A Contemporary Chemical Entities Infiltrating in the Antimalarial Therapy Era: A Comprehensive Review

Malaria, a life-threatening disease, is caused by parasitic single-celled microorganisms. It is specifically transmitted by the anopheles female mosquito of the Plasmodium family. There are a lot of drugs available in the market to treat this life-challenging disease. Chloroquine, a cheaper molecule that is available worldwide, is one of them. Drug resistance has been observed with chloroquine as well as with some other quinine derivatives and with artemisinin derivatives in the southeast region of Asia in countries like Cambodia, Thailand, Myanmar, and Vietnam country since 1957. After 1970, the drug resistance has been further increased and it has been expanded in several localities of India. Also, antimalarial agents, particularly chloroquine, have so many side effects such as nausea, vomiting, blurred vision, abdominal cramps, diarrhea, headache, appetite loss, deprivation of hearing, skin color change, baldness, reduced body weight, and seizures. Furthermore, this drug cannot be given to pregnant women. Hence, it is the right time to design and develop newer antimalarial agents so that this kind of drug resistance, as well as side effects of the drugs, can be overcome.


INTRODUCTION
Malaria is a life-threatening infectious disease that occurs due to biting of anopheles female mosquito. Mosquito biting leads to the introduction of parasites from the mosquito saliva into host blood. The parasites then shift to the infected host liver and go through maturation and reproduction stage. A total of five Plasmodium species has been summarized that can infect and be spread by a human. Among these, P. falciparum can cause death whereas P. vivax, P. ovale and P. malariae can cause a benign form of malaria. P. knowlesi species barely cause disease in humans. These microorganisms can affect both humans and animals.
Signs and symptoms of malaria can be seen in a person ten to fifteen days after being bitten by mosquitos. Typically, malaria can cause fever, headache, vomiting, tiredness, joint pains, shivering, jaundice, hemolytic anaemia, and haemoglobin in urine-like symptoms. Whereas in severe condition, it can cause retinal damage, yellow skin, seizures and coma, and if it is not cured, it may lead to death. In some cases, some other conditions like sepsis, gastroenteritis, and viral diseases can also be seen.
Malaria disease can be well treated with combination therapy. The combination of this antimalarial medication includes an artemisinin derivative with the second medication will be either chloroquine or mefloquine or lumefantrine or sulfadoxine/pyrimethamine. In some cases, when the artemisinin derivative is not available, then a combination therapy of quinine with doxycycline can also be used. Chloroquine and other quinine derivative enter the host RBC and accumulate there forming a complex with heme (toxic to the parasite). These inhibit the conversion step of heme into hemozoin (nontoxic to the parasite). So the concentration of heme will be increased that will destroy the malarial parasite. Fig. 1 shows structures of antimalarial drugs currently available in the market. 1

MMV390048
It is chemically 3-(6-(Trifluoromethyl)pyridine-3-yl)-5-(4-(methylsulfonyl)phenyl)pyridine-2-amine (Fig. 3). Paquet et al. have screened a small molecule library against human P. falciparum parasite and invented a newer 2-aminopyridine derivative, MMV390048, which was active against multiple parasite life cycle stages. They have reported that the drug is active against drug resistant parasites also. They have summarized the molecular mechanism of this drug which blocks the phosphatidylinositol 4-kinase (PI4K) and stated that this drug may be used for malaria control as a single dose combination treatment. 9 Sinxadi et al. have assessed the safety, tolerability, pharmacokinetics and antimalarial activity of MMV390048 in healthy human subjects of Ethiopia. After observing all the results they have reported that this drug is well tolerated in humans and by checking pharmacokinetic properties, they have concluded that it has a potential for prophylaxis of malaria as well as treatment of malaria in a single dose. 10    Fig. 5). It is under phase 1 clinical trial. Dubar et al. have addressed a novel antimalarial drug ferroquine that currently is in development at Sanofi-Aventis. They have reported FQ, the first organometallic molecule containing ferrocenyl group that covalently linked with 4-aminoquinoline and a basic alkylamine. They have communicated that FQ can overcome the resistance problem of chloroquine. This drug targets lipids and inhibits hemozoin formation and generate reactive oxygen species. 13 Kondratskyi et al. have reported that the anticancer ferroquine can be the next generation potential antimalarial agent. 14 newer in development 4-aminoquinoline derivative drug.

Quinoline derivatives Ferroquine (SR97193)
It is under phase 1 clinical trial and has structural similarity with chloroquine. It contains shorter diaminoalkyl side chain and it can be used for the patients suffering from malaria that is resistant to chloroquine and other antimalarial agents. 15 Koita et al. have addressed AQ13 that contains 4-aminoquinoline ring with modified side chains.
They have compared the activity of AQ13 with artemether plus lumefantrine combination to treat uncomplicated P. falciparum malaria and concluded that this drug was active against resistant parasites. 16  Fig. 7). It is used to treat malaria with single exposure radical cure as well as resistant management. Rottmann et al. have performed an antimalarial combination study of this drug with pyronaridine, which is hemozoin formation inhibitor, and reported that this drug works on the novel mechanism that it inhibits P. falciparum elongation factor 2 (EF2). 17

Trioxane derivatives CDRI 97/78
It is chemically a trioxane peroxide which is water soluble synthetic derivative of artemisinin (Fig. 9). It was developed by CDRI and Ipca laboratories. Shafiq et al. have performed a detailed study of CDRI 97/78 on 50 healthy volunteers in ascending single doses, randomized, placebo-controlled and double-blind design. They reported that this drug was found to be pharmacologically and toxicologically safe and effective. 19

CDRI 99/411
It is chemically a trioxane peroxide which is highly efficacious and orally active agent (Fig. 10)

Methylene blue
It is chemically [7-(Dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride (Fig. 11). It is under phase 2 clinical trial. Schirmer et al. have reported intrinsic activity of methylene blue and concluded that this drug can act as chloroquine sanitizer. They have addressed that methylene blue prevents methemoglobunemia that is a serious complication of malarial anemia. Methylene blue inhibits glutathione reductase in malarial parasites. 21  ties compared with the tertiary one. In the secondary amino ozonoids, addition of the polar functional groups leads to a decrease of the antimalarial efficacy. They found that primary and tertiary amino ozonoids with cycloalkyl and heterocyclic groups can give better activity than having acyclic group. 23 Phyo et al. have assessed efficacy, tolerability and pharmacokinetics of artefenomel at variable doses in patient with P. falciparum and P. vivax. They reported that that this drug could be well tolerated in volunteers at the dose of 1600 mg. They have summarized that artefenomel is a novel synthetic trioxolane having improved pharmacokinetic properties. 24

Heparin analogue Sevuparin (DF02)
It is developed from heparin. It is a polysaccharide of heparin analogue (Fig. 13). It has the antiadhesive activities of heparin without the antithrombin properties. Saiwaew et al. have reported that sevuparin has been designed to maintain antiadhesive properties with reducing the anticoagulant activity. This drug can disrupt the formation of P. falciparum rosette in a single dose and inhibits cycloadherence to endothelial cells. 25 Leitgeb et al. revealed that sevuparin blocked invasion of merosoite and transiently de-sequesters infected erythrocytes in humans with P. falciparum malaria. They have concluded that the drug was safe and well tolerated in malaria patients. 26 Artefenomel A = H, F B = O, CH 2 , CONR, SO 2 NR C = alkyl, cycloalkyl D = weak base ± polar functional groups

Pyrimidine derivatives P218
P218 is chemically 3-(2-(3-(2,4-Diaminopyrimin-5-yloxy) propoxy)phenyl)propanoic acid (Fig. 15). Chughlay et al. have reported first-in-clinical trial of P218 that assessed the safety, tolerability, pharmacokinetics and food effects in healthy individuals. They have addressed a short half-life of P218 so a long acting formulation must be required for the treatment of malaria. 29

Fosmidomycin
It is chemically 3-[Formyl(hydroxy)amino]propylphosphonic acid (Fig. 17). Lell et al. have addressed the previous antimalarial study of fosmidomycin on mouse models and assessed 20 adults for the treatment of uncomplicated P. falciparum in Gabon and Thailand. They have taken an uncontrolled trial taking fosmidomycin at an oral dose of 1200 mg every 8 hours for 7 days and concluded that this drug is efficient as an antimalarial drug for the clearance of asexual parasitemia at both countries. 32 Umeda et al. have communicated the molecular mechanism of fosmidomycin that this drug inhibits 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in malarial parasites. DXR is the enzyme of nonmevalonate pathway and it is absent in humans. 33

Tafenoquine (SB-252263, WR238605)
It is chemically N-[2,6-Dimethoxy-4-methyl-5[3-(trifluoromethyl)phenoxy]quinoline-8-yl]pentane-1,4-diamine (Fig. 18). The USFDA has approved this drug for prophylaxis of malaria and radical cure of P. vivax malaria. It is prepared under the brand name of Krintafel by Sun pharmaceuticals, India and in Washington, USA it is prepared under the brand name of Arakoda. It has been approved for medical use in Australia and in the United States in 2018. Duparc et al. have reported that tafenoquine, an 8-aminoquinoline antimalarial drug has been approved as a single-dose therapy (300 mg) for prevention of P. vivax relapse when coadministered with chloroquine. They summarized that 200 mg of tafenaquine weekly after a loading dose has been approved as travelling prophylaxis. 34 36 Patil et al. have reported a fixed dose combination therapy of arterolane and piperaquine as a newer aspect in the treatment of malaria. 37 Uhlemann et al. have communicated that arterolane is active against all erythrocytic stages of P. falciparum. This drug inhibits heme detoxification and Pf-encoded sarcoplasmic endoplasmic reticulum calcium ATPase (PfATP6). 38

CONClUsIONs AND FUTURE PERsPECTIvEs
The developed chloroquine and artemisinin drug resistance has created the need to design and develop potential antimalarial agents so that the side effects as well as the developed resistance can be overcome. Here we present a detailed review of newer potential antimalarial agents. This review reveals the molecules, effective against P. falciparum parasites, that are under different clinical trials. Amongst these all tafenoquine and arterolane have passed clinical trial 3 and now are available at the market. The remaining candidates are still studied to find whether they are effective as potent antimalarial agents and could be released in the society for better treatment.

Human and animal rights
No animals/humans were used in the studies analysed in this research.