Anais da Academia Brasileira de Ciências (2018) 90(1 Suppl. 2): 1251-1271 (Annals of the Brazilian Academy of Sciences) Printed version ISSN 0001-3765 / Online version ISSN 1678-2690 http://dx.doi.org/10.1590/0001-3765201820170830 www.scielo.br/aabc | www.fb.com/aabcjournal Current Antimalarial Therapies and Advances in the Development of Semi-Synthetic Artemisinin Derivatives LUIZ C.S. PINHEIRO1, LÍVIA M. FEITOSA1,2, FLÁVIA F. DA SILVEIRA1,2 and NUBIA BOECHAT1 1Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos Farmanguinhos, Fiocruz, Departamento de Síntese de Fármacos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil 2Universidade Federal do Rio de Janeiro, Programa de Pós-Graduação em Química, Avenida Athos da Silveira Ramos, 149, Cidade Universitária, 21941-909 Rio de Janeiro, RJ, Brazil Manuscript received on October 17, 2017; accepted for publication on December 18, 2017 ABSTRACT According to the World Health Organization, malaria remains one of the biggest public health problems in the world. The development of resistance is a current concern, mainly because the number of safe drugs for this disease is limited. Artemisinin-based combination therapy is recommended by the World Health Organization to prevent or delay the onset of resistance. Thus, the need to obtain new drugs makes artemisinin the most widely used scaffold to obtain synthetic compounds. This review describes the drugs based on artemisinin and its derivatives, including hybrid derivatives and dimers, trimers and tetramers that contain an endoperoxide bridge. This class of compounds is of extreme importance for the discovery of new drugs to treat malaria. Key words: malaria, Plasmodium falciparum, artemisinin, hybrid. Abbreviations: fixed-dose combination - FDC amodiaquine - AQ Medicines for Malaria Venture - MMV artemisinin - ART mefloquine - MQ artemisinin-based combination therapy - ACT p-aminobenzoic acid - PABA chloroquine - CQ pharmaceutical fixed-dose combination - FDC chloroquine-resistant - CQR Plasmodium falciparum - P. falciparum dihydroartemisinin - DHA Plasmodium knowlesi - P. knowlesi dihydrofolate reductase - DHFR Plasmodium malariae - P. malariae, dihydropteroate synthase - DHPS Plasmodium ovale - P. ovale Drugs Initiative for Neglected Diseases - DNDi Plasmodium vivax - P. vivax, European Medicines Agency - EMA primaquine - PQ Correspondence to: Nubia Boechat E-mail: [email protected] pyronaridine - PYR * Contribution to the centenary of the Brazilian Academy of quinine - QN Sciences. World Health Organization - WHO An Acad Bras Cienc (2018) 90 (1 Suppl. 2) 1252 LUIZ C.S. PINHEIRO et al. INTRODUCTION countries, among children under 5 years of age (WHO 2016). Malaria is one of the most important public health Malaria is caused by single-celled protozoa problems worldwide, with almost half of the global of the genus Plasmodium and is considered a population exposed to the risk of contamination. severe, infectious, parasitic disease. This disease This disease is present in 91 countries, mostly is transmitted by the bite of the female mosquito in tropical and subtropical regions of the planet. of the genus Anopheles infected with the protozoa, However, due to globalization, the incidence of of which five species are responsible for infecting malaria has been alarming in virtually all countries, humans: Plasmodium falciparum, P. vivax, P. given that malaria cases are increasing in first- malariae, P. ovale and P. knowlesi (Garcia 2010). world countries. In 2016, it was estimated using The life cycle of Plasmodium species (Figure data from the World Health Organization (WHO) 1) is divided into different phases and between two that there were 212 million malaria cases in the hosts: a vertebrate and the mosquito. The onset of world, leading to 429,000 deaths, mainly in African infection occurs with the bite of an infected female Figure 1 - Plasmodium falciparum life cycle (CDC 2017). An Acad Bras Cienc (2018) 90 (1 Suppl. 2) ARTEMISININ AND ITS SEMISYNTHETIC DERIVATIVES 1253 Anopheles mosquito. As the mosquito performs parasite in the tissue cycle of the species P. vivax blood repast, the salivary glands release sporozoites and P. ovale, interrupting the transmission of the on the skin, and after reaching the bloodstream parasite and avoiding relapses. Various drugs are the sporozoites rapidly invade liver cells, starting available for achieving these goals, where each acts the infection. In the liver cells, the sporozoites in a specific way to inhibit the development of the differentiate and multiply asexually into thousands parasite in the host (Teixeira et al. 2014, Biamonte of merozoites, which invade the erythrocytes et al. 2013). and proceed to multiply. In this phase, begin the Antimalarial chemotherapy has been based symptoms of malaria. Based on the species, the on an endless search for the next agent to combat duration of the erythrocytic stage will be different: Plasmodium parasites when they are able to prevent 48 h for P. falciparum, P. vivax and P. ovale and 72 the effect of current drugs. A great challenge for h for P. malariae. malaria treatment in recent decades has been to Some merozoites will not reproduce asexually; overcome the parasite’s ability to acquire resistance these develop into sexual forms called gametocytes, to antimalarials, requiring the development of more which are ingested by the female Anopheles effective drugs (Seder et al. 2013, Raj et al. 2014, mosquito during hematophagy, beginning the Teixeira et al. 2014). sexual cycle in the stomach of the mosquito. The Antimalarial chemotherapy is based on natural new sporozoites move to the salivary glands of the products, semi-synthetic and synthetic compounds mosquito, and their inoculation into a new human developed since the 1940s. Safe drugs used in the host restarts the life cycle of Plasmodium. Some treatment of the disease are divided into three main merozoites evolve into a latent form of the parasite classes: quinoline derivatives (Figure 2), antifolates (hypnozoites), whose reactivation is responsible (Figure 3) and artemisinin derivatives (Figure 4) for the recurrence of malaria (in cases of infection (Staines and Krishna 2012, Leite et al. 2013). caused by P. vivax and P. ovale) (Schlitzer 2008, Midha et al. 2015, MMV 2017a, CDC 2017). QUINOLINE DERIVATIVES Historically, quinolines are among the most widely CURRENT CHEMOTHERAPY FOR MALARIA used drugs for the treatment of malaria. Quinine The main means used to eliminate or reduce the (QN 1) (Figure 2), an alkaloid isolated from the bark number of cases of malaria are the development of Cinchona trees, was first used to treat malaria of vaccines, vector control, chemoprophylaxis as early as the beginning of the 17th century, and and chemotherapy employing antimalarial drugs became the standard therapy for malaria from the (Rappuoli and Aderem 2011). mid-19th century to the 1940s. The extraction of QN Antimalarials mostly act by mechanisms that is still more economically viable than its synthetic seek to inhibit one or two stages of the parasite’s production (Achan et al. 2011). The emergence of life cycle. The treatment aims to act on the resistant strains of P. falciparum, in addition to the parasite in two different ways. One of them is to high toxicity, has contributed to the limitation of interrupt the schizogonic blood stage responsible the use of QN. However, this drug still used against for the symptoms of the disease, that is, to kill the malaria in the clinic, most often combined with parasite during the evolutionary cycle. The other a second agent to shorten the duration of therapy is to employ drugs that prevent the development and thus minimize the adverse effects (Achan et al. of gametocytes, in other words, to destroy the 2011, Giao and Vries 2001). An Acad Bras Cienc (2018) 90 (1 Suppl. 2) 1254 LUIZ C.S. PINHEIRO et al. Figure 2 - Quinoline derivatives used in the treatment of malaria. At the beginning of the 20th century, research for a long time, but its uncontrolled use soon conducted by Bayer gave rise to the first synthetic led to the emergence of chloroquine-resistant antimalarial drug, an 8-aminoquinoline, pamaquine (CQR) P. falciparum strains, only 15 years after (2) (Figure 2), whose clinical use was abandoned the introduction of CQ as first-line antimalarial due to its high toxicity and limited activity chemotherapy (Cunico et al. 2008, Kaur et al. (Tekwani and Walker 2006). After this discovery 2010). came mepacrine, also known as quinacrine ( ) 3 Primaquine (PQ 5) (Figure 2), an (Figure 2), an acridine derivative that was widely 8-aminoquinoline clinically used since 1950, is still used in the 1930s during World War II. During the only drug used worldwide for the treatment of this time, Bayer discovered chloroquine (CQ 4) relapsing P. vivax malaria caused by hypnozoites, (Figure 2), a 4-aminoquinoline that has become the and it inhibits the formation of gametocytes (Waters most important antimalarial drug due to its high efficacy, low cost, and tolerable adverse effects and Edstein 2012). (Krafts et al. 2012, O’Neill et al. 2012, Teixeira et This fact intensified the need to obtain new al. 2014). Being a weak base, CQ accumulates in drugs with anti-P. vivax activity. New quinoline the acidic food vacuole of the parasite and exerts derivatives with side chain modifications its activity by binding free heme and inhibiting were synthesized, giving rise to new drugs hematin biocrystallization (hemozoin formation). such as amodiaquine (AQ 6) (Figure 2), a CQ was the first choice for antimalarial treatment 4-phenylaminoquinoline (Teixeira et al. 2014). An Acad Bras Cienc (2018) 90 (1 Suppl. 2) ARTEMISININ AND ITS SEMISYNTHETIC DERIVATIVES 1255 Piperaquine (7) (Figure 2) is a bis-4- form stage, followed by the schizonts, and then the aminoquinoline discovered in 1960s that showed trophozoites. It was more active against all of these activity against CQR strains. It is a bisquinoline, stages than CQ (Croft et al. 2012). and although its precise mechanism of action is Mefloquine (MQ 9) (Figure 2), developed unknown, it is thought to be similar to that of CQ, by the United States Army, came into use in the which is structurally similar.