**5. Novel compounds in the pipeline**

Mentioned above, the evolving of resistant strains and absence of newer drugs are the limiting aspects in the fight against malaria. These factors prompt the continuing need of studies to bring novel grups of antimalarial compounds, and a re-examination of the present ones. That's why; synthetic peroxides (ozonides) are approved to be viable substitutes of artemisinin. **OZ277** (the first generation ozonide discovered in 2004 and subsequently called **arterolane)** was developed through a collaborative effert between Ranbaxy and MMV (Medicines for Malaria Venture). After a limited phase-3 trials on the combination effects of arterolane and piperaquine, the combined drug has got approval under the trade name **Synriam** in India in 2013, followed by approval in 7 African nations in 2014 [95]. Many new combination treatments, including **azithromycin-chloroquine** [96], **pediatric pyronaridine-artesunate**, **pediatric DHA-piperaquine** [97] and **trimethoprimsulfamethoxazole** [95], are in phase-3 trials.

A lot of novel chemicals are in phase-II clinical trials (**Table 2**). **Ferroquine (SR97193)** is new organometallic drug completed phase-2 trials in combination with artesunate [98]. Ferroquine retains *in vitro* activity against piperaquine- and chloroquine-resistant *Plasmodium* species. It has a long elimination half-life (16 days). Ferroquine is only moderately effective as single therapy but when combined to artesunate (daily dose of 4/6 mg/kg ferroquine plus 4 mg/kg artesunate for three days); the PCR corrected efficacy at 28 days in treating uncomplicated *falciparum* malaria was 99% [103]. **OZ439** (a synthetic trioxolane) possesses curative and transmission-blocking capacity, and is active against artemisinin-resistant malaria parasites. Much like the current peroxide containing antimalarial agents, the exact mechanism of action of OZ439 has yet to be revealed but it is believed that oxidative stress plays a major role as shown in **Figure 3**. OZ439 [discovered in 2011 by a partnership between Monash University, the University of Nebraska and the Swiss Tropical and Public Health Institute (STPHI)] possesses significantly lower solubility and slightly lower potency than OZ277 [100]. In contrast to other synthetic peroxides and artemisinin derivatives, OZ439 **(**artefenomel**)** totally cured mice infected with *P. berghei* at a single oral dose (20 mg/kg) and showed higher prophylactic effect compared to most antimalarial drugs. Next to reports on its safety and pharmacokinetic properties, a combination of artefenomel (fast- and


#### *Malaria: Introductory Concepts, Resistance Issues and Current Medicines DOI: http://dx.doi.org/10.5772/intechopen.98725*

#### **Table 2.**

*Promising new antimalarial agents in phase II clinical development.*

long-acting drug) with ferroquine was progressed into a phase-2 trials in 2015 to assess the efficacy of a single oral dose in adults and children aimed at replacing the current three doses of artemisinin derivatives. **Artefenomel–ferroquine** has an elimination half-life of 46–62 h. An advantage of this product is that neither of the constituent drugs has been deployed as monotherapy previously [79, 103].

**Artemisone** (second-generation semi-synthetic artemisinin derivative developed at the Hong Kong University of Science and Technology), a drug in phase-II study, provides a single dose cure in Aotus monkeys infected with *falciparum* malaria at 10 mg/kg when combined with mefloquine 5 mg/kg [104]. Artemisone

#### **Figure 3.**

*Schematic representation of intra-erythrocytic trophozoite showing sites of action of newer antimalarials. Agents in red are still in development [100].*

has shown to be efficacoiuse as artesunate and possess improved pharmacokinetic properties such as longer half-life and lower neuro- and cytotoxicity than the first generation artemisinins [105]. With the motivation of urgent requirement to develop new artemisinins in combination with new drugs that impart activities toward both intra-erythrocytic asexual and transmissible gametocyte stages, in particular, those of resistant parasites, amino-artemisinins (oxidant drug in which an amino group replaces the oxygen-bearing substituents attached to carbon number 10 of the present clinical artemisinin derivatives DHA, artemether and artesunate) including artemisone and artemiside exhibit potent *in vitro* activities against the asexual erythrocytic stages of *falciparum* malaria. Particularly, these compounds are active against late erythrocytic stage *falciparum* gametocytes, and are highly synergistic in combination with the redox active agent methylene blue. In order to strengthen the selection of best amino-artemisinins for development into novel triple combination treatments also active against artemisinin-resistant *P. falciparum* mutants, new amino-artemisinins were formulated based on the easily accessible and low-priced drug DHA-piperazine. DHA-piperazine was converted into alkyl sulfonamides, aryl sulfonamides, ureas and amides. These derivatives were screened together with the comparator drugs DHA and the amino-artemisinins (until now most active compounds against asexual and sexual erythrocytic stages of *falciparum* and hepatic stage *P. berghei* sporozoites) artemisone and artemiside. Many new amino-artemisinins that contain aryl-urea and -amide groups are found to be potently active against both asexual and late erythrocytic stage gametocytes. Although the activities are superior to those of artemiside and artemisone, the latter (aryl sulfonamide, the aryl urea, and the aryl amides) are more active against the liver stage *P. berghei* sporozoites. In addition, these compounds tend not to display reduced susceptibility against *Plasmodium* species bearing the *Pf* Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant *falciparum* malaria. Thus, the advent of the amino-artemisinins will enable the development of novel combination drugs that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking abilities and may be effective against artemisinin-resistant *falciparum* malaria [106, 107].

*Malaria: Introductory Concepts, Resistance Issues and Current Medicines DOI: http://dx.doi.org/10.5772/intechopen.98725*

Novartis currently has 2 new antimalarial compounds (**KAE609 (Cipargamin)** and **KAF156)** in phase-II clinical testing (**Table 2**) [99]. The occurrence of resistance in artemisinin raises the concern of cross-resistance with arterolane and artefenomel due to chemical similarities between the two groups of compounds. By contrast, cipargamin and KAF156 are structurally unrelated to the artemisinin derivatives. KAE609 has inhibitory effect on *falciparum* cation channel/P-type ATPase-4 transporter (*PfATPase4*) resulting in a build up of Na+ inside the parasite, leading to cell death. **Cipargamin** was discovered by a partnership between Novartis, the STPHI and the Wellcome Trust. It is equially potent against drugresistant *Plasmodium* strains and as effective as artesunate against *falciparum* and *vivax* malaria. KAE609 displays a good safety with low cytotoxicity, cardiotoxicity and mutagenic activity. Cipargamin has the ablity to clear parasitaemia quickly in adult individuals (30 mg/day for 3 days) with uncomplicated *falciparum* or *vivax* malaria. This drug is also shows low body clearance, long half-life and excellent bioavailability [100].

**KAF156** (identified in 2008 by Novartis and The Scripps Research Institute) is with potential to treat and prevent malaria, and has an elimination half-life of around 48 h. KAF156 is shown to have potent *in vitro* activity against both asexual and sexual blood stages and the pre-erythrocytic liver stages of *Plasmodium* species. In the causal prophylactic rodent malaria model, a single oral dose of 10 mg/ kg was shown to be fully protective. KAF156 has also shown transmission blocking activity in the berghei model. A recent phase-2 trial among adults with acute *falciparum*/*vivax* malaria at five centers in Thailand and Vietnam has showed that KAF156 cleared parasites more rapidly than SP or malarone®, though this rate was slightly slower than artemisinin and DSM265. Additionally, therapeutic responses to treatment by KAF156 suggested effectiveness against *falciparum* and *vivax* infections resistant to each and every one of currently available antimalarials without evident safety concerns. The mode of action of KAF156 is still unclear although mutations have been identified in three genes (*P. falciparum* Cyclic Amine Resistance Locus [*PfCARL*], UDP-galactose and Acetyl-CoA transporters) through culturing of resistant strains [79, 100]. **DSM265** is another compound that complete phase-2a trials (**Table 2**) and inhibit DHODH both in *falciparum* and *vivax* species [104]. It was discovered through collaboration between the University of Texas (UT) Southwestern, the University of Washington, and Monash University. DSM265 has an excellent safety profile, a very low clearance rate and a long half-life in humans. *In vitro* studies suggest a relatively low barrier to resistance selection, so measures to protect this drug, such as matching with a partner with similar elimination kinetics and deploying only as part of a fixed-dose combination will be important [103].

**Fosmidomycin**, a natural antibacterial drug that inhibit 1-deoxy-D-xylulose 5-phosphate reductoisomerase (an enzyme involved in the synthesis of isoprenoids), is under combination therapy trial with piperaquine (NCT02198807) in phase 2 in order to destroy blood schizonts of uncomplicated *falciparum* malaria [97, 108]. **AQ-13**, a modified chloroquine (differ to chloroquine only in the amine side-chain), last completed phase-II trial (NCT01614964) at the end of 2017 [100], retains activity against chloroquine-resistant strains [109]. The result showed that there are no serious adverse events and the asexual parasites were cleared by day 7 in both groups [79].

**Methylene blue**, a drug used to treat methaemoglobinemia, acts by inhibiting *falciparum* glutathione reductase and as a result prevents haem polymerization. It is being developed in combination (phase II) with artesunate–amodiaquine as a strategy to protect against emergence of artemisinin resistance secondary to its *falciparum* schizonticidal effect and reduce transmission owing to gametocytocidal activity [110]. **Rosiglitazone**, an anti-diabetic drug, is currently in clinical trials (NCT02694874) as an adjunctive therapy for severe malaria. **Imatinib**, a cancer therapy, is now in phase-2 trials (NCT03697668) as a triple combination with DHA-piperaquine [100]. Polysaccharide heparin analogue **Sevuparin (DF02),** which is taken as an adjunctive therapy, retains the anti-adhesive effects of heparin without the antithrombin properties and has been shown to block merozoite invasion, cytoadherence and rosetting [111]. Sevuparin, a drug treating sickle cell disease, was completed its phase-1/2 trials (NCT01442168) in 2014 as a combination with atovaquone-proguanil [100]. **MMV390048** is an aminopyridine currently in phase-2a trials (NCT02880241) and its target was identified to be lipid *P. falciparum* phosphatidylinositol 4-kinase (*PfPI4K*). This blood schizonticidal drug has destructive activity on multiple stage of the *Plasmodium* with possible efforts for chemoprevention as it inhibits gametocytogenesis and oocyst formation [102, 112]. **Albitiazolium (SAR97276) or bisthiazolium salt**, discovered and developed by Sanofi in 2005, has also reached phase-2 clinical tests (NCT01445938), however further study was terminated in 2012 [100]. It acts mainly by deterring the transport of choline into the parasite [113]. Descoverd in 2012 by a team at the Cape Town University, South Africa, **MMV048** has shown 99.3% reduction in parasitaemia in the *P. berghei* mouse model at a single dose of 30 mg/kg with no signs of parasites after 30 days. This highlights the potential of this compound to act as a single dose therapy. Its target is *PfPI4K*, eukaryotic enzyme that phosphorylates lipids to allow them to regulate intracellular signaling and trafficking. Inhibiting the ATP-binding pocket of *PI4K* (recently revealed as a novel mechanism of action for antimalarial agents) causes disruption in the intracellular distribution of PI4 phosphate (*PI4P*), which inturn results in decreased late-stage development of the parasite. MMV048 is now in phase-2 clinical studies [100].

Quinoline-4-carboxamide **DDD107498 (**previously known as **M5717**) is additional treatment panorama that was developed in 2015 by the Drug Discovery Unit (DDU) in Dundee. It is an inhibitor of *P. falciparum* translational elongation factor 2 (*PfeEF2*) with activity against pre-erythrocytic and blood stages as well as mature male and female gametocytes. Henece, it can act as curative and transmission blocking drug. *PfeEF2* is responsible for catalyzing the translocation of mRNA and tRNA. The overall efficacy of drugs that target this elongation factor may be increased due to the expression of *PfeEF2* in multiple stages of the *Plasmodium* life cycle [77, 114]. DDD107498 has shown excellent activity against a number of drug-resistant strains of *Plasmodium* species, and exhibited superior potency than artesunate against *falciparum* and *vivax* in *ex vivo* assays. It has been also demonstrated magnificent pharmacokinetic profiles including better oral bioavailability and long plasma half-life (critical for chemoprevention and single dose therapy) in pre-clinical species. Owing to its *PfeEF2* inhibition and its ability to clear blood stage parasites completely, DDD107498 satisfies the requirements to be a long duration partner and could be used as part of a combination therapy with a fast-acting compounds. In late 2017, DDD107498 was cleared for progression from development to phase-1 clinical tests for volunteers in Australia (NCT03261401) [79, 100].

A dihydroisoquinolone compound **(+)-SJ733**, which inhibits gametocytogenesis and blood schizonts in *falciparum* and *vivax*, is now in human trial. The pre-clinical trials showed that SJ733 (inhibitor of *PfATP4*) worked against *Plasmodium* species that are resistant to current frontline agents. It binds to a malaria parasite protein that serves as a sodium pump to interfere with the protein or to disrupt the malaria parasite's capability to remove excess Na**+** from RBCs [115, 116]. When sodium builds up, infected cells become develop rigidity (less flexible) and as a result distroyed by our immune system or get caught in small blood vessels. Currently, around 38 healthy volunteers were recruited as part of the phase-Ia trial in Memphis

#### *Malaria: Introductory Concepts, Resistance Issues and Current Medicines DOI: http://dx.doi.org/10.5772/intechopen.98725*

and phase-Ib test in Brisbane, Australia. In Memphis, about 23 healthy volunteers received increasing doses of the new compound to understand dosing, absorption, safety profile and metabolism. Based on those results, the 15 Australian volunteers received SJ733 after being infected with malaria to understand the antimalarial effectiveness of this novel molecule. No significant SJ733 treatment related side effects were notified in any of the volunteers [117].

Additionally, **CDRI97/78** (fast-acting trioxane first synthesized in 2001 by a team at the Council of Scientific and Industrial Research in India), **ACT-451840** (phenylalanine-based compound developed in 2016 through collaboration between Actelion Pharmaceuticals and the STPHI, **P218** (2,4-diaminopyridine analog and *PfDHFR* inhibitor discovered by BIOTEC Thailand in 2012) and **GSK369796** (N-tert-butyl isoquine developed at the Liverpool School of Tropical Medicine in 2009) are also among componds under/completed phase-1 trials [95, 102]. CDRI97/78 (blood schizonticidal molecule) was well-tolerated in healthy adult volunteers with a half-life of around 12 h. It has shown few and not severe adverse effects. ACT-451840 has the potential to be a fast-acting drug with a long half-life. This agent has shown efficacy against multiple life cycle (asexual and sexual) stages of both *falciparum* and *vivax* malaria, and also harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The new two step mechanism of action for binding to *PfDHFR* allows P218 to conquer resistance that has emerged after clinical use of pyrimethamine. P218 showed high selectivity to bind malarial than human DHFR, which translates into reduced toxicity. P218 is highly efficacious against *falciparum* and *chabaudi* in mice with ED90 of 1 mg/kg and 0.75 mg/kg, respectively. Along with its high potency and good safety profile, P218 has the potential to be a replacement for pyrimethamine combination with cycloguanil in areas where *PfDHFR* resistance has emerged. P218 has currently completed phase-I trials (NCT02885506). GSK369796 was designed as an alternative to amodiaquine. It completed pre-clinical experments, and was last in phase-I trials in 2008 (NCT00675064) [100].

**DM1157**, part of a class of compounds known as "reversed chloroquines", was designed to overcome chloroquine-resistant (the parasites expel the drug before it can affect them) strains of *falciparum* malria. Like chloroquine, DM1157 (discovered in 2010 by a research team in Portland State University and further developed by DesignMedix) interferes with the parasite's metabolism, but it also inhibits the parasite's ability to expel the drug. It is currently in Phase I trials (NCT03490162) to evaluate its safety and pharmacokinetics in humans, which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Results of earlier tests in animals suggest that DM1157 could have the same safety and efficacy as chloroquine [100, 118]. Human trials of innovative antimalarial compounds are in the pipeline following Kenyan scientists fruitfully used a derivative from bacteria to kill *Plasmodium* that causes malaria. According to the Kenya Medical Research Institute and its global health partners, the breakthrough could potentially lead to the discovery of new approach for tackling malaria. The promise of a new treatment comes after trials in Burkina Faso found that ivermectin, a conventional drug used for non-malaria parasitic diseases, reduced the transmission rate of malaria. The drug is acted by making the blood of repeatedly treated people lethal to mosquitoes. The experment also revealed that ivermectin can kill *P. falciparum* in mosquitoes that fed on humans who took the drug. As they are more vulnerable, the study is more focused on pregnant women and children and the researchers are getting very encouraging lead compunds. In the near future, latest antimalarial drugs could be in the market if the recent research findings are going ahead. The same bacteria known to kill dangerous pathogens including scabies and river blindness can also be applied in malaria [119].

After identification of a lead compound, optimization of the chemical structure can be started. This step mainly involves examination of the structural activity relationships (SARs) of the compound and optimization of properties such as potency (*in vitro* and *in vivo*), solubility and metabolic stability. The new candidate must also be evaluated for any possible toxicity including cytotoxicity and genotoxicity in pre-clinical trials. **NPC1161B** (the chiral 8-aminoquinoline derivative), developed at the University of Mississippi, was in late preclinical studies for relapse prevention. This compound has a multi-stage activity and there is a development plan to see whether this single enantiomer drug has a more favorable hematological toxicity profile than tafenoquine in Phase-I. **AN13762** (blood schizonticidal), a novel class of benzoxaborole anti-malarial compounds, is emerged in 2017 as the lead compound, showing excellent activity in *in vitro* and *in vivo* (pre-clinical) studies. It has multi-strain efficacy and the ability to act rapidly. It has been shown to be equally potent across a wide range of drug resistant strains. AN13762 has exhibit similar *in vivo* clearance rate when compared to artesunate. The precise mechanism of action for AN13762 remains unknown, though initial studies on hit compound (AN3661) identified the P. *falciparum* cleavage and polyadenylation specificity factor 3 (*PfCPSF3*) as a potential target [100, 103, 120].

Triaminopyrimidine **MMV253** (identified by AstraZeneca in 2015) and an aminomethylphenol **JPC-3210** (active against multidrug resistant falciparum *in vitro*) are long-acting blood schizonticidal agents present in early preclinical experiments [121, 122]. MMV253 (previously AZ13721412) has shown good *in vitro* potency and *in vivo* efficacy. When screened against several mutant resistant strains with different mechanisms of resistance, MMV253 displayed no spontaneous decline in potency which can be attributed to its new mode of action (inhibition of *PfATP4*). Good *in vitro* and *in vivo* correlation was shown with a forecasted human half-life of ~36 h, which is long compared to another fast killing agent (artemisinin, human half-life of 1 h). As of late 2016, Cadila Healthcare pharmaceutical company owns the license for the compound series and is now making further lead development in order to progress the chemical through pre-clinical trials. At the same time that the *Plasmodium* is regulating its Na<sup>+</sup> concentration using *PfATP4*, it also brings in H<sup>+</sup> via the same pathway. To control this increasing concentration of H<sup>+</sup> and maintain an intracellular pH of about 7.3, the *Plasmodium* uses a complementary V-type ATPase transporter to pump out H<sup>+</sup> ion. It was shown that MMV253 has the ability to inhibit the V-type H+ ATPase as its mechanism of action. **UCT943** (identified in 2016 by a team at the Cape Town University, South Africa in the same campaign as MMV048) is a key compound in a novel class of 2-aminopyrazine antimalarials that has shown single dose curing capability *in vivo* and potential as a clinical candidate. UCT943 (target *PfPI4K*) is potent across multiple life stages of both *falciparum* and *vivax* malaria. UCT943 was in originally in place as a back-up to MMV048, however, due to pre-clinical toxicity, this candidate has been withdrawn [100]. A Mannich base compound, **MK-4815** (2-aminomethyl-3, 5-di-tert-butylphenol), showed potent *in vitro* activity against *falciparum* and hundred percent survival was seen in mice orally treated with 25/12.5/6.25 mg/kg once on the day of infection and then twice daily for an additional 4 days. While comparable volume of distribution at steady state was seen in mice and rhesus monkey, the compound exhibited lower clearance and long plasma half-life in monkeys, indicating the drug possess better pharmacokinetic parameters in the higher species. Although the mechanism of action is still remains unclear, evidences indicate the involvement of the mitochondrial electron transport chain of the *Plasmodium*. Owing to its structural simplicity, effectiveness against MDR *falciparum* strains, good pharmacokinetic profiles and capability to cure acute *P. berghei* infection at a single dose of 50 mg/kg, MK-4815 has a potential

#### *Malaria: Introductory Concepts, Resistance Issues and Current Medicines DOI: http://dx.doi.org/10.5772/intechopen.98725*

as an antiplasmodial agent and of course, is now under additional assessment by MMV as a pre-clinical candidate [79].

In an attempt to identify antiplasmodial agents with new mechanism of action, Kato and his colleagues found a lead compound coded as **BRD7929**. It was shown to target the cytosolic *falciparum* phenylalanyl-tRNA synthetase. This enzyme serves to enable transfer-RNAs deliver the amino acid phenylalanine to nascent proteins during RNA translation and protein synthesis. This bicyclic azetidine showed *in vivo* against *falciparum* and *berghei* infected mice at a single low doses. This molecule was also very potent against the hepatocytic and asexual stages of *falciparum* and exihibited transmission-blocking effect at concentrations that achieved single dose cures of asexual erythrocytic stage infections. Even if BRD7929 showed good (80%) oral bioavailability, improved aqueous solubility and longer half-life in mice (32 h), moderate cytotoxicity was seen thus presenting possible setbacks, which would have to be addressed during further optimization. Nonetheless, the capability of this lead molecule to eliminate blood stage (asexual and sexual) and liver stage parasites suggests that this compound has the potential to cure the disease, provide prophylaxis and block transmission. Currently, a tetraoxane-based antiplasmodial drug candidate, **E209** that can overcome *PfK13* Cys-580-Tyr dependent artemisinin resistance was identified. Further evaluation revealed retention of *in vitro* potency against sensitive and MDR *falciparum* isolates, with no observable cross-resistance with artemisinin. Compound E209 also exhibited equipotent *ex vivo* activity against *vivax* and *falciparum* Indonesian clinical isolates while screening for gametocytocidality showed a transmission reducing profile consistent with the endoperoxides. Equally important *in vivo* studies in *P. berghei* infected mice showed complete parasite clearance with an estimated oral ED50 of 4 mg per kg after 3 doses and a 66 percent cure rate following a 30 mg/kg single oral dose. Therefore, this chemical has the potential to use in a superior combination therapies with a partner drug devoid of *in vivo* resistance liabilities hence offers a substantial improvement on the current ACTs and provides an urgently needed alternative agent for malaria treatment and elimination. Moreover, its efficacy against *vivax* and gametocytes indicates the potential of E209 to prevent relapse and block transmission, respectively [79].

**SC83288**, an amicarbalide derivative developed in 2017 by a team at Heidelberg University, is the only agents in pre-clinical study that are going to treat sever malaria [123]. This new mlecule was shown to be fast-acting and cured *falciparum* infection in a humanized mouse model, with pre-clinical pharmacokinetic and toxicological studies revealing no apparent shortcomings. While the precise mode of action is uknown, *PfATP6* was identified as a putative determinant of resistance to SC83288. However, it has been shown that SC83288 does not directly inhibit this target suggesting *PfATP6* may have a less direct role in its mechanism of action. SC83288 has been evaluated against artemisinins, showing no cross resistance. *Pfmdr*2 has been identified as another possible mechanism of resistance, facilitating the clearance of the drug from the parasite. Its distinct chemotype, ability to rapidly kill parasites, potentially new mechanism of activity and good safety indices than artesunate and quinine support the clinical development of SC83288 as an IV application for the treatment of severe malaria when combined with a slow-acting partner drug. Presently, Heidelberg University Hospital and the German Centre for Infection Research are collaboratively in the process of conducting the regulatory preclinical procedures with the hope of initiating clinical trials in due course [79, 100]. More recently, Miguel-Blanco and his co-workers identified a compound coded as **DDD01034957**. This new antiplasmodial molecule is fast-acting and potent against resistant strains *in vitro*, *in vivo*, and possesses a resistance mechanism linked to the membrane transporter *P. falciparum* ATP-binding cassette-I3

(*PfABCI3*). These finding support further medicinal chemistry lead-optimization of DDD01034957 as a new antimalarial chemical class and provide latest insights to further reduce *in vivo* metabolic clearance [124].

A 4(1*H*)-quinolone derivative **ELQ-300**, structurally engineered from pyridone analogue by Oregon Health and Science University, was potently inhibited blood stages of *falciparum* and *vivax* malaria in clinical field isolates as well as liver stages and transmissible stages of the parasite. ELQ-300 is proved to be highly selective against plasmodial cytochrome *bc*1 complexes like atovaquone, suggesting minimized possibility of causing side effects by inhibiting the host enzyme. Similar to atovaquone, it is a slow acting molecule with a delayed parasite reduction ratio, and exhibited strong synergy with proguanil. Mutant selection studies failed to achieve variants, signifying a significantly low susceptibility for resistance. ELQ-300 was extremely potent in *berghei* infected mice with an ED50 of 0.016 mg/kg/day and cures the infection by doses as low as 0.1 mg/kg/day, thus owing the capacity to be a combination partner aimed of single dose cure. Further safety assessment indicated that there are no remarkable off target pharmacological activities by this compound. The main obstacle in the clinical development of ELQ-300 is its relatively poor water solubility, which limits the absorption to the extent that only low blood concentrations can be achieved with oral doses. Even though these low blood levels are adequate for treatment, the concentrations remain too low to establish an acceptable safety margin necessary for clinical development. The way forward intended to design bioreversible alkoxycarbonate ester pro-drugs has currently been effectively explored to overcome the physicochemical problems of ELQ-300 and attain bloodstream levels adequate for safety and toxicological studies, as well as getting single dose cures [79]. It is also possible to list **Genz-668764**, **ML238**, **ACT-213615, SAR121** and **TDR84420** within the new chemical entity group [77, 103].

Besides, a **pyrazoleamide 21A092**, which targets sodium channel (ATPase4) like KAE609 and SJ733, is in preclinical discovery phase [125]. **Dantrolene** was identified as a novel inhibitor of plasmodial surface anion channel (PSAC) and it may be a lead compound for antimalarial drug development [126]. **Acridinones** such as **WR249685** and **T3.5**, new class of selective malaria parasite mitochondrial *bc*1 inhibitors, had a great potential to become novel antimalarial drugs [127, 128]. Some antibiotics that have shown potential effects on malaria parasite have been recently studied *in vitro* or *in vivo* intensively. **Macrolide antibiotics** were identified for the first time that they inhibit *in vitro* RBC invasion by merozoite of Plasmodium species. This result directs the development of safe and effective macrolide antibiotics with dual modalities to combat malaria and reduce the parasite's options for resistance. Other antibiotics, such as **quinolones**, **tigecycline**, **co-trimoxazole** or **fusidic acid**, could be used to prevent malaria in the future. Antiadhesion adjunctive therapies, including **levamisole**, are under research in the laboratory [129, 130]. Both *in vitro* and *in vivo* experments showed that an antibacterial and anticancer drug **acriflavine** impairs DNA replication foci formation in *P. berghei* malaria and affects the enzymatic activities of apicoplast specific Gyrase protein. This attention-grabbing work tells us the potential of this old compound to become future antimalarial agent [131]. In another pre-clinical studies, the receptor protein *PfATP6* has been recognized as the common target of curcumin and artemisinin. This reseach was initiated to evaluate the anti-malarial activity of 6 **derivatives of curcumin** based on their binding affinities and correlating the *in silico* docking outcome with the *in vitro* anti-malarial screening results. The *in vitro* results superimpose the results obtained from the *in silico* study thereby encouraging development of promising curcumin leads in the battle against malaria [132]. One approach to discover new biologically active compounds is to combine a steroid skeleton with structural elements endowed with appropriate biological activities.

*Malaria: Introductory Concepts, Resistance Issues and Current Medicines DOI: http://dx.doi.org/10.5772/intechopen.98725*

Recently, Krieg and his co-workers reported on low molecular weight **arylmethylamino steroids** with varying constitutions of the basic gonane core and exhibiting excellent antimalarial activity [79]. Moreover, researchers' team has recently discovered thioredoxin enzymes, which are different from the human enzyme but critical for the survival of malaria parasite by balancing the redox state inside the *Plasmodium*. So that, a team is doing experments in collaboration to industry partners to develope novel drugs, which will successfully target this enzyme and kill the parasite without affecting the human host [133]. Although many drugs are in the pipeline, most of them are not able to kill both gametocytes and hypnozoites.
