Malaria is a mosquito borne blood disease, which remains a devastating global health problem. It is caused by the obligate intraerythrocytic protozoa belonging to genus Plasmodium. Due to the increased preventive measures including insecticide-treated bed nets and safety measures such as artemisinin based combination treatments (ACTs) the global malaria mortality rate has reduced by 30% (Bhattarai et al., 2007). Nevertheless, according to World Health Organization (WHO), it is estimated that approximately 200 million people around the world contract malaria resulting in 20% of deaths (WHO, 2016).
Current malaria drugs and their efficacy
Currently, the WHO recommends the usage of ACTs as the first-line of treatment for uncomplicated malaria (Bosman and Mendis, 2007). Artemisinin as well as its derivatives are potent and fast acting drugs (t1/2~1h) that induce a rapid decline in parasitemia only after few days of treatment (Oguche et al., 2014, Morris et al., 2011). Thus, the ACTs have replaced previously recommended drugs sulfadoxine-pyrimethamine and chloroquine (Chatterjee and Yeung, 2012, Dechy-Cabaret and Benoit-Vical, 2012). When the parasite infection gradually progresses into the liver, primaquine is the only drug that is approved for eliminating liver hypnozoites (Grayson, 2012). On the contrary, although primaquine could induce haemolysis, a low dosage is highly effective in reducing the disease transmissibility (Dicko et al., 2016).
Of the five ACTs drugs that WHO recommends, Artemether-Lumefantrine (AL) is the most widely prescribed drug due to its efficacy, safety and quality (Nega et al., 2016). This drug displayed a significant gametocidal effect by rapidly eradicating parasitaemia and fever to achieve a highly effective cure rate of >95% (Makanga and Krudsood, 2009). Another fixed dose ACT combination that is mostly used is Artesunate-amodiaquine (ASAQ). This drug was found to be as effective and well tolerated as compared to AL in malarial patients belonging to all age groups for the treatment of uncomplicated malaria (Yavo et al., 2015).
Therefore, the main drugs developed over the previous decades to fight malaria include:
- Artesunate-amodiaquine (ASAQ)
Need for novel drug mechanisms and current status
A significant concern in breakdown in using ACTs is the resistance to artemisinins that is characterized by a reduced parasite clearance. This resistance in combination with increased prevalence causes a huge set back in efforts to terminate malaria. Thus, novel malaria therapeutics to curb malaria is urgently needed. One potential approach that is being currently implemented to limit the emerging resistance is by using combination drugs. One example is treatment by combining dihydroartemisinin and piperaquine improved the effectiveness by 50% and making the patients aparasitaemic (Zani et al., 2014). Some studies have suggested the use of other drugs such as verapamil, desipramine etc. for reversing the resistance but the exact reversal mechanisms are currently under investigation (Ridley, 2002, van Schalkwyk et al., 2001).
Another promising approach in anticipation to resistance is by using metalloantimalarial agents (Sharma, 2005). Among these agents ferroquine (FQ) is the most successful metal-based drug designed for malaria therapy (Biot et al., 2011). This drug is currently in phase II of clinical trails with interesting biological effects and antimalarial activity (Bahl et al., 2010). Also, diverse studies have been carried out to understand the FE mode of action. Increasing evidence indicate that the mechanism of action of FQ is similar to that of chloroquine (Navarro et al., 2011).
FQ exerts its antimalarial activity by its localization to the food vacuole of the parasite and inhibits the haemozoin formation, which finally proceeds to membrane damage and parasite death (Biot et al., 2005). Additionally, FQ generates small amounts of hydroxyl radicals from its ferrocene moiety that can severely damage the membranes of the parasite’s food vacuole (Chavain et al., 2008, Dubar et al., 2012). FQ is a strong inhibitor of hematin formation and highly potent suggesting that it is an attracting alternative to chloroquine.
Recent new drugs to overcome drug resistence
A novel drug that has been designed and developed to widen the scope of treatment and to overcome the drug resistance is DDD10498 (Baragana et al., 2015). This drug has been proven to be more efficacious than all the currently available antimalarial agents. DDD10498 has an unique mechanism of action, which acts on multiple stages of the parasite life cycle. The molecular target of DDD1098 has been identified recently as translation elongation factor 2 (eEF2). This factor is responsible for protein synthesis that occurs through the GTP dependent translocation of ribosome along mRNA (messenger ribonucleic acid). DDD1098 binds to the complex between eEF2 and ribosome to prevent the disassociation and thereby, blocking protein synthesis. Thus, DDD107498 represents an exciting prospect for the development of antimalarial drugs against drug resistance. This super drug has progressed to phase I human clinical trials (Bhagavathula et al., 2016).
Upcoming promising medicines
Cipargamin (KAE609) is a novel synthetic antimalarial compound that has reached to phase II trials and exhibited promising results (White et al., 2014). The membrane P-type cation translocating ATPase, PfATP4 is the molecular target for cipargamin. Upon parasitic exposure, cipargamin binds to PfATP4 resulting in disruption of cytosolic Na+ and subsequently, parasite death (Spillman and Kirk, 2015). This drug is seven times more potent than the commercially available ACTs suggesting that it is an ideal candidate to prevent malarial drug resistance.
In addition to the above drugs, DSM265 and OZ277 are being tested clinically for safety and efficacy. DSM265 is a dihydroorotate dehydrogenase inhibitor, which acts in the liver stage of malaria cycle (Phillips et al., 2015). OZ277 (arterolane) is the first highly active ozonide compound that was more effective than chloroquine (Charman et al., 2011). Combination of this compound with another drug piperaquine and found to be more efficacious. OZ277 currently reached phase III clinical trails but the mechanism of action is not fully understood.
New imaging techniques for curbing the spread of malaria
A delay in identification and appropriate treatment of malaria leads to morbidity and mortality. Since the last two decades, malarial infection rates have been reduced dramatically by >50%. However, total eradication still remains a major challenge and requires multifaceted strategies. Although there is a significant enhancement in the development of new generation antimalarial drugs, very few compounds are superior to gold standard classical drugs (ACTs). Although the malarial drug discovery process is hindered by the absence of high-throughout screening, new imaging techniques are current alternatives. To prevent the drug resistance setback, development strategies should focus on targeting the blood stage with transmission blocking properties. Furthermore, a meta-analysis of drugs developed against malaria is helpful to assess the potential risks of drug usage and to estimate the treatment efficacy. Therefore the proceeding article exhibits a meta-analysis of important studies on Artemisinin drug developed against malaria.
- Bahl, D., Athar, F., Soares, M. B., De Sa, M. S., Moreira, D. R., Srivastava, R. M., Leite, A. C. & Azam, A. 2010. Structure-activity relationships of mononuclear metal-thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities. Bioorg Med Chem, 18, 6857-64.
- Baragana, B.,et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature, 522, 315-20.
- Bhagavathula, A. S., Elnour, A. A. & Shehab, A. 2016. Alternatives to currently used antimalarial drugs: in search of a magic bullet. Infect Dis Poverty, 5,
- Bhattarai, A., Ali, A. S., Kachur, S. P., Martensson, A., Abbas, A. K., Khatib, R., Al-Mafazy, A. W., Ramsan, M., Rotllant, G., Gerstenmaier, J. F., Molteni, F., Abdulla, S., Montgomery, S. M., Kaneko, A. & Bjorkman, A. 2007. Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar. PLoS Med, 4,
- Biot, C., Nosten, F., Fraisse, L., Ter-Minassian, D., Khalife, J. & Dive, D. 2011. The antimalarial ferroquine: from bench to clinic. Parasite, 18, 207-14.
- Biot, C., Taramelli, D., Forfar-Bares, I., Maciejewski, L. A., Boyce, M., Nowogrocki, G., Brocard, J. S., Basilico, N., Olliaro, P. & Egan, T. J. 2005. Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity. Mol Pharm, 2, 185-93.
- Bosman, A. & Mendis, K. N. 2007. A major transition in malaria treatment: the adoption and deployment of artemisinin-based combination therapies. Am J Trop Med Hyg, 77, 193-7.
- Charman, S. A., Arbe-Barnes, S., Bathurst, I. C., Brun, R., Campbell, M., Charman, W. N., Chiu, F. C., Chollet, J., Craft, J. C., Creek, D. J., Dong, Y., Matile, H., Maurer, M., Morizzi, J., Nguyen, T., Papastogiannidis, P., Scheurer, C., Shackleford, D. M., Sriraghavan, K., Stingelin, L., Tang, Y., Urwyler, H., Wang, X., White, K. L., Wittlin, S., Zhou, L. & Vennerstrom, J. L. 2011. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci U S A, 108, 4400-5.
- Chatterjee, A. K. & Yeung, B. K. 2012. Back to the future: lessons learned in modern target-based and whole-cell lead optimization of antimalarials. Curr Top Med Chem, 12, 473-83.
- Chavain, N., Vezin, H., Dive, D., Touati, N., Paul, J. F., Buisine, E. & Biot, C. 2008. Investigation of the redox behavior of ferroquine, a new antimalarial. Mol Pharm, 5, 710-6.
- Dechy-Cabaret, O. & Benoit-Vical, F. 2012. Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate. J Med Chem, 55, 10328-44.
- Dicko, A., Brown, J. M., Diawara, H., Baber, I., Mahamar, A., Soumare, H. M., Sanogo, K., Koita, F., Keita, S., Traore, S. F., Chen, I., Poirot, E., Hwang, J., Mcculloch, C., Lanke, K., Pett, H., Niemi, M., Nosten, F., Bousema, T. & Gosling, R. 2016. Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial. Lancet Infect Dis, 16, 674-684.
- Dubar, F., Bohic, S., Slomianny, C., Morin, J. C., Thomas, P., Kalamou, H., Guerardel, Y., Cloetens, P., Khalife, J. & Biot, C. 2012. In situ nanochemical imaging of label-free drugs: a case study of antimalarials in Plasmodium falciparum-infected erythrocytes. Chem Commun (Camb), 48, 910-2.
- Flannery EL, Chatterjee AK, Winzeler EA. Antimalarial drug discovery – approaches and progress towards new medicines. Nature reviews Microbiology. 2013 Dec;11(12):849-62. PubMed PMID: 24217412. Pubmed Central PMCID: 3941073.
- Makanga, M. & Krudsood, S. 2009. The clinical efficacy of artemether/lumefantrine (Coartem). Malar J, 8 Suppl 1,
- Morris, C. A., Duparc, S., Borghini-Fuhrer, I., Jung, D., Shin, C. S. & Fleckenstein, L. 2011. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J, 10,
- Navarro, M., Castro, W., Martinez, A. & Sanchez Delgado, R. A. 2011. The mechanism of antimalarial action of [Au(CQ)(PPh(3))]PF(6): structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces. J Inorg Biochem, 105, 276-82.
- Nega, D., Assefa, A., Mohamed, H., Solomon, H., Woyessa, A., Assefa, Y., Kebede, A. & Kassa, M. 2016. Therapeutic Efficacy of Artemether-Lumefantrine (Coartem(R)) in Treating Uncomplicated P. falciparum Malaria in Metehara, Eastern Ethiopia: Regulatory Clinical Study. PLoS One, 11,
- Oguche, S., Okafor, H. U., Watila, I., Meremikwu, M., Agomo, P., Ogala, W., Agomo, C., Ntadom, G., Banjo, O., Okuboyejo, T., Ogunrinde, G., Odey, F., Aina, O., Sofola, T. & Sowunmi, A. 2014. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old Nigerian children. Am J Trop Med Hyg, 91, 925-35.
- Phillips, M. A., et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med, 7,
- Ridley, R. G. 2002. Medical need, scientific opportunity and the drive for antimalarial drugs. Nature, 415, 686-93.
- SHARMA, V. 2005. Therapeutic drugs for targeting chloroquine resistance in malaria. Mini Rev Med Chem, 5, 337-51.
- Spillman, N. J. & Kirk, K. 2015. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs. Int J Parasitol Drugs Drug Resist, 5, 149-62.
- Van Schalkwyk, D. A., Walden, J. C. & Smith, P. J. 2001. Reversal of chloroquine resistance in Plasmodium falciparum using combinations of chemosensitizers. Antimicrob Agents Chemother, 45, 3171-4.
- White, N. J., Pukrittayakamee, S., Phyo, A. P., Rueangweerayut, R., Nosten, F., Jittamala, P., Jeeyapant, A., Jain, J. P., Lefevre, G., Li, R., Magnusson, B., Diagana, T. T. & Leong, F. J. 2014. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med, 371, 403-10.
- 2016. World Malaria Report 2015 [Online]. Available: http://www.who.int/features/factfiles/malaria/en/.
- Yavo, W., Konate, A., Kassi, F. K., Djohan, V., Angora, E. K., Kiki-Barro, P. C., Vanga-Bosson, H. & Menan, E. I. 2015. Efficacy and Safety of Artesunate-Amodiaquine versus Artemether-Lumefantrine in the Treatment of Uncomplicated Plasmodium falciparum Malaria in Sentinel Sites across Cote d’Ivoire. Malar Res Treat, 2015,
- Zani, B., Gathu, M., Donegan, S., Olliaro, P. L. & Sinclair, D. 2014. Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev.