms

and associated mortality of malaria. Several strategies are currently being deployed to prevent or to treat malaria such as

i) use of vaccines [3], ii) development of vector control methods and iii) use of novel human stage drugs. Currently, the

most advanced malaria vaccine, RTS,S/AS01, is in clinical development. Results, from a phase III clinical trial, have

shown that RTS,S/AS01 is able to prevent malaria cases, particularly among children in high impact areas [4].

Strategies to control mosquitoes (insecticide-treated nets and indoor residual spraying) have been very effective in

the past but are currently at risk due to increased resistance of mosquitoes to insecticides used (mainly pyrethroids) [5].

In this review, we focus on the antimalarial drugs currently available that target the human stage parasitic cycle.

After a brief description of new therapeutic approaches and drug development strategies, we will describe the

chemical antimalarial candidates currently evaluated in clinical trials.

2. Current antimalarial agents

During the last century, several antimalarial drugs were developed. Currently available antimalarial agents are classified

according to their biological activity and chemical structure (schizontocides, gametocytocides). In this part, we present

Antimicrobial research: Novel bioknowledge and educational programs (A. Méndez-Vilas, Ed.)

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seven main classes of antimalarial drugs: i) arylaminoalcohols, ii) 4-aminoquinolines, iii) 8-aminoquinoleines, iv)

artemisinins, v) antifolates, vi) antibiotics and vii) inhibitors of the respiratory chain.

2.1 Arylaminoalcohols

Arylaminoalcohol derivatives such as quinine 1, mefloquine (MQ 2) and lumefantrine (LM 3), presented in Fig.1, are

among the oldest antimalarial agents. These drugs target the Plasmodium erythrocytic stage although their mechanisms

of action are not identical and completely solved. Quinine 1, first 4-methanol quinoline, was isolated from the Cinchona

tree, in 1820s, and its first synthesis was accomplished in 1944 [6]. Quinine 1 (human t1/2 = 10-12 hours) inhibits the

formation of haemozoin into the parasite’s digestive vacuole (DV). Many quinine 1 resistances are reported due

essentially to mutations of genes encoding for transporter proteins such as P. falciparum chloroquine (CQ 4) resistance

transporter (PfCRT), P. falciparum multidrug resistance transporter 1 (PfMDR1) and P. falciparum sodium/proton

exchanger 1 (PfNHE1) [7]. Now, quinine is used to treat severe cases of malaria as a second line treatment, or in

combination with antibiotics such as doxycycline 18 or clindamycin 20 to treat resistant malaria [8].

MQ 2 was developed in 1970s to counter the quinine 1 and CQ 4 resistances. MQ 2 is commercially available as a

racemate of two isomers of the erythro-mefloquine: (-)-(11R,12S)-erythro MQ 2 and (+)-(11S, 12R)-erythro MQ 2.

This antimalarial drug possesses a good pharmacokinetic profile with a long human plasmatic half-life (human t1/2 =

14-18 days) [9]. However, emergence of resistance to MQ 2 and its associated neuropsychiatric side effects have

limited its use. It was demonstrated that (-)-(11R,12S)-MQ 2 is responsible to this neurotoxicity [10]. Antimalarial

mechanisms of action are not completely elucidated. MQ 2 inhibits partially haemozoin formation in DV and it is

supposed that principal targets are located in the parasitic cytosol [11]. MQ 2 resistances are mediated by PfMDR1

polymorphism which, by amplification, increases the concentration of MQ 2 into the DV [12]. Since 1995, MQ 2 is

used as partner drug in an artemisinin-based combination therapy (ACT) with artesunate to counter the resistances [8].

In a resistance malaria and Vietnam War contest, Chinese scientists have developed, in 1970s, the LM 3 (human t1/2 =

3-5 days) [13]. LM 3 interacts with heme detoxification in the DV, but also interferes with the synthesis of nucleic acids

and proteins in the parasitic cytosol. It is demonstrated that PfMDR1 (N86Y mutation) and PfCRT (K76T mutation)

polymorphisms are implicated in LM 3 resistances [14]. LM 3 is administered in combination with artemether to limit

resistance phenomenon and is effective against all Plasmodium species pathogenic to humans [15].

2.2 4-Aminoquinolines

4-aminoquinolines such as CQ 4, amodiaquine (AQ 5) and piperaquine (PPQ 6) are blood schizontocides and

gametocytocides and possess similar mechanisms of action (Fig. 1). These drugs prevent the haemozoin polymerization

forming complexes with ferriprotoporphyrine IX [16, 17]. 4-Aminoquinoline resistances implicate the efflux pumps

PfCRT located at the DV membrane. PfCRT is identified as the main transporter protein implied in CQ 4 resistance.

PfMDR1 modulates also the degree of CQ 4 resistance in some Plasmodium strains. P. falciparum resistance to CQ 4

(human t1/2 = 40-70 hours) is now predominant in nearly all malaria endemic regions. Nowadays, CQ 4 is used in

monotherapy or combined with primaquine 7 for the treatment of P. vivax, P. ovale, P. malariae and P. knowlesi in

blood stage infections. In prophylaxis, CQ 4 reduces recurrent P. vivax malaria. AQ 5 is the second 4-aminoquinoline

marketed in 1948. The antimalarial activity is thought to be exerted by the primary metabolite,

monodesethylamodiaquine (human t1/2 = 9-18 days) [18, 19]. A partially cross-resistance is observed between CQ 4 and

AQ 5 but some CQ 4 resistance parasites remain susceptible to AQ 5, these particularity suggest a different mechanism

of action [8]. The last 4-aminoquinoline family developed in 1970s was bis-quinoline PPQ 6 (human t1/2 = 5 weeks)

[20]. Currently, PPQ 6 is used in Artemisinin Combination Therapy (ACT) strategy with dihydroartemisinin (DHA 8)

in severe malaria infections [8].

Fig. 1 Arylaminoalcohol and aminoquinoline derivatives.


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2.3 8-Aminoquinolines

Among 8-aminoquinolines, primaquine 7 (human t1/2 = 6 hours), presented in Fig. 1, is used in monotherapy against the

hypnozoite forms of P. vivax and P. ovale since 1950s. Like most antimalarial drugs, its mechanisms of action are not

totally understood. It is thought to interfere with the cellular respiration of the parasite by generating oxygen free

radicals and deregulating the electron transports [21]. This drug acts quickly on mature gametocytes and reduces their

transmissibility to mosquitoes. It is suggested that primaquine 7 can be bound to PfCRT and inhibits the CQ 4 transport

to restore the CQ 4 sensitive [22].

2.4 Artemisinins

During Vietnam War, greatest efforts to discover new antimalarial agents were realized by China to fight the resistance

emergences observed with arylaminoalcohols. In this context, artemisinin compound was isolated from the Artemisia

annua plant [23]. Artemisinin and its derivatives are sesquiterpenic lactones, characterized by an endoperoxide bond

that is required for antimalarial activity [24]. This compound is slightly soluble in water and has a poor oral

bioavailability. Pharmacomodulations were then realized to give analogues with better pharmacokinetic properties such

as DHA 8, ATM 9 and ART 10 [25]. These derivatives, presented in Fig. 2, are effective against both the asexual stages

(pre-erythrocytic and erythrocytic) and the sexual stages. To exert their action artemisinin derivatives has to be

activated. Their endoperoxide bridge reacts in a heme mediated degradation pathway to generate free radical species

[26–28]. The resulting artemisinin-derived free radicals can inhibit the haemozoin polymerization and parasite

biomolecules resulting in parasite’s death. Artemisinin can also be activated by a mitochondria pathway to generate

reactive oxygen species (ROS) involved in lipid peroxidation and can induce the depolarization of the parasite

mitochondrial and plasma membranes [29]. Artemisinin also targets the P. falciparum encoded sarcoplasmic–

endoplasmic reticulum ATPase 6 (PfATP6) (a calcium pump) [30]. Artemisinin resistances are associated to mutation

in PfATP6 with decreased ATM 9 susceptibility. Decreased artemisinin susceptibility is also observed with PfMDR1

amplification [31,32]. In monotherapy, these resistances appeared only 3 days after drug administration. Artemisinin

derivatives are generally safe and well-tolerated. They act faster and possess rapid clearance (human t1/2 = 1 hour). They

are combined with slow clearance drugs to kill residual parasites. Typical combinations are ART 10-MQ 2, ATM 9-LM

3, DHA 8-PPQ 6, ART 10-sulfadoxine 17-pyrimethamine 15 and ART 10-doxycycline 18 or clindamycin 20 [33,34].

These associations allow i) reduction of multiple dose regimens (than monotherapy), ii) improve the efficacy and iii)

regulate the progression of Plasmodium resistance.

Fig. 2 Artemisinin, antifolate and antibiotic derivatives.

2.5 Antifolates

Folate metabolism pathway in Plasmodium is involved in the tetrahydrofolate biosynthesis, a cofactor essential for the

nucleic acids synthesis. Consequently, in antimalarial therapy approach, the two targeted main enzymes are

dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) [35]. The combination of DHFR and DHPS

inhibitors is synergistic in the treatment of malaria [36]. Sulfonamides such as sulfadoxine 17 and sulfalene 16,

presented in Fig. 2, inhibit DHPS, absent in mammals [37]. Diaminopyrimidine family, such as pyrimethamine 15,

proguanil 11 and chlorproguanil 12, acts as inhibitor of Plasmodium DHFR with a greater selectivity than human

DHFR [38]. Proguanil 11 and chlorproguanil 12 are prodrugs which are metabolized in situ via oxidative ring closure in

cycloguanil 13 and chlorcycloguanil 14 respectively [39]. Sulfadoxine 17, sulfalene 16 and pyrimethamine 15 possess

long elimination profile with half-lives higher than 80 hours. Antifolate resistances have emerged, in the late 1980s, and

mutations in PfDHFR and PfDHPS are implicated in these phenomena. Proguanil 11 (human t1/2 = 12-21 hours) was

used alone as a prophylactic agent against malaria or in combination with CQ 4. More recently, this drug is associated

with atovaquone 21 as prophylactic agent against malaria [40]. It is active against all stages of malaria parasite life


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cycle, excepted hypnozoite forms. The pyrimethamine 15-sulfadoxine 17-sulfalene 16 combination is active against

later asexual parasites development stages [41]. Associations of sulfadoxine 17–pyrimethamine 15 with AQ 5 or ART

10 are being developed.

2.6 Antibiotics

Tetracyclines (minocycline 19 and doxycycline 18) and lincosamide as clindamycin 20, are antibiotics exhibiting

antimalarial activities. Tetracyclines belong to broad-spectrum antibiotics discovered in the early 1940s. Their

activities, against P. falciparum and P. vivax, were highlighted in 1950s. Doxycycline 18 (human t1/2 = 16-22 hours)

directly inhibits mitochondrial protein synthesis and decreases activity of dihydroorotate dehydrogenase (DHOHD), a

mitochondrial enzyme involved in de novo pyrimidine synthesis [42]. Minocycline 19 decreases transcription of i) P.

falciparum mitochondrial genes (subunit I of cytochrome C oxidase and apocytochrome B) and ii) apicoplast genes

(subunit rpoB/C of RNA polymerase) [43]. Currently, doxycycline 18 is co-associated, with quinine 1 and ART 10, for

curative and prophylaxis therapies in multidrug resistance areas, particularly in Southeast Asia [44]. Clindamycin 20

(human t1/2= 2-4 hours), introduced in the 1970s as an antimalarial, possesses a mechanism of action similar to

tetracyclines. Clindamycin 20 is recommended by WHO in combination with quinine 1 for the treatment of

uncomplicated malaria in pregnant women during the first trimester [45,46]. No cross-resistances are observed with

other antimalarial drugs aforementioned due to their different mechanisms of action. Consequently, these antibiotics are

used in Plasmodium drug resistant areas.

2.7 Inhibitors of the respiratory chain

Atovaquone 21, presented in Fig. 2, is an hydroxynaphtoquinone, able to inhibit the electron-transport to the

cytochrome bc1 complex (coenzyme Q) in Plasmodium mitochondria membrane [47]. It is related to ubiquinol, which

is an important coenzyme in the electron transport chain, it is supposed that atovaquone 21 binds to parasite Cyt B

protein. In monotherapy, the treatment shown rapid selection of resistant strains, due in part to mutations in its target

(Y268S) [48]. Atovaquone 21 (human t1/2 = 2-3 days) presents synergy in association with biguanides as proguanil 11

and chlorproguanil 12. Atovaquone 21 blocks the electron transport while proguanil 11 acts on the secondary pathway

(adenine nucleotide translocases (ANT) or ATP/ADP transporter)). Currently this compound is used, in combination

with proguanil 11, for the prophylaxis and therapy of uncomplicated malaria [8].

3. Chemotherapeutic approach and drug development

Antimalarial drug development encounters many difficulties such as Plasmodium drug resistance, toxicity and higher

costs. In response, different approaches are explored to increase the antimalarial chemotherapeutic efficiency by the i)

repurposing of drug existing, ii) optimization of existing antimalarial drugs, iii) identification of new targets and iv)

discovery of new scaffolds.

3.1 Repurposing of existing drugs

Associations of different drugs, that possess different targets, pharmacokinetic properties such as half-lives, improve the

efficacy especially against the multidrug-resistant P. falciparum strains. For developing an ACT, drug associated to

artemisinin derivatives should be ideally i) structurally different, ii) slowly eliminated in vivo and iii) efficient with low

level of Plasmodium resistance. The first therapies used were non-artemisinin-based combinations, such as AQ 5-

sulfadoxine 17-pyrimethamine 15 or atovaquone 21-proguanil 11 [40]. A non-artemisinin-based combination, like MQ

2-penfluridol (antipsychotic drug), restores MQ 2 sensibility by inhibiting the PfMDR1 [49]. Verapamil (calcium

channel inhibitor) and desipramine (tricyclic antidepressant) reverse the effects of CQ 4 resistances inhibiting the

PfCRT [50]. Recommended by WHO since 2001, ACTs are adopted in 67 malaria-endemic countries to treat the

uncomplicated malaria, such as ART 10-AQ 5 or ATM 9-LM 3 [8,51]. ACTs promote a fast reduction of the parasite

growth and a rapid decrease of clinical symptoms [52]. Other medicines are important sources of scaffolds and/or active

antimalarial drugs such as aforementioned doxycycline 18 (used first against intra-cellular bacteria), verapamil,

desipramine and penfluridol drugs. Anti-HIV agents such as saquinavir, ritonavir and indinavir, shown antimalarial

activities by inhibiting the Plasmodium proteases [53,54]. Antitumor drugs that target cellular programs like cell

proliferation, cell differentiation and cell death are explored as antimalarial compounds. For example, belinostat, an

histone deacetylase inhibitor, presents an antimalarial activity [55,56].

3.2 Optimization of existing antimalarial drug

Development of drug analogs by chemical modifications constitutes a strategy to counter: i) emergence of Plasmodium

strains resistances and ii) problem of toxicity or bioavailability for some drugs. Drug analogs strategy enabled to obtain

mostly antimalarial drugs (CQ 4, PQ 6, MQ 2, ART 10 or ATM 9). Tafenoquine, an analog of PPQ 6 (related to MQ 2)


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https://en.wikipedia.org/wiki/Tricyclic_antidepressant

has been developed in 1990s. Tafenoquine is currently in phase 3 clinical trial. The ferroquine (FQ 27), a CQ 4 analog,

synthesized in 1993, is currently in phase 2b clinical trial. Another strategy to restore the sensitivity of antimalarial drug

consists to use a covalent bitherapy. In this case, two distinct chemical moieties, which act on different or same

biological targets, are covalently linked [57]. Artemisinin-based hybrids constitute a good alternative for fighting P.

falciparum resistance phenomenon. Trioxaquine, a hybrid molecule trioxane-aminoquinoline, is more effective against

Plasmodium than each individual fragment [58,59]. It acts against the heme detoxification by two different mechanisms

respectively due to trioxane core (heme alkylation) and aminoquinoline moiety (binding to haemozoin).

3.3 Discovery of new active scaffolds

The screening strategy is the major mode of discovery of new lead scaffolds. It exists three main categories of

screening: i) virtual screening, ii) target-based high-throughput screening, and iii) phenotypic high-throughput

screening. Scaffolds tested can be natural or synthetic products. They come from drug databases or, in the case of

synthetic compounds, can be obtained by combinatory chemistry. Virtual screening is a fast in silico evaluation of

chemical structure libraries in order to identify the compounds that are most likely to bind to a specific drug target

(protein receptors or enzymes). In some cases, this approach helps to understand the mechanism of action of

antimalarial compounds [60,61]. As example, a new artemisinin target, PfATP6, was identified via this strategy [62].

The high-throughput screening, target-based or phenotypic, is a major strategy to obtain new scaffolds [63]. The

target-based strategy involves the screening of library of compounds against a specific target (typically a recombinant

protein) while the phenotypic screening is an in vitro assay realized against the whole cell. A genetic study can be

realized in complement to high-throughput screening to identify new targets [64]. When a scaffold is selected

(pharmacophore core), many derivatives are then synthesized and evaluated by high-throughput screening to define

Structure Activity Relationships (SAR) [65].

4. Recent Drug candidates involved in clinical trials

The discovery of new antimalarial medicines is correlated to the discovery of new drug targets. Currently, the drug

candidates in the pipeline are developed to be used in new therapeutic strategies such as “Single Encounter Radical

Cure and Prophylaxis” (SERCaP) or for a 3-days treatment. However, those strategies imply the use of high doses

risking toxicity problems particularly in very young patients or in pregnant women. The chemical drugs exposed in this

chapter are currently in clinical trials independently of the phase they reached. Some of them are still recruiting in 2017.

They are selected from the registry of clinical trials (ClinicalTrials.gov) of the National Institute of Health (NIH)

database. Cipargamin 22 (KAE609) and SJ733 23, presented in Fig. 3, are new candidates targeting recently discovered

P. falciparum ATPase. MMV390048 24a, DSM265 25a and OZ439 26a, in Fig. 3, are innovative drug candidates also

described in this chapter.

Fig. 3 Structures of clinical drug candidates and frontrunners.

The following part describes their drug discovery stories, mechanism(s) of action, succinct target descriptions and

current clinical trial explanations.

Some of them, used since many years like aminoquinolines (ferroquine 27 (FQ), pyronaridine 28 and PPQ 6), are

still in clinical development combined with existing antimalarial drugs to evaluate their synergistic efficacy in malaria

resistance zone.


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4.1 Cipargamin (KAE 609) 22 and SJ73323

The spiroazepineindole KAE609 22 (cipargamin) and tetraisoquinoline SJ733 23 are both P. falciparum ATPase type 4

(PfATP4) inhibitors. These compounds were identified through a high-throughput screening driven by the St Jude

Children’s Research Hospital in 2010 [66]. After optimization of the spiroindolone core, KAE 609 22, developed by

Novartis Institute for tropical disease, was the most active compound and the (1R,3S)-enantiomer led to the best activity

[67]. The target of KAE609 22 was identified as the Potassium/Sodium efflux pump PfATP4 by genomic study. This

one is located at the external membrane of the parasite and is responsible of the intracellular sodium homoeostasis of

the pathogen. PfATP4 inhibition led to the dysregulation of the sodium efflux resulting in the parasite’s death. In

parallel, the sodium dysregulation induces a pro-apoptotic signal in the erythrocyte host cells called “eryptosis”. These

combined effects result in the massive and rapid clearance of the parasite. KAE609 22 also induces the rapid clearance

of ring-stage malaria parasites [68]. Phase 1 trial assesses the efficacy of KAE609 22, in asexual and sexual blood-

stages of P. falciparum [69]. KAE609 22 clears rapidly parasitemia in adults with a dose of 30 mg/day for 3 days

[70,71].

More recently, pharmacological and chemical optimization of tetraisoquinoline core led to the identification of the

SJ733 23 as the more suitable compound for clinical investigations [72]. SJ733 23 is also a PfATP4 selective inhibitor

[73,74]. The major difference between JS733 23 and KAE609 22 is about their pharmacokinetic profiles. SJ733 23 is a

drug candidate clinically useful as a flash single dose according to the SERCaP therapeutic strategy. SJ733 23 is a rare

product of medicinal chemistry involved in phase 1 trials, in 2017. Two investigations are currently under progress to

assess its efficacy in infected human and its safety profile in healthy adult volunteers [75,76].

4.2 3,5-Di-substituted-2-aminopyridine MMV390048 24a

The story of this compound began with the lead identification by GlaxoSmithKline, in 2010 [77], of the antimalarial

potential of 3,5-di-substituted-2-aminopyridines. In 2012, the discovery of their potential biological target was realized

by imaged-based high-throughput of a kinase library [78]. Then, Younis et al. have obtained the MMV390048 24a by

different 3,5-diaryl-2-aminopyridine pharmacomodulations with a special focus on their druggability [79].

Pharmacologically, 2-aminopyridine-based compounds had been described as kinase inhibitors [80], G protein-

coupled receptor antagonists [81] and ion channel modulators [82]. These biological properties give to MMV390048

24a intrinsic synergistic effects to induce P. falciparum death. The radiolabelled with Carbon-14 for tissue distribution

evaluation, realized by Sonopo et al, made MMV390048 24a suitable for clinical investigations [83]. Medicines for

Malarial Venture (MMV), funded in 1999 in Switzerland, promotes the MMV390048 24a for clinical development. The

trial is actually in recruiting phase 2a. This clinical trial will assess the efficacy, safety, tolerability and

pharmacokinetics of a single dose of MMV390048 24a against P. vivax or P. falciparum [84].

4.3 Triazolopyrimidine DSM265 25a

DSM265 25a is a rare example of a target-based strategy leading to identification of a new antimalarial medicine.

DSM265 25a is a triazolopyrimidine disturbing the de novo pyrimidine biosynthesis by inhibiting selectively P.

falciparum DHODH (PfDHODH). In 2002, Baldwin et al. have identified PfDHODH as a promising target for novel

antimalarial chemotherapy providing direct evidence that the PfDHODH active site is different from the host enzyme

[85]. In 2008, high-throughput screening identified the first triazolopyrimidine compounds with very good PfDHODH

inhibition activity (nanomolar activity) with potent antimalarial activity in whole cells [86]. Pharmacokinetic and

pharmacodynamic studies, realized by Coteron et al., distinguished DSM265 25a as a lead for preclinical development

[87]. Preclinical study described DSM265 25a as a long-duration PfDHODH inhibitor and provide efficacy

concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. These results shown that

DSM265 25a is suitable candidate for a clinically development in prevention and treatment of malaria [88]. Last phase

2a trial, sponsored by MMV, investigated the capacity of DSM265 25a to treat P. falciparum or P. vivax infections and

was completed in 2016 [89]. A single 400 mg dose phase 1 assay is currently running, testing DSM265 25a in P.

falciparum malaria prophylaxis.

4.4 Ozonide OZ 439 26a

The scaffold ozonide was developed to circumvent artemisinin chemical, biopharmaceutical and treatment limitations.

The first registered synthetic trioxolane ozonide was OZ277 26b, also known as arterolane, is also a drug candidate

widely studied in its maleate salt form [90]. With stronger stability, higher activity and lesser toxicity compare to

OZ277 26b, OZ439 26a is a greater compound to use in SERCaP strategies [91]. It is hypothesized that trioxolanes and

artemisinin would have common targets by sharing the same protein alkylation profile. But the actions of these

compounds conserving endoperoxide function seems to be quite different in terms of their ways of producing ROS [92].

It was shown, from a Phase 2a clinical trial, published in 2015, that OZ439 26a possesses a good safety profile and

clears parasitemia rapidly [93]. OZ439 26a efficacy was compared to DSM265 25a, in a phase 1b trial, completed in

march 2017 [94]. These trials conclude that OZ439 26a has a long half-life and suggests a possible use as single-dose


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treatment in association with other drugs. Different combinations will be evaluated in clinical trials soon. First phase 2b

trials concern drug combination OZ439 26a with FQ 27 for uncomplicated P. falciparum malaria as a single-dose cure

(see chapter 0.), the study is currently recruiting patients and the primary results will be presented in October 2018 [95].

4.5 Aminoquinolines combined with artemisinin analogues

Pyronaridine 28, FQ 27 and PPQ 6 are aminoquinolines that have yet proven their efficacy against malaria. In the aim

to fight and reduce P. falciparum resistances and to have better pharmacokinetic profiles, these compounds are still in

clinical trials combined with artemisinin analogues. Pyronaridine 28 was firstly synthesized and described as an

antimalarial agent, in 1979, and was used as antimalarial in early eighties by China’s army [96].

Pyronaridine 28 acts by inhibiting the hemozoin production on the same way than CQ 4 with a 100 fold efficiency [97].

This compound is also able to inhibit glutathione-dependent haem degradation and the decatenation activity of P.

falciparum DNA topoisomerase II [98]. Since 2015, pyronaridine 28, combined with artesunate, is in phase 3 trial in

Western Kenya in comparison to ATM 9/LM 3 combination [99]. Pyronaridine 28/ART 10 received approval by EMA,

in 2012, for the treatment of uncomplicated P. falciparum and P. vivax malaria [100]. The outcomes of phases 2 and 3

trials, accomplished between 2014-2015, showed that this combination is not allowed in western Cambodia despite high

efficacy elsewhere in Asia and Africa [101].

FQ 27 is the most successful organo-metallic antimalarial drug candidate. The ferrocene containing chloroquine

analogue is 5 to 20 times more potent than chloroquine 4 on chloroquine-resistant P. falciparum strains [102]. FQ 27 is

an efficient drug because of its preferential accumulation in the P. falciparum DV in which the ferrocene group act as a

Fenton reaction initiator (ROS production) synergistically with its stronger haemozoin formation inhibition. FQ 27 is a

long duration product that possesses active metabolites including the main metabolite N-desmethyl-ferroquine

(SSR97213) [103]. Phase 2 pilot study led on induced blood-stage malaria volunteers was published in 2016. The

determination of the pharmacokinetic and pharmacodynamics FQ 27 profile was realized [104]. FQ 27 possesses a long

in vivo half-life due to its active metabolite and could offer soon to FQ 27 the way to additional safety, efficacy and

tolerability trials. A combination FQ 27/OZ439 26a is also now in phase 2b clinical trial in order to determine a single

dose combination to treat uncomplicated P. falciparum malaria in adults and children [95].

PPQ 6 is a bis-4-aminoquinoline possessing a half-life nearly of 5 weeks. It is still in phase 3 clinical trials in

association with DHA 8. Unfortunately, the rate of treatment failure using PPQ 6/DHA 8 has increased by a factor of

more than 5 in Cambodia and Thailand [105]. So, nowadays PPQ 6 is combined to DHA 8 and MQ 2 in a “3-drug mix”

to assess the efficacy, safety and tolerability in patient with uncomplicated malaria in Cambodia [106], the completion

date of this study is scheduled in 2020.

5. Conclusion

Toward this chapter built on drug design solutions to fight malaria, actual approved medicines and evaluated drugs have

been described. The combined efforts to eradicate malaria had never been such important and the drug design is a part

of the solution putting us on the right way, making flash therapeutic strategies with the aim to develop available and

easily usable medicines everywhere in the world. We illustrated that activity and toxicity of such drugs are important to

select a lead. Pharmacokinetic profile is also extremely important as half-life parameter, especially for an antimalarial

agent. Important efforts have been realized to understand the molecular mechanisms for drug action and resistance and

to find new antimalarial compounds. Clinical trials are essential to the search of the most effective combination that is

the most able to fight against Plasmodium resistances. Other therapeutic strategies are being developed such as new

pharmaceutical forms and administration ways. Those actions coordinated by the WHO and guaranteed by numerous

worldwide foundations must be pursued, in terms of clinical development as well as prevention, vector control and

humanitarian aid.

Acknowledgements J.S.was the recipient of a grant from DGA (Direction Générale de l’Armement, Ministère de la Défense,

France) and Région Picardie.

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