BR102019004351A2

BR102019004351A2 - D-GLYCOSAMINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES

Info

Publication number: BR102019004351A2
Application number: BR102019004351-2A
Authority: BR
Inventors: Ricardo José Alves; Ana Luiza De Faria E Silva; Lucas Lopardi Franco; Cristiane Aparecida E Silva; Fernando de Pilla Varotti; Amanda Luisa Da Fonseca; Alex Gutterres Taranto; Moacyr Comar Júnior
Original assignee: Universidade Federal De Minas Gerais; Fundação De Amparo À Pesquisa Do Estado De Minas Gerais - Fapemig; Universidade Federal De São João Del Rei - Ufsj
Priority date: 2019-03-01
Filing date: 2019-03-01
Publication date: 2020-09-29

Abstract

a presente tecnologia se refere a derivados da d-glicosamina obtidos por síntese, assim como a composições farmacêuticas contendo os compostos e ao uso desses derivados da d-glicosamina ou das composições para obtenção de medicamentos com atividade antimalárica. os compostos da presente tecnologia apresentam atividade em concentração nanomolar e constituem uma nova abordagem de substâncias antiplasmodiais de interesse terapêutico. uma vez que o tratamento da malária é feito com associação de fármacos, para evitar o desenvolvimento de resistência, o desenvolvimento de fármacos com mecanismo de ação diferente dos demais é de grande relevância.the present technology refers to derivatives of d-glucosamine obtained by synthesis, as well as to pharmaceutical compositions containing the compounds and the use of these derivatives of d-glucosamine or compositions to obtain drugs with antimalarial activity. the compounds of the present technology have activity in nanomolar concentration and constitute a new approach to antiplasmodial substances of therapeutic interest. since the treatment of malaria is done with a combination of drugs, to avoid the development of resistance, the development of drugs with different mechanisms of action is of great relevance.

Description

D-GLYCOSAMINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES

[001] A presente tecnologia se refere a derivados da D-glicosamina obtidos por síntese, assim como a composições farmacêuticas contendo os compostos e ao uso desses derivados da D-glicosamina ou das composições para obtenção de medicamentos com atividade antimalárica. Os compostos da presente tecnologia apresentam atividade em concentração nanomolar e constituem uma nova abordagem de substâncias antiplasmodiais de interesse terapêutico. Uma vez que o tratamento da malária é feito com associação de fármacos, para evitar o desenvolvimento de resistência, o desenvolvimento de fármacos com mecanismo de ação diferente dos demais é de grande relevância.[001] The present technology refers to derivatives of D-glucosamine obtained by synthesis, as well as pharmaceutical compositions containing the compounds and the use of these derivatives of D-glucosamine or compositions to obtain drugs with antimalarial activity. The compounds of the present technology have activity in nanomolar concentration and constitute a new approach to antiplasmodial substances of therapeutic interest. Since the treatment of malaria is done with a combination of drugs, to prevent the development of resistance, the development of drugs with a different mechanism of action is of great relevance.

[002] A malária é um problema que, de acordo com a Organização Mundial de Saúde (OMS), afeta mais de 216 milhões de pessoas no mundo, ocasionando cerca de 445 mil mortes a cada ano, podendo levar a mais óbitos do que a AIDS devido ao seu alcance epidemiológico e pela possibilidade de desenvolvimento de quadros graves. Entre 2014 e 2016, apesar das reduções no número de casos de malária no mundo, a incidência aumentou substancialmente.[002] Malaria is a problem that, according to the World Health Organization (WHO), affects more than 216 million people worldwide, causing about 445 thousand deaths each year, which can lead to more deaths than AIDS due to its epidemiological reach and the possibility of developing severe conditions. Between 2014 and 2016, despite reductions in the number of malaria cases worldwide, the incidence increased substantially.

[003] A alarmante resistência aos fármacos empregados na quimioterapia da malária levou a OMS a prever que, na ausência de novas estratégias para o combate à malária, o número de pessoas parasitadas duplique em todo o globo. Ressalta-se, porém, que a malária é uma doença evitável e tratável, desde que sejam implantadas adequadamente as intervenções que incluem o controle do vetor através do uso adequado de mosquiteiros empregados com inseticidas, quimioprofilaxia em hospedeiros mais vulneráveis, diagnóstico rápido em casos de suspeita e o tratamento com medicamentos de acordo com o agente etiológico.[003] The alarming resistance to drugs used in malaria chemotherapy has led WHO to predict that, in the absence of new strategies to combat malaria, the number of parasitized people will double across the globe. It is noteworthy, however, that malaria is a preventable and treatable disease, provided that interventions that include vector control through the proper use of mosquito nets employed with insecticides, chemoprophylaxis in the most vulnerable hosts, rapid diagnosis in cases of suspicion and treatment with drugs according to the etiological agent.

[004] O Plasmodium falciparum é o agente etiológico mais comum no mundo conforme relata a OMS. No entanto, a parasitose provocada pelo Plasmodium vivax, que foi previamente considerada benigna, é associada a casos fatais.[004] Plasmodium falciparum is the most common etiological agent in the world as reported by the WHO. However, parasitosis caused by Plasmodium vivax, which was previously considered benign, is associated with fatal cases.

[005] A expansão global da malária tem sido atribuída, principalmente, ao fracasso dos programas de controle de vetores e propagação da resistência à cloroquina (CQ) e outros antimaláricos. Apesar de inúmeros fármacos utilizados na terapêutica antimalárica, a resistência a eles em P. falciparum, P. malariae e P. vivax tem sido documentada. Em P. falciparum, a resistência tem sido observada em todos os antimaláricos atualmente utilizados. Em P. malariae foi observada resistência a cloroquina e a pirimetamina. Em P. vivax tem-se demonstrado o aparecimento rápido de resistência à sulfadoxina-pirimetamina em muitas áreas, enquanto a resistência à cloroquina está em grande parte da Indonésia, Papua Nova Guiné, Timor-Leste e outras partes da Oceania. Isso representa uma grande ameaça ao controle da malária.[005] The global expansion of malaria has been attributed mainly to the failure of vector control programs and the spread of resistance to chloroquine (QC) and other antimalarials. Despite numerous drugs used in antimalarial therapy, resistance to them in P. falciparum, P. malariae and P. vivax has been documented. In P. falciparum, resistance has been observed in all antimalarial drugs currently used. P. malariae showed resistance to chloroquine and pyrimethamine. P. vivax has shown the rapid appearance of resistance to sulfadoxine-pyrimethamine in many areas, while resistance to chloroquine is found in much of Indonesia, Papua New Guinea, Timor-Leste and other parts of Oceania. This poses a major threat to malaria control.

[006] Não há relatos de introdução de novas classes químicas de antimaláricos na prática clínica desde 1980, quando foram introduzidos a artemisinina e seus derivados.[006] There are no reports of the introduction of new chemical classes of antimalarials in clinical practice since 1980, when artemisinin and its derivatives were introduced.

[007] Disso decorre que a descoberta e desenvolvimento de novos antimaláricos é um dos maiores desafios para o controle da malária. A eliminação da malária em vez do controle é cada vez mais endossada globalmente, exigindo novas abordagens com erradicação total da presença da infecção. Dessa forma, torna-se relevante o desenvolvimento de novos compostos que atuem inviabilizando o ciclo de vida do parasito. Esta mudança de visão ganhou urgência à medida que a resistência às terapias de combinação de artemisinina se espalharam na sub-região do Grande Mekong que representa uma ameaça à segurança sanitária global.[007] It follows that the discovery and development of new antimalarials is one of the biggest challenges for malaria control. The elimination of malaria instead of control is increasingly endorsed globally, requiring new approaches with total eradication of the presence of the infection. Thus, it becomes relevant to develop new compounds that act to make the parasite's life cycle unfeasible. This shift in vision took on urgency as resistance to artemisinin combination therapies spread across the Greater Mekong sub-region that poses a threat to global health security.

[008] A busca de novos alvos farmacológicos faz com que seja necessário compreender o desenvolvimento e os processos realizados pelo parasito. Sabe-se que quando em seus hospedeiros humanos, os parasitos da malária passam a maior parte de seu tempo alojados dentro de vacúolos de eritrócitos e de hepatócitos, dispondo de proteínas efetoras exclusivas. Tais proteínas podem, portanto, ser utilizadas no desenvolvimento de novos alvos farmacológicos, uma vez que são essenciais para a sobrevivência do parasito.[008] The search for new pharmacological targets makes it necessary to understand the development and the processes carried out by the parasite. It is known that when in their human hosts, malaria parasites spend most of their time housed within erythrocyte and hepatocyte vacuoles, with exclusive effector proteins. Such proteins can therefore be used in the development of new pharmacological targets, since they are essential for the survival of the parasite.

[009] Foi caracterizado como promissor para o desenvolvimento de novos fármacos o transportador de hexose do P. falciparum (PfHT) e o motivo é que o parasito encontra-se no interior de eritrócitos envolvido pelo VP e as moléculas de glicose devem passar por sua membrana antes de serem transportadas até o parasito, além da grande necessidade de glicose em decorrência de metabolismo energético dos parasitos.[009] The P. falciparum hexose transporter (PfHT) was characterized as promising for the development of new drugs and the reason is that the parasite is found inside the erythrocytes involved by the VP and the glucose molecules must pass through its membrane before being transported to the parasite, in addition to the great need for glucose due to the energy metabolism of the parasites.

[0010] Os derivados glicosídeos apresentam atividade antimalárica tanto em PfHT como no transportador de hexose do P. vivax (PvHT) que, assim como a PfHT transporta tanto glicose como frutose.[0010] The glycoside derivatives have antimalarial activity both in PfHT and in the P. vivax hexose transporter (PvHT) which, like PfHT, transports both glucose and fructose.

[0011] Os artigos “Use of a Selective Inhibitor To Define the Chemotherapeutic Potential of the Plasmodial Hexose Transporter in Different Stages of the Parasite’s Life Cycle” de Slavic K e colaboradores (04/03/2011) e “Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti- Malarial Compounds” de Ortiz D e colaboradores (20/04/2015), descrevem substâncias capazes de inibir PfHT. (Ksenija Slavic, Michael J. Delves, Miguel Prudeˆncio, Arthur M. Talman, Ursula Straschil, Elvira T. Derbyshire, Zhengyao Xu, Robert E. Sinden, Maria M. Mota, Christophe Morin, Rita Tewari, Sanjeev Krishna, and Henry M. Staines. Use of a Selective Inhibitor To Define the Chemotherapeutic Potential of the Plasmodial Hexose Transporter in Different Stages of the Parasite’s Life Cycle. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2011, p. 2824-2830 Vol. 55, No. 6Ortiz D, Guiguemde WA, Johnson A, Elya C, Anderson J, Clark J, et al. (2015) Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. PLoS ONE 10(4): e0123598)[0011] The articles “Use of a Selective Inhibitor To Define the Chemotherapeutic Potential of the Plasmodial Hexose Transporter in Different Stages of the Parasite's Life Cycle” by Slavic K and collaborators (03/04/2011) and “Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds ”by Ortiz D and collaborators (20/04/2015), describe substances capable of inhibiting PfHT. (Ksenija Slavic, Michael J. Delves, Miguel Prudeˆncio, Arthur M. Talman, Ursula Straschil, Elvira T. Derbyshire, Zhengyao Xu, Robert E. Sinden, Maria M. Mota, Christophe Morin, Rita Tewari, Sanjeev Krishna, and Henry M Use of a Selective Inhibitor To Define the Chemotherapeutic Potential of the Plasmodial Hexose Transporter in Different Stages of the Parasite's Life Cycle. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2011, p. 2824-2830 Vol. 55, No. 6Ortiz D, Guiguemde WA, Johnson A, Elya C, Anderson J, Clark J, et al. (2015) Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. PLoS ONE 10 (4): e0123598)

[0012] O Artigo intitulado “Interaction of O-(undec-10-en)-yl-D-glucose derivatives with the Plasmodium falciparum hexose transporter (PfHT)”, de Ionita M e colaboradores, publicado em 10/06/2007, relata uma comparação de derivados da glicose com o objetivo de desvendar o melhor local de substituição para modificações adicionais de D-glicose, visando aumento da atividade inibitória de PfHT. O derivado mais potente foi aquele que apresenta o substituinte na posição 2 da D-glicose. O artigo ainda afirma que um comprimento de cadeia entre C8 a C13 é necessário para tornar os derivados de hexose mais inibitórios à PfHT (Marina Ionita, Sanjeev Krishna, Pierre-Marc Le'o, Christophe Morina, Asha Parbhu Patelb. Interaction of O-(undec-10-en)-yl-D-glucose derivatives with the Plasmodium falciparum hexose transporter (PfHT) Bioorganic & Medicinal Chemistry Letters 17 (2007) 4934-4937).[0012] The Article entitled “Interaction of O- (undec-10-en) -yl-D-glucose derivatives with the Plasmodium falciparum hexose transporter (PfHT)”, by Ionita M et al., Published on 06/10/2007, reports a comparison of glucose derivatives with the objective of discovering the best substitution site for additional D-glucose modifications, aiming at increasing PfHT inhibitory activity. The most potent derivative was that which has the substituent at position 2 of D-glucose. The article further states that a chain length between C8 to C13 is necessary to make hexose derivatives more inhibitory to PfHT (Marina Ionita, Sanjeev Krishna, Pierre-Marc Le'o, Christophe Morina, Asha Parbhu Patelb. Interaction of O- (undec-10-en) -yl-D-glucose derivatives with the Plasmodium falciparum hexose transporter (PfHT) Bioorganic & Medicinal Chemistry Letters 17 (2007) 4934-4937).

[0013] Não foram encontrados no estado da técnica compostos derivados da D-glicosamina com atividade antimalárica. Apesar dos documentos do estado da técnica que indicam PfHT como potencial alvo para novos fármacos antimaláricos, os compostos relatados até o momento são muito diferentes dos pleiteados na presente tecnologia. Ainda, dentre os derivados de D-glicose com atividade inibitória de PfHT, apesar de alguns apresentarem substituição na posição 2, de forma semelhante ao proposto na presente tecnologia, sabe-se que a substituição da posição 2 da D-glicose é difícil, uma vez que são necessárias várias etapas de proteção e desproteção de todas as outras hidroxilas. Além do mais, não há qualquer semelhança entre os radicais, seja em relação ao tamanho e formato da cadeia, seja em termos dos hetero-átomos e grupos funcionais determinantes de sua polaridade.[0013] No compounds derived from D-glucosamine with antimalarial activity were found in the prior art. Despite the state of the art documents that indicate PfHT as a potential target for new antimalarial drugs, the compounds reported so far are very different from those claimed in the present technology. Still, among the D-glucose derivatives with PfHT inhibitory activity, although some present substitution in position 2, similarly to what is proposed in the present technology, it is known that the substitution of position 2 of D-glucose is difficult, a since several steps of protection and deprotection of all other hydroxyls are necessary. Furthermore, there is no similarity between the radicals, either in relation to the size and shape of the chain, or in terms of the hetero-atoms and functional groups that determine their polarity.

[0014] Os compostos da presente tecnologia são obtidos a partir da d-glicosamina, sendo possível a substituição da posição 2 em uma única etapa com alto rendimento. Além disso, os compostos apresentam atividade em concentração nanomolar, sendo, portanto, muito potentes. Ademais, constituem uma nova abordagem de substâncias antiplasmodiais de interesse terapêutico, não existindo no arsenal terapêutico nenhum fármaco antimalárico derivado da D-glicosamina que atue por esse mecanismo. Considerando que o tratamento da malária é feito preferencialmente com associação de fármacos, para evitar o desenvolvimento de resistência, o desenvolvimento de fármacos com mecanismo de ação diferente dos demais é de grande relevância.[0014] The compounds of the present technology are obtained from d-glucosamine, being possible the substitution of position 2 in a single step with high yield. In addition, the compounds have activity in nanomolar concentration, and are therefore very potent. In addition, they constitute a new approach to antiplasmodial substances of therapeutic interest, with no therapeutic antimalarial drug derived from D-glucosamine in the therapeutic arsenal that acts by this mechanism. Considering that the treatment of malaria is preferably done with the association of drugs, to avoid the development of resistance, the development of drugs with a different mechanism of action is of great relevance.

BRIEF DESCRIPTION OF THE FIGURES

[0015] A Figura 1 apresenta a estrutura dos derivados obtidos, sendo 1a a estrutura geral dos derivados obtidos e 1b a estrutura química dos radicais de cada composto obtido.[0015] Figure 1 shows the structure of the obtained derivatives, 1a being the general structure of the obtained derivatives and 1b the chemical structure of the radicals of each compound obtained.

[0016] A Figura 2 apresenta o esquema geral de síntese das substâncias da presente tecnologia.[0016] Figure 2 presents the general synthesis of the substances of the present technology.

[0017] A Figura 3 apresenta o esquema de síntese dos ácidos carboxílicos obtidos para condensação com a D-glicosamina para obtenção das substâncias da presente invenção.[0017] Figure 3 shows the synthesis scheme of the carboxylic acids obtained for condensation with D-glucosamine to obtain the substances of the present invention.

[0018] A Figura 4 é a representação gráfica da captação de glicose com composto 1 na concentração de 0,069μΜ em cultura de P. falciparum.[0018] Figure 4 is the graphical representation of glucose uptake with compound 1 at a concentration of 0.069μΜ in P. falciparum culture.

[0019] A Figura 5 é a representação gráfica da captação de glicose com composto 1 na concentração 0,138μΜ em cultura de P. falciparum.[0019] Figure 5 is the graphical representation of glucose uptake with compound 1 at 0.138μΜ concentration in P. falciparum culture.

[0020] A Figura 6 é a representação gráfica da captação de glicose com composto 3361 na concentração 0,119μΜ em cultura de P. falciparum.[0020] Figure 6 is the graphical representation of glucose uptake with 3361 compound at the concentration of 0.119μΜ in culture of P. falciparum.

[0021] A Figura 7 é a representação gráfica da captação de glic ose com composto 3361 na concentração 0,238μM em cultura de P. falciparum.[0021] Figure 7 is the graphical representation of the uptake of glycose with 3361 compound at 0.238μM concentration in P. falciparum culture.

DETAILED TECHNOLOGY DESCRIPTION

[0022] A presente tecnologia se refere a derivados da D-glicosamina obtidos por síntese, assim como a composições farmacêuticas contendo os compostos e ao uso desses derivados da D-glicosamina ou das composições para obtenção de medicamentos com atividade antimalárica. Os compostos da presente tecnologia apresentam atividade em concentração nanomolar e constituem uma nova abordagem de substâncias antiplasmodiais de interesse terapêutico. Uma vez que o tratamento da malária é feito com associação de fármacos, para evitar o desenvolvimento de resistência, o desenvolvimento de fármacos com mecanismo de ação diferente dos demais é de grande relevância.[0022] The present technology refers to derivatives of D-glucosamine obtained by synthesis, as well as pharmaceutical compositions containing the compounds and the use of these derivatives of D-glucosamine or compositions to obtain drugs with antimalarial activity. The compounds of the present technology have activity in nanomolar concentration and constitute a new approach to antiplasmodial substances of therapeutic interest. Since the treatment of malaria is done with a combination of drugs, to prevent the development of resistance, the development of drugs with a different mechanism of action is of great relevance.

[0023] Os derivados de D-glicosamina da presente invenção são caracterizados pela seguinte estrutura geral:

[0023] The D-glucosamine derivatives of the present invention are characterized by the following general structure:

[0024] Em que R pode ser:

arila, heteroarila, arilalquila, heteroarilalquila, arilalquenila (cis e trans), heteroarilalquenila (cis e trans), cicloalquila, cicloalquila substituído, heterociclo, heterociclo substituído, alquila ou alquila substituído; os grupos arila ou heteroarila podem ser opcionalmente substituídos com 1 a 5 substituintes, em que cada substituinte é independentemente selecionado a partir dos substituintes alquila, alquenila, alcóxi, halo, haloalquila, hidróxi, hidroxialquila, arila, heteroarila, heterociclo, cicloalquila, alcanoíla, alcoxicarbonila, amino, imino, alquilamino, acilamino, nitro, trifluormetila, trifluormetóxi, carbóxi, acetamido, acetóxi, acetila, benzamido, benzenossulfinila, benzenossulfonamido, benzenossulfonila, benzenossulfonilamino, benzoíla, benzoilamino, benzoilóxi, benzila, benzilóxi, benziloxicarbonila, benziltio, carbamoíla, carbamato, isocianato, sulfamoíla, sulfinamoíla, sulfino, sulfa, sulfoamino, tiossulfo; “Alquila”, que refere-se a um radical de hidrocarboneto (C1-C18) com cadeia carbônica linear, ramificada ou cíclica, compreendendo os grupos metila, etila, 1-propila, 2-propila, 1-butila, 2-metil-1-propila (iso-butila, -CH2CH(CH3)2), 2-butil (sec-butila, -CH(CH3)CH2CH3), 2-metil-2-propila (tert-butila, -C(CH3)3), 1 -pentila, 2-pentila, 3-pentila, 2-metil-2-butila, 3-metil-2-butila, 3-metil-1-butila, 2-metil-1-butila, 1-hexila, 2-hexila, 3-hexila, 2-metil-2-pentila, 3-metil-2-pentila, 4-metil-2-pentila, 3-metil-3-pentila, 2-metil-3-pentila, 2,3-dimetil-2-butila ou 3,3-dimetil-2-butila; “Alquila” pode ainda ser um substituinte derivado de hidrocarboneto divalente como o alquileno; alquila pode ser parcialmente insaturado fornecendo um alquenila ou alquinila; “Alquileno”, que refere-se a um substituinte derivado de um hidrocarboneto saturado de 1 a 18 átomos de carbono de cadeia carbônica linear, ramificada ou cíclica. O alquileno possui dois centros radicalares monovalentes derivados da remoção de dois átomos de hidrogênio do mesmo átomo de carbono ou de átomos de carbonos diferentes de um alcano parente; Alquilenos típicos compreendem, não limitante, o metileno (-CH2-), 1,2-etileno (-CH2CH2-), 1,3-propileno (-CH2CH2CH2-), 1,4-butileno (-CH2CH2CH2CH2-); “Alquenileno” que refere-se a um substituinte derivado de um hidrocarboneto insaturado de 1-18 átomos de carbono de cadeia carbônica linear, ramificada ou cíclica; o alquenileno possui dois centros radicalares monovalentes derivados da remoção de dois átomos de hidrogênio do mesmo átomo de carbono ou de átomos de carbonos diferentes de um alqueno parente; dentre os alquenilenos, um exemplo típico, não limitante, é o 1,2-etenileno (-CH=CH-); o alquila, alquileno e alquenileno podem possuir grupos intercalantes de cadeias e compreendem óxi (-O-), tio (-S-), amino (-N(H)-), metileno dióxi (-OCH2O-), metileno óxi (-OCH2-), carbonila (-C(=O)-), carbóxi (-C(=O)O-), carbonildióxi (-OC(=O)O-), carboxilato (-OC(=O)-), imino (-C=NH-), sulfinila (SO) ou sulfonila (SO2); “Grupos intercalates” indica que um ou mais grupos são inseridos entre dois átomos de carbonos adjacentes ou entre um átomo de carbono de um grupo alquila e o átomo de carbono do grupo no qual o alquila está ligado; a inserção do grupo resulta em uma substância estável na qual a valência de qualquer átomo não é excedida; “Arila” refere-se a um grupo carbocíclico aromático insaturado contendo de 6 a 20 carbonos formando um anel simples (como exemplo, fenila) ou anéis múltiplos fundidos nos quais pelo menos um anel é aromático (como exemplos, naftila, diidrofenantrenila, fluorenila ou antrila); O arila pode ser opcionalmente um substituinte divalente, nesse caso denominado arileno; “Carbociclo” refere-se a um anel saturado, insaturado ou aromático contendo de 3 a 8 átomos de carbono quando monocíclico, 7 a 12 átomos de carbono quando bicíclico, e até cerca de 30 átomos de carbono quando policíclico; Carbociclos compreendem ciclopropila, ciclobutila, ciclopentila, 1-ciclopent-1-enila, 1-ciclopent-2-enila, 1-ciclopent-3-enila, ciclohexila, 1-ciclohex-1-enila, 1-ciclohex-2-enila, 1-ciclohex-3-enila, fenila, espirila e naftila; “Cicloalquila” refere-se a um grupo alquila cíclico contendo de 3 a 20 átomos de carbono; cicloalquila pode ser um anel cíclico simples ou anéis múltiplos fundidos - compreende o anel simples ciclopropila, ciclobutila, ciclopentila e ciclooctila, não limitantes; e anéis múltiplos adamantanila, não limitantes; cicloalquila pode ser opcionalmente pelo menos parcialmente insaturado, fornecendo assim um cicloalquenila; o cicloalquila pode ser opcionalmente um substituinte divalente resultando em um cicloalquileno; “Heteroarila” é definido como um sistema mono, bi ou policíclico contendo um, dois ou três anéis aromáticos e pelo menos um átomo de nitrogênio, oxigênio ou enxofre em um anel aromático; heteroarila pode ser opcionalmente um substituinte divalente denominado heteroarileno; heteroarila compreende 2H-pirrolila, 3H-indolila, 4H-quinolizinila, 4nHcarbazolila, acridinila, benzo[b]tienila, benzotiazolila, β-carbolinila, carbazolila, cromenila, cinaolinila, dibenzo[b,d]furanila, furazanila, furila, imidazolila, imidazolidinila,imidazolinila, imidizolila, indazolila, indolisinila, indolila, isobenzofuranila, isoindolila, isoquinolila, isoquinolinila, isotiazolila, isoxazolila, naftiridinila, oxazolila, fenantridinila, fenantrolinila, fenarsazinila, fenazinila, fenotiazinila, fenoxatinila, fenoxazinila, ftalazinila, naftilpiridinila, pteridinila, purinila, piranila, pirazinila, pirazolila, piridazinila, piridila, pirimidinila, pirrolila, quinazolinila, quinolila, quinolinila, quinolizinila, quinoxalinila, tiadiazolila, tiantrenila, tiazolila, tienila, triazolila, tetrazolila e xantenila; “Heterociclo” refere-se a um sistema anelar parcialmente insaturado ou saturado contendo pelo menos um átomo de oxigênio, nitrogênio e enxofre; Os heterociclos podem ser monocíclicos, bicíclicos ou policíclicos; O heterociclo pode também conter um grupo oxo (=O) ligado ao anel; Heterociclos compreendem, não limitante, 1,3-diidrobenzofuranila, 1,3-dioxolanila, 1,4-dioxanila, 1,4-ditianila, 2H-piranila, 2-pirazolinila, 4H-piranila, cromanilila, imidazolidinila, imidazolinila, indolinila, isocromalina, isoindolinila, morfolinila, piperazinila, piperidinila, piperidila, pirazolidinila, pirazolinila, pirrolidinila, pirrolinila, quinuclidinila e tiomorfolina; “Substituído” é utilizado para indicar que um ou mais hidrogênios em um átomo foi substituído com um grupo adequado resultando em uma substância estável na qual nenhum átomo excede a valência; alquila, alquileno, alquenileno, cicloalquila e heterociclo podem opcionalmente serem substituídos com um ou mais alquila, alquenila, alcóxi, halo, haloalquila, hidróxi, hidroxialquila, arila, heteroarila, heterociclo, cicloalquila, alcanoila, alcoxicarbonila, amino, imino, alquilamino, acilamino, nitro, trifluormetila, trifluormetoxi, carbóxi, carboxialquila, ceto, tioxo, alquiltio, alquilsufinila, alquilsulfonila, ciano, acetamido, acetóxi, benzamido, benzenossulfinila, benzenossulfonamido, benzenossulfonila, benzenossulfonilamido, benzoíla, benzoilamido, benzoilóxi, benzil, benzilóxi, benzila, benzilóxi, benziloxicarbonila, benziltio, carbamoíla, carbamato, isocianato, sulfamoíla, sulfinamoíla, sulfino, sulfa, sulfoamino, tiossulfo, NRXRY e/ou COORX, em que cada RX e RY são independentemente hidrogênio, alquila, alquenila, arila, heteroarila, heterociclo, cicloalquila ou hidróxi; quando o substituinte é um grupo oxo (=O) ou tioxo (=S), dois hidrogênios são substituídos; “Alcóxi” refere-se a um grupo alquil-O-, compreendendo metóxi, etóxi, n-propóxi, iso-propóxi, n-butóxi, tert-butóxi, sec-butóxi, n-pentóxi, n-hexóxi, e 1,2-dimetilbutóxi, não limitantes, os quais também podem ser substituídos; “Alcanoíla” refere-se a um grupo alquil-C(=O)-, compreendendo metanoíla, etanoíla, n-propanoíla, iso-propanoíla, n-butanoíla, tert-butanoíla, sec-butanoíla, n-pentanoíla, n-hexanoíla e 1,2-dimetilbutanoíla, não limitantes, os quais também podem ser substituídos; “Alcoxicarbonila” refere-se a um grupo alquil-CO2-, compreendendo metoxicarbonila, etoxicarbonila, n-propoxicarbonila, iso-propoxicarbonila, n-butoxicarbonila, tert-butoxicarbonila, sec-butoxicarbonila, n-pentoxicarbonila, n-hexoxicarbonila, e 1,2-dimetilbutoxicarbonila, não limitantes, os quais também podem ser substituídos; “Alquilamino” refere-se a -NR2, no qual pelo menos um R é um grupo alquila e o segundo R é alquila ou hidrogênio; “Acilamino” refere-se a N(R)C(=O)R, no qual R é independentemente hidrogênio, alquila ou arila; “Halo” refere-se a flúor, cloro, bromo e iodo; “Haloalquila” refere-se a um alquila substituído por 1-4 grupos halo iguais ou diferentes que compreendem trifluormetila, 3-fluordodecila, 2-bromooctila e 3-bromo-6-cloroheptila, não limitantes. “Carbóxi” refere-se a -COOH.[0024] Where R can be:

aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl (cis and trans), heteroarylalkenyl (cis and trans), cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, alkyl or substituted alkyl; aryl or heteroaryl groups can be optionally substituted with 1 to 5 substituents, where each substituent is independently selected from the alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonyl, benzene sulfonyl, benzene, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfine, sulfa, sulfoamino, thiosulfo; “Alkyl”, which refers to a hydrocarbon radical (C1-C18) with a linear, branched or cyclic carbon chain, comprising methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl- 1-propyl (iso-butyl, -CH2CH (CH3) 2), 2-butyl (sec-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (tert-butyl, -C (CH3) 3 ), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl or 3,3-dimethyl-2-butyl; "Alkyl" can also be a substituent derived from divalent hydrocarbons such as alkylene; alkyl can be partially unsaturated providing an alkenyl or alkynyl; "Alkylene", which refers to a substituent derived from a saturated hydrocarbon of 1 to 18 carbon atoms in a linear, branched or cyclic carbon chain. Alkylene has two monovalent radical centers derived from the removal of two hydrogen atoms from the same carbon atom or from different carbon atoms of a parent alkane; Typical alkylenes include, but are not limited to, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-); "Alkenylene" which refers to a substituent derived from an unsaturated hydrocarbon of 1-18 carbon atoms of a linear, branched or cyclic carbon chain; alkenylene has two monovalent radical centers derived from the removal of two hydrogen atoms from the same carbon atom or from different carbon atoms of a parent alkene; among alkenylenes, a typical, non-limiting example is 1,2-ethylene (-CH = CH-); alkyl, alkylene and alkenylene may have intercalating groups of chains and comprise oxide (-O-), thio (-S-), amino (-N (H) -), methylene dioxide (-OCH2O-), methylene oxide (- OCH2-), carbonyl (-C (= O) -), carboxy (-C (= O) O-), carbonyldioxy (-OC (= O) O-), carboxylate (-OC (= O) -), imino (-C = NH-), sulfinyl (SO) or sulfonyl (SO2); "Intercalate groups" indicates that one or more groups are inserted between two adjacent carbon atoms or between a carbon atom of an alkyl group and the carbon atom of the group to which the alkyl is attached; the insertion of the group results in a stable substance in which the valence of any atom is not exceeded; “Aryl” refers to an unsaturated aromatic carbocyclic group containing 6 to 20 carbons forming a single ring (eg, phenyl) or multiple fused rings in which at least one ring is aromatic (eg, naphthyl, dihydrophenanthrenyl, fluorenyl or anthryl); Aryl can optionally be a divalent substituent, in this case called arylene; “Carbocycle” refers to a saturated, unsaturated or aromatic ring containing 3 to 8 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 30 carbon atoms when polycyclic; Carbocycles comprise cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spirila and naphthyl; "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 20 carbon atoms; cycloalkyl can be a single cyclic ring or multiple fused rings - comprises the simple cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl ring, not limiting; and multiple adamantanyl rings, non-limiting; cycloalkyl may optionally be at least partially unsaturated, thereby providing a cycloalkenyl; cycloalkyl may optionally be a divalent substituent resulting in a cycloalkylene; "Heteroaryl" is defined as a mono, bi or polycyclic system containing one, two or three aromatic rings and at least one nitrogen, oxygen or sulfur atom in an aromatic ring; heteroaryl may optionally be a divalent substituent called heteroarylene; heteroaryl comprises 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nHcarbazolyl, acridinyl, benzo [b] thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo [b, d] furanyl, furanyl, furazil, furanil, furazan, furanil, furazil, furanil, furanil, furazil, furanil, furanil, furanil, furanil, furazil, furazil, imidazolidinila, imidazolinila, imidizolila, indazolila, indolisinila, indolyl, isobenzofuranila, isoindolila, isoquinolila, isoquinolinila, isotiazolila, isoxazolyl, naftiridinila, oxazolyl, fenantridinila, fenantrolinila, fenarsazinila, fenazinila, fenotiazinila, fenoxatinila, fenoxazinila, ftalazinila, naftilpiridinila, pteridinila, purinila, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinolinyl, quinolizinyl, quinoxalinyl, thiadiazolyl, thiantrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl and xant; “Heterocycle” refers to a partially unsaturated or saturated ring system containing at least one atom of oxygen, nitrogen and sulfur; Heterocycles can be monocyclic, bicyclic or polycyclic; The heterocycle may also contain an oxo group (= O) attached to the ring; Heterocycles comprise, but are not limited to, 1,3-dihydrobenzofuranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-dithianyl, 2H-pyranyl, 2-pyrazolinyl, 4H-pyranyl, chromanylyl, imidazolidinyl, imidazolinyl, indolinyl, isochromalin, isoindolinyl, morpholinyl, piperazinyl, piperidinyl, piperidyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl and thiomorpholine; "Substituted" is used to indicate that one or more hydrogens in an atom has been replaced with a suitable group resulting in a stable substance in which no atom exceeds the valence; alkyl, alkylene, alkenylene, cycloalkyl and heterocycle can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino , nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxus, alkylthio, alkylsufinyl, alkylsulfonyl, cyano, acetamido, acetoxy, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonyl, benzene, benzoyl, benzene, benzene , benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfine, sulfa, sulfoamino, thiosulfo, NRXRY and / or COORX, where each RX and RY are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl or hydroxy; when the substituent is an oxo (= O) or thioxo (= S) group, two hydrogens are substituted; “Alkoxy” refers to an alkyl-O- group, comprising methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy, non-limiting, which can also be replaced; "Alkanoyl" refers to a C-alkyl group (= O) -, comprising methanoyl, ethanoyl, n-propanoyl, iso-propanoyl, n-butanoyl, tert-butanoyl, sec-butanoyl, n-pentanoyl, n-hexanoyl and 1,2-dimethylbutanoyl, non-limiting, which can also be substituted; "Alkoxycarbonyl" refers to an alkyl-CO2- group, comprising methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentoxicarbonyl, n-hexoxycarbonyl, and 1, 2-dimethylbutoxycarbonyl, non-limiting, which can also be replaced; "Alkylamino" refers to -NR2, in which at least one R is an alkyl group and the second R is alkyl or hydrogen; "Acylamino" refers to N (R) C (= O) R, in which R is independently hydrogen, alkyl or aryl; "Halo" refers to fluorine, chlorine, bromine and iodine; "Haloalkyl" refers to alkyl substituted by 1-4 the same or different halo groups comprising trifluoromethyl, 3-fluordodecyl, 2-bromooctyl and 3-bromo-6-chloroheptyl, non-limiting. "Carboxy" refers to -COOH.

[0025] A estrutura geral dos compostos está detalhada na Figura 1.[0025] The general structure of the compounds is detailed in Figure 1.

[0026] As composições farmacêuticas da presente tecnologia são caracterizadas por conter os compostos descritos acima e excipientes farmacêutica e farmacologicamente aceitáveis.[0026] The pharmaceutical compositions of the present technology are characterized by containing the compounds described above and pharmaceutically and pharmacologically acceptable excipients.

[0027] A invenção se refere ainda ao uso dos compostos ou das composições para fabricação de medicamentos para o tratamento da malária.[0027] The invention also refers to the use of compounds or compositions for the manufacture of medicines for the treatment of malaria.

[0028] A invenção pode ser mais bem compreendida pelos seguintes exemplos, não limitantes.[0028] The invention can be better understood by the following non-limiting examples.

Example 1 - Synthesis

[0029] Os cloretos de ácido necessários à obtenção dos derivados foram obtidos pela reação dos ácidos carboxílicos apropriados com cloreto de tionila, sob refluxo (Figuras 2 e 3). Os ácidos carboxílicos selecionados nesta invenção são derivados dos ácidos 3- e 4-hidroxicinâmicos, os quais foram preparados por modificação da reação de Knoenavenagel, conhecida como modificação de Doebner. A alilação dos ácidos cinâmicos com brometo de alila forneceu os derivados correspondentes (compostos 1 e 2 da Fig. 1). Redução desses por hidrogenação catalítica forneceu os derivados 3- ou 4-propil-hidrocinâmicos correspondentes (compostos 3 e 4 da Fig. 1). Redução prévia dos ácidos cinâmicos antes da condensação com o brometo de alila forneceu os derivados 3- ou 4-alil-di-hidrocinâmicos (compostos 5 e 6 da Fig. 1). Finalmente, reação dos ácidos 3- ou 4-hidrocinâmicos com brometo de n-propila forneceu os ácidos 3- ou 4-propilcinâmicos correspondentes (compostos 7 e 8 da Fig. 1).[0029] The acid chlorides necessary to obtain the derivatives were obtained by reacting the appropriate carboxylic acids with thionyl chloride, under reflux (Figures 2 and 3). The carboxylic acids selected in this invention are derived from 3- and 4-hydroxycinnamic acids, which were prepared by modifying the Knoenavenagel reaction, known as Doebner modification. Allylation of cinnamic acids with allyl bromide provided the corresponding derivatives (compounds 1 and 2 of Fig. 1). Reduction of these by catalytic hydrogenation gave the corresponding 3- or 4-propylhydrodynamic derivatives (compounds 3 and 4 of Fig. 1). Previous reduction of cinnamic acids before condensation with allyl bromide provided 3- or 4-allyl-dihydrocinamic derivatives (compounds 5 and 6 of Fig. 1). Finally, reaction of 3- or 4-hydrokinamic acids with n-propyl bromide provided the corresponding 3- or 4-propylcinamic acids (compounds 7 and 8 in Fig. 1).

Example 2 - In vitro tests - Cytotoxicity, cell viability and IC50 determination

[0030] A linhagem celular humana utilizada para análise de toxicidade foi WI-26VA4 (fibroblasto pulmonar ATCC CCL-95.1). O conteúdo do criotubo (linhagem celular com 5% de dimetilsulfóxido e soro), que estava mantido em nitrogênio líquido no banco de criopreservação (CryoPlus 7405/Thermo Scientific, EUA), foi descongelado a 37°C, transferido para um tubo de centrífuga de 15 mL (Corning, EUA) contendo 2 mL de meio RPMI 1640 incompleto e então submetido à centrifugação durante cinco minutos (mod. CS-6R, Becman, EUA). O sobrenadante foi descartado e a massa celular presente no fundo do tubo foi ressuspendida em 5 mL de meio RPMI 1640 suplementado com 10% de Soro Bovino Fetal (SBF) inativado pelo calor. A suspensão celular foi transferida para garrafas plásticas de cultivo celular T75 (75 cm2), tratada para promover a adesão celular, mantidas como monocamadas a 37°C em estufa (Thermo electron co. EUA) com atmosfera úmida de 5% de CO2 por 72 horas. Para a manutenção da linhagem, após a adesão celular, o meio de cultura foi substituído a cada 48 horas de forma a garantir a renovação dos nutrientes. Sendo que a morfologia celular e formação da monocamada foram observadas ao microscópio invertido com a objetiva em um aumento de 40x no mesmo intervalo de tempo (modelo Olympus, CKX 41). No momento em que a cultura apresentou formação de monocamada com 80% de confluência fez-se um repique utilizando a enzima tripsina (1:250) para remover as células aderidas no fundo da garrafa. As células soltas foram ressuspendidas em 5mL de meio e recolhidas em tubo de centrífuga. O tubo foi centrifugado por 5 minutos e o sobrenadante descartado. A massa celular foi ressuspendida em 5mL de meio e 50µL da suspensão foi retirada para misturar com 50µL de azul de tripan para contagem manual de células viáveis em câmara de neubauer ao microscópio óptico com a objetiva em um aumento de 20x. Após contagem, as células foram distribuídas em placas de 96 poços para realização do ensaio de viabilidade celular.[0030] The human cell line used for toxicity analysis was WI-26VA4 (pulmonary fibroblast ATCC CCL-95.1). The cryotube content (cell line with 5% dimethylsulfoxide and serum), which was kept in liquid nitrogen in the cryopreservation bank (CryoPlus 7405 / Thermo Scientific, USA), was thawed at 37 ° C, transferred to a centrifuge tube. 15 mL (Corning, USA) containing 2 mL of incomplete RPMI 1640 medium and then subjected to centrifugation for five minutes (mod. CS-6R, Becman, USA). The supernatant was discarded and the cell mass at the bottom of the tube was resuspended in 5 mL of RPMI 1640 medium supplemented with 10% Fetal Bovine Serum (SBF) inactivated by heat. The cell suspension was transferred to T75 cell culture plastic bottles (75 cm2), treated to promote cell adhesion, maintained as monolayers at 37 ° C in an oven (Thermo electron co. USA) with a humid atmosphere of 5% CO2 for 72 hours. hours. For the maintenance of the lineage, after cell adhesion, the culture medium was replaced every 48 hours in order to guarantee the renewal of nutrients. The cell morphology and formation of the monolayer were observed under an inverted microscope with the objective at a 40x magnification in the same time interval (Olympus model, CKX 41). When the culture showed a monolayer formation with 80% confluence, a peak was made using the enzyme trypsin (1: 250) to remove the adhered cells at the bottom of the bottle. The loose cells were resuspended in 5mL of medium and collected in a centrifuge tube. The tube was centrifuged for 5 minutes and the supernatant was discarded. The cell mass was resuspended in 5mL of medium and 50µL of the suspension was removed to mix with 50µL of trypan blue for manual counting of viable cells in a neubauer chamber under the optical microscope with the objective in a 20x magnification. After counting, the cells were distributed in 96-well plates to perform the cell viability assay.

[0031] A citotoxicidade dos compostos sintéticos em linhagem celular foi avaliada pelo ensaio do MTT [3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium], que tem por objetivo avaliar a viabilidade celular. O MTT é um sal tetrazólico que é clivado por desidrogenases mitocondriais presentes apenas em células metabolicamente viáveis formando um cristal de cor violeta, insolúvel em água, o formazam, que é solubilizado em dimetilsulfóxido (DMSO). Assim sendo, a produção de formazan reflete o estado funcional da cadeia respiratória (Mosmann 1983). Para cálculo da viabilidade celular faz-se leitura da absorbância a 550 nm em um leitor de placas de Elisa. Para este ensaio, as células aderentes foram transferidas para uma placa de 96 poços na concentração de 1 x 106 células/ poço, em meio RPMI . A placa foi incubada em estufa de CO2, a 37°C e atmosfera úmida de CO2 a 5% por 24h. Após esse período os poços foram lavados com solução salina tamponada (PBS). Os compostos a serem testados foram diluídos a fim de obter as concentrações de 100; 10; 1; 0,1 e 0,01 μg/mL em meio de cultivo, contendo 1% de soro fetal bovino (SFB) e adicionados à placa. Após 48 horas de incubação, os poços foram lavados com PBS novamente, e adicionou-se 100µL do sal tetrazólico MTT na concentração de 5 mg/mL, diluído em meio incompleto. A placa foi incubada por 3 horas. Então, retirou-se o sobrenadante e aplicou-se 50µL de DMSO em cada poço para solubilizar os cristais de formazan. A absorbância por poço foi medida no leitor de microplacas Spectramax M5E a um comprimento de onda de 550nm utilizando o Gen5 (Data Analysis Software - Bio-Tek). Os dados foram analisados a partir de três experimentos independentes. A concentração que inibiu 50% do crescimento das células (IC50) na presença dos compostos testes foi determinada em comparação com células cultivadas sem a presença de compostos (considerada 100% de viabilidade).[0031] The cytotoxicity of synthetic compounds in cell line was evaluated by the MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium] assay, which aims to assess cell viability. MTT is a tetrazolic salt that is cleaved by mitochondrial dehydrogenases present only in metabolically viable cells forming a violet-colored crystal, insoluble in water, formazam, which is solubilized in dimethylsulfoxide (DMSO). Therefore, formazan production reflects the functional state of the respiratory chain (Mosmann 1983). To calculate cell viability, absorbance at 550 nm is read on an Elisa plate reader. For this assay, adherent cells were transferred to a 96-well plate at a concentration of 1 x 106 cells / well in RPMI medium. The plate was incubated in a CO2 oven at 37 ° C and a humid atmosphere of 5% CO2 for 24 hours. After this period, the wells were washed with buffered saline (PBS). The compounds to be tested were diluted in order to obtain concentrations of 100; 10; 1; 0.1 and 0.01 μg / mL in culture medium, containing 1% fetal bovine serum (SFB) and added to the plate. After 48 hours of incubation, the wells were washed with PBS again, and 100 µL of the tetrazolic salt MTT was added at a concentration of 5 mg / mL, diluted in incomplete medium. The plate was incubated for 3 hours. Then, the supernatant was removed and 50 µL of DMSO was applied to each well to solubilize the formazan crystals. The absorbance per well was measured in the Spectramax M5E microplate reader at a wavelength of 550nm using Gen5 (Data Analysis Software - Bio-Tek). The data were analyzed from three independent experiments. The concentration that inhibited 50% of cell growth (IC50) in the presence of the test compounds was determined in comparison with cells cultured without the presence of compounds (considered 100% viability).

[0032] A inibição do crescimento de 50% da linhagem celular foi obtida por meio de uma curva dose-resposta, em função da regressão linear. Foi utilizado o programa OriginPro versão 8.0 (OriginLb Corporation, Northampton, MA, USA) para confecção das curvas de IC50. Nos testes realizados, a citotoxicidade em linhagem celular normal (WI-26VA4) foi registrada como a porcentagem de redução na absorbância. Os compostos não apresentaram atividade citotóxica, com valores de IC50 > 356µM (Tab. 1).[0032] The inhibition of the 50% growth of the cell line was obtained by means of a dose-response curve, as a function of linear regression. The OriginPro program version 8.0 (OriginLb Corporation, Northampton, MA, USA) was used to make the IC50 curves. In the tests performed, cytotoxicity in normal cell line (WI-26VA4) was recorded as the percentage of reduction in absorbance. The compounds did not show cytotoxic activity, with IC 50 values> 356 µM (Table 1).

[0033] Cepas de P. falciparum cloroquina-resistente (W2) foram cultivadas em hemácias humanas sob condições estabelecidas por Trager e Jensen (Trager, W. and J. B. Jensen (2005). "Human Malaria Parasites in Continuous Culture." Journal of Parasitology 91(3): 484-486). As hemácias foram mantidas em placas de petri com meio RPMI-1640 suplementado com 25mM de HEPES, 21mM de bicarbonato de sódio, 300μΜ de hipoxantina, 2g/L e 1g/L de glicose, 40μg/ml de gentamicina, 10% (v/v) de plasma humano inativado (meio completo) e hematócrito a 5%. As hemácias foram lavadas com meio RPMI incompleto através de centrifugação a 2000 rpm por 30 minutos para retirada das células brancas. As placas de petri contendo os parasitos foram condicionadas à 37oC em dissecadores, nos quais a concentração gasosa (O2 5%, CO2 5% e N 90%) foi obtida pela combustão de uma vela. Diariamente foi realizada a troca de meio completo do cultivo.[0033] Chloroquine-resistant P. falciparum strains (W2) were grown in human red cells under conditions established by Trager and Jensen (Trager, W. and JB Jensen (2005). "Human Malaria Parasites in Continuous Culture." Journal of Parasitology 91 (3): 484-486). Red blood cells were kept in petri dishes with RPMI-1640 medium supplemented with 25mM HEPES, 21mM sodium bicarbonate, 300μΜ hypoxanthine, 2g / L and 1g / L glucose, 40μg / ml gentamicin, 10% (v / v) inactivated human plasma (complete medium) and 5% hematocrit. Red blood cells were washed with incomplete RPMI medium by centrifugation at 2000 rpm for 30 minutes to remove white cells. The petri dishes containing the parasites were conditioned at 37oC in desiccators, in which the gas concentration (O2 5%, CO2 5% and N 90%) was obtained by burning a candle. The complete culture medium was changed daily.

[0034] A parasitemia foi monitorada diariamente através de esfregaços sanguíneos em lâminas, secos ao ar, fixados com metanol e corados com Giemsa 0,93% em água tamponada em pH=6,8 (5 gotas de corante para cada 1mL de água tamponada). Após 20 minutos com o corante, o esfregaço foi lavado em água corrente, seco ao ar novamente e levado ao microscópio óptico com aumento de 1000x para proceder à contagem. A parasitemia foi estimada pelo número total de hemácias por campo microscópico em um total de 50 a 100 campos, estimando-se o número de hemácias infectadas.[0034] The parasitemia was monitored daily through blood smears on slides, air dried, fixed with methanol and stained with Giemsa 0.93% in buffered water at pH = 6.8 (5 drops of dye for each 1mL of buffered water) ). After 20 minutes with the dye, the smear was washed under running water, air dried again and taken to an optical microscope with a 1000x magnification to proceed with the counting. Parasitemia was estimated by the total number of red cells per microscopic field in a total of 50 to 100 fields, estimating the number of infected red cells.

[0035] Para o ensaio de sincronização dos parasitos, antes de cada teste de atividade antimalárica, os parasitos cultivados foram sincronizados pelo método do sorbitol (Lambros and Vanderberg 1979). Na placa de cultivo contendo o parasito, o meio foi retirado e adicionou-se 10mL de sorbitol e este foi homogenizado. Incubou-se a placa de petri em dissecador com a concentração gasosa (O2 5%, CO2 5% e N2 90%) a 37°C por 10 minutos. Após esse tempo, transferiu-se todo o conteúdo para um tubo falcon de 15mL e centrifugou-se por 5 min. O sobrenadante foi retirado e o sedimento ressuspendido com meio RPMI suplementado com plasma humano inativado, ajustando-se o hematócrito para 2%. Posteriormente, foi realizado um esfregaço sanguíneo para determinação da parasitemia. O hematócrito e a parasitemia, ambos a 2%, foram ajustados com a adição de hemácias e meio RPMI completo. Esse método permite selecionar os trofozoítos jovens (anéis) e assim garantir que o composto teste atue logo no início do ciclo eritrocítico.[0035] For the parasite synchronization test, before each antimalarial activity test, the cultivated parasites were synchronized by the sorbitol method (Lambros and Vanderberg 1979). In the culture plate containing the parasite, the medium was removed and 10mL of sorbitol was added and it was homogenized. The petri dish was incubated in a dissector with the gas concentration (O2 5%, CO2 5% and N2 90%) at 37 ° C for 10 minutes. After that time, the entire contents were transferred to a 15mL falcon tube and centrifuged for 5 min. The supernatant was removed and the pellet resuspended with RPMI medium supplemented with inactivated human plasma, adjusting the hematocrit to 2%. Subsequently, a blood smear was performed to determine the parasitemia. Hematocrit and parasitemia, both at 2%, were adjusted with the addition of red blood cells and complete RPMI medium. This method allows the selection of young trophozoites (rings) and thus ensures that the test compound acts early in the erythrocytic cycle.

[0036] As culturas sincronizadas com 2% de parasitemia no estágio de anel e 2% de hematócrito foram distribuídas em microplacas de 96 poços contendo 200µl por poço. Os compostos, a serem testados foram adicionados em diferentes concentrações à placa contendo os parasitos. Inicialmente foi feita uma triagem com duas concentrações, 50 e 25 μg/mL, para verificar se os compostos apresentavam atividade, posteriormente realizou-se a diluição seriada. Em cada placa de teste havia poços controles constituídos por hemácias infectadas (controle positivo) em meio de cultivo sem adição de compostos. A cloroquina foi utilizada em cada experimento como composto padrão. Após 48 horas de incubação em dissecadores a 37 °C, com troca diária de meio, foram confeccionados esfregaços correspondentes a cada poço. Depois de fixados com metanol e corados com Giemsa, os esfregaços foram utilizados para proceder à contagem da parasitemia ao microscópio óptico (1000x). A atividade dos compostos foi expressa pela porcentagem de redução da parasitemia em relação aos controles sem fármacos, que foi considerada como 100% de crescimento do parasito. Os experimentos foram realizados em triplicatas e a leitura através de lâminas codificadas. A metade da concentração máxima inibitória (IC50) foi determinada. A parasitemia foi calculada conforme a fórmula abaixo:

[0036] Cultures synchronized with 2% ring-stage parasitemia and 2% hematocrit were distributed in 96-well microplates containing 200µl per well. The compounds to be tested were added in different concentrations to the plate containing the parasites. Initially, a screening was carried out with two concentrations, 50 and 25 μg / mL, to check if the compounds had activity, then the serial dilution was performed. In each test plate there were control wells made up of infected red cells (positive control) in culture medium without addition of compounds. Chloroquine was used in each experiment as a standard compound. After 48 hours of incubation in desiccators at 37 ° C, with daily change of medium, smears corresponding to each well were made. After fixed with methanol and stained with Giemsa, the smears were used to count the parasitemia under an optical microscope (1000x). The activity of the compounds was expressed by the percentage of reduction of parasitemia in relation to controls without drugs, which was considered as 100% of growth of the parasite. The experiments were carried out in triplicates and reading through coded slides. Half of the maximum inhibitory concentration (IC50) was determined. Parasitemia was calculated according to the formula below:

[0037] O índice de seletividade (IS), que corresponde à relação entre as atividades citotóxicas e antiparasitárias de cada composto, foi obtido através da razão entre o valor do IC50: SI = IC50 WI-26VA4 / IC50 P. falciparum. Em que o valor de SI deve ser maior que 10 para indicar alta seletividade e um potencial antimalárico (Katsuno, K., J. N. Burrows, et al. (2015). "Hit and lead criteria in drug discovery for infectious diseases of the developing world." Nat Rev Drug Discov 14(11): 751-758).[0037] The selectivity index (IS), which corresponds to the relationship between the cytotoxic and antiparasitic activities of each compound, was obtained through the ratio between the IC50 value: SI = IC50 WI-26VA4 / IC50 P. falciparum. Where the SI value must be greater than 10 to indicate high selectivity and an antimalarial potential (Katsuno, K., JN Burrows, et al. (2015). "Hit and lead criteria in drug discovery for infectious diseases of the developing world . "Nat Rev Drug Discov 14 (11): 751-758).

[0038] O teste tradicional para verificação do efeito antimalárico dos compostos foi realizado a partir de quatro experimentos com a concentração padrão da glicose no meio de cultura (2g/L) sendo o último experimento, para obter-se a confirmação do IC50 dos compostos. O experimento I iniciou-se com as concentrações dos compostos (Tab. 1) em 50μg/mL e 25µg/mL (concentrações aplicadas em triplicata). Com o procedimento realizado foi possível selecionar os compostos mais ativos (1, 2 e 3) com redução da parasitemia maior que 70% na concentração de 25 μg/mL dos compostos. No experimento II foi realizada a primeira diluição seriada (concentração dos compostos de 50µg/mL a 0,39μg/mL - aplicadas em triplicata). No experimento III (concentração dos compostos 5µg/mL a 0,03µg/mL - aplicadas em triplicata) também não houve determinação da IC50. A partir do experimento IV (concentração dos compostos 0,31µg/mL a 0,005µg/mL - aplicadas em triplicata), foi possível determinar os valores de IC50 (Tab. 1). Portanto esse procedimento foi realizado mais duas vezes, com as mesmas concentrações (0,31µg/mL a 0,005µg/mL), para confirmação dos resultados e obtenção das triplicatas.[0038] The traditional test to check the antimalarial effect of the compounds was carried out from four experiments with the standard concentration of glucose in the culture medium (2g / L) being the last experiment, to obtain confirmation of the IC50 of the compounds . Experiment I started with the concentrations of the compounds (Table 1) in 50μg / mL and 25 µg / mL (concentrations applied in triplicate). With the procedure performed, it was possible to select the most active compounds (1, 2 and 3) with a reduction of parasitemia greater than 70% in the concentration of 25 μg / mL of the compounds. In experiment II, the first serial dilution was performed (concentration of compounds from 50µg / mL to 0.39μg / mL - applied in triplicate). In experiment III (concentration of compounds 5µg / mL to 0.03µg / mL - applied in triplicate) there was also no determination of the IC50. From experiment IV (concentration of compounds 0.31µg / mL to 0.005µg / mL - applied in triplicate), it was possible to determine the IC50 values (Table 1). Therefore, this procedure was performed two more times, with the same concentrations (0.31 µg / mL to 0.005 µg / mL), to confirm the results and obtain triplicates.

[0039] Após a determinação do IC50 para os derivados glicosídeos contra a cepa P. falciparum (W2) cultivada em meio de cultura com glicose na concentração de 2g/L foi realizada outra triplicata do experimento, porém usando o meio de cultura com glicose na concentração de 1 g/L. A redução da glicose neste experimento foi realizada para verificar se a concentração de glicose do meio de cultura poderia influenciar na determinação da IC50, uma vez que o alvo estudado é transportador de hexose. No entanto não houve variação significativa nos experimentos realizados com 2g/L e 1g/L de glicose (Tab. 1).[0039] After determining the IC50 for the glycoside derivatives against the P. falciparum (W2) strain grown in a culture medium with glucose at a concentration of 2g / L, another triplicate of the experiment was performed, but using the culture medium with glucose in the concentration of 1 g / L. The glucose reduction in this experiment was carried out to verify whether the glucose concentration of the culture medium could influence the determination of the IC50, since the target studied is hexose transporter. However, there was no significant variation in the experiments carried out with 2g / L and 1g / L of glucose (Table 1).

[0040] Na determinação da IC50 com 2g/L de glicose no meio, o valor variou entre 0,069μΜ a 0,156μΜ; para a IC50 com 1g/L de glicose no meio, o valor variou entre 0,074μΜ a 0,169μΜ, estando o composto 1 presente nos dois experimentos com menor valor de IC50, sugerindo como um potencial fármaco. Além disso, obteve-se o IS dos compostos (Tab. 1). Estes dados indicam a PfHT como um potencial alvo quimioterapêutico. Os compostos 1, 2 e 3 foram ativos com IC50 semelhante ao antimalárico controle (cloroquina) e o derivado de D-glicose (controle sintetizado - 3361).

3361: 3-O-(undec-10-en)-yl-D-glucose. UGLN- N-undecernil-D-glicosamina[0040] In determining the IC50 with 2g / L of glucose in the medium, the value varied between 0.069μΜ to 0.156μΜ; for the IC50 with 1g / L of glucose in the medium, the value varied between 0.074μΜ to 0.169μΜ, with compound 1 being present in the two experiments with a lower IC50 value, suggesting as a potential drug. In addition, the IS of the compounds was obtained (Tab. 1). These data indicate PfHT as a potential chemotherapeutic target.

Compounds

1, 2 and 3 were active with IC 50 similar to the antimalarial control (chloroquine) and the derivative of D-glucose (synthesized control - 3361).

3361: 3-O- (undec-10-en) -yl-D-glucose. UGLN- N-undecernyl-D-glucosamine

Example 3 - Glucose uptake test

[0041] Para o teste de captação de glicose foi utilizado o Kit Glicose PAP Liquiform (Labtest Diagnóstica) o qual é um sistema enzimático para determinação da glicose no sangue por ponto final.[0041] For the glucose uptake test, the PAP Liquiform Glucose Kit (Labtest Diagnóstica) was used, which is an enzymatic system for determining blood glucose by end point.

[0042] A captação foi observada na presença e ausência dos compostos em intervalos de 60 minutos durante 360 minutos em cultura de P. falciparum com retenção de glicose e cultura de hemácias, ambas com hematócrito a 5%.[0042] Uptake was observed in the presence and absence of compounds at 60-minute intervals for 360 minutes in P. falciparum culture with glucose retention and erythrocyte culture, both with 5% hematocrit.

[0043] Para este ensaio foi escolhido o composto 1 por apresentar menor valor absoluto de IC50 e o 3361 como controle. Os resultados dos ensaios de captação de glicose permitem inferir que nas culturas de P. falciparum sem o composto há captação e consequente consumo de glicose pelo parasito devido seu alto metabolismo (Patel, Staines et al. 2008). Na presença dos compostos testados (1 e 3361), observou-se diminuição da captação de glicose, indicando a eliminação dos parasitos pelo composto (Figuras 4 a 7 e Tabelas 2 a 5).

[0043] For this test, compound 1 was chosen because it has the lowest absolute value of IC50 and 3361 as a control. The results of glucose uptake tests allow us to infer that in P. falciparum cultures without the compound there is uptake and consequent consumption of glucose by the parasite due to its high metabolism (Patel, Staines et al. 2008). In the presence of the tested compounds (1 and 3361), a decrease in glucose uptake was observed, indicating the elimination of parasites by the compound (Figures 4 to 7 and Tables 2 to 5).

[0044] Dos dados demonstrados nos gráficos (Fig. 4 a 7) e tabelas 2 a 5 a partir da análise estatística realizada pode-se inferir que há diferença significativa com p < 0,05 quando se compara a captação de glicose entre os intervalos 60 a 360 na presença e ausência dos compostos 1 e 3361 para cepa de P. falciparum (W2). Estes dados sugerem que a captação de glicose pode estar sendo inibida pela presença dos compostos.[0044] From the data shown in the graphs (Fig. 4 to 7) and tables 2 to 5 from the statistical analysis performed, it can be inferred that there is a significant difference with p <0.05 when comparing glucose uptake between intervals 60 to 360 in the presence and absence of compounds 1 and 3361 for the P. falciparum (W2) strain. These data suggest that glucose uptake may be being inhibited by the presence of the compounds.

Claims

D-glucosamine derivatives characterized by the following general structure:

where R can be:

aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl (cis and trans), heteroarylalkenyl (cis and trans), cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, alkyl or substituted alkyl; aryl or heteroaryl groups can be optionally substituted with 1 to 5 substituents, where each substituent is independently selected from the alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonyl, benzene sulfonyl, benzene, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfine, sulfa, sulfoamino, thiosulfo; “Alkyl”, which refers to a hydrocarbon radical (C1-C18) with a linear, branched or cyclic carbon chain, comprising methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl- 1-propyl (iso-butyl, -CH2CH (CH3) 2), 2-butyl (sec-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (tert-butyl, - C (CH3) 3 ), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl or 3,3-dimethyl-2-butyl; "Alkyl" can also be a substituent derived from divalent hydrocarbons such as alkylene; alkyl can be partially unsaturated providing an alkenyl or alkynyl; "Alkylene", which refers to a substituent derived from a saturated hydrocarbon of 1 to 18 carbon atoms in a linear, branched or cyclic carbon chain; alkylene has two monovalent radical centers derived from the removal of two hydrogen atoms from the same carbon atom or from different carbon atoms of a parent alkane; Typical alkylenes comprise, but are not limited to, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-); "Alkenylene" which refers to a substituent derived from an unsaturated hydrocarbon of 1-18 carbon atoms of a linear, branched or cyclic carbon chain; alkenylene has two monovalent radical centers derived from the removal of two hydrogen atoms from the same carbon atom or from different carbon atoms of a parent alkene; among alkenylenes, a typical, non-limiting example is 1,2-ethylene (-CH = CH-); alkyl, alkylene and alkenylene may have intercalating groups of chains and comprise oxide (-O-), thio (-S-), amino (-N (H) -), methylene dioxide (-OCH2O-), methylene oxide (- OCH2-), carbonyl (-C (= O) -), carboxy (-C (= O) O-), carbonyldioxy (-OC (= O) O-), carboxylate (-OC (= O) -), imino (-C = NH-), sulfinyl (SO) or sulfonyl (SO2); "Interleaving groups" indicates that one or more groups are inserted between two adjacent carbon atoms or between a carbon atom of an alkyl group and the carbon atom of the group to which the alkyl is attached; the insertion of the group results in a stable substance in which the valence of any atom is not exceeded; “Aryl” refers to an unsaturated aromatic carbocyclic group containing 6 to 20 carbons forming a single ring (eg, phenyl) or multiple fused rings in which at least one ring is aromatic (eg, naphthyl, dihydrophenanthrenyl, fluorenyl or anthryl); Aryl can optionally be a divalent substituent, in this case called arylene; “Carbocycle” refers to a saturated, unsaturated or aromatic ring containing 3 to 8 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 30 carbon atoms when polycyclic; Carbocycles comprise cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spirila and naphthyl; "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 20 carbon atoms; cycloalkyl can be a single cyclic ring or multiple fused rings - comprises the simple cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl ring, not limiting; and multiple adamantanyl rings, non-limiting; cycloalkyl may optionally be at least partially unsaturated, thereby providing a cycloalkenyl; cycloalkyl may optionally be a divalent substituent resulting in a cycloalkylene; "Heteroaryl" is defined as a mono, bi or polycyclic system containing one, two or three aromatic rings and at least one nitrogen, oxygen or sulfur atom in an aromatic ring; heteroaryl may optionally be a divalent substituent called heteroarylene; heteroaryl comprises 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nHcarbazolyl, acridinyl, benzo [b] thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo [b, d] furanyl, furanyl, furazil, furanil, furazan, furanil, furazil, furanil, furanil, furazil, furanil, furanil, furanil, furanil, furazil, furazil, imidazolidinila, imidazolinila, imidizolila, indazolila, indolisinila, indolyl, isobenzofuranila, isoindolila, isoquinolila, isoquinolinila, isotiazolila, isoxazolyl, naftiridinila, oxazolyl, fenantridinila, fenantrolinila, fenarsazinila, fenazinila, fenotiazinila, fenoxatinila, fenoxazinila, ftalazinila, naftilpiridinila, pteridinila, purinila, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinolinyl, quinolizinyl, quinoxalinyl, thiadiazolyl, thiantrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl and xant; “Heterocycle” refers to a partially unsaturated or saturated ring system containing at least one atom of oxygen, nitrogen and sulfur; Heterocycles can be monocyclic, bicyclic or polycyclic; The heterocycle may also contain an oxo group (= O) attached to the ring; Heterocycles comprise, but are not limited to, 1,3-dihydrobenzofuranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-dithianyl, 2H-pyranyl, 2-pyrazolinyl, 4Hpyranyl, chromanylil, imidazolidinyl, imidazolinyl, indolinyl, isochromalin, isoindolinyl, morpholinyl, piperazinyl, piperidinyl, piperidyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl and thiomorpholine; "Substituted" is used to indicate that one or more hydrogens in an atom has been replaced with a suitable group resulting in a stable substance in which no atom exceeds the valence; alkyl, alkylene, alkenylene, cycloalkyl and heterocycle can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino , nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxus, alkylthio, alkylsufinyl, alkylsulfonyl, cyano, acetamido, acetoxy, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonyl, benzene, benzoyl, benzene, benzene , benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfine, sulfa, sulfoamino, thiosulfo, NRXRY and / or COORX, where each RX and RY are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl or hydroxy; when the substituent is an oxo (= O) or thioxo (= S) group, two hydrogens are substituted; “Aloxy” refers to an alkyl-O- group, comprising methoxy, ethoxy, n-propoxy, iso-propoxy, nbutoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy, non-limiting, which can also be replaced; "Alkanoyl" refers to a C-alkyl (= O) - group, comprising methanoyl, ethanoyl, n-propanoyl, iso-propanoyl, n-butanoyl, tert-butanoyl, sec-butanoyl, n-pentanoyl, nhexanoyl and 1 , 2-dimethylbutanoyl, non-limiting, which can also be substituted; "Alkoxycarbonyl" refers to an alkyl-CO2- group, comprising methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, secbutoxycarbonyl, n-pentoxicarbonyl, n-hexoxycarbonyl, and 1,2-dimethylcarbonyl, and 1,2-dimethyl non-limiting, which can also be replaced; "Alkylamino" refers to –NR2, in which at least one R is an alkyl group and the second R is alkyl or hydrogen; "Acylamino" refers to N (R) C (= O) R, in which R is independently hydrogen, alkyl or aryl; "Halo" refers to fluorine, chlorine, bromine and iodine; "Haloalkyl" refers to alkyl substituted by 1-4 the same or different halo groups comprising trifluoromethyl, 3-fluordodecyl, 2-bromooctyl and 3-bromo-6-chloroheptyl, non-limiting; "Carboxy" refers to -COOH.

Pharmaceutical compositions characterized by containing the compounds defined in claim 1, of general structure:

where R can be:

aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl (cis and trans), heteroarylalkenyl (cis and trans), cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, alkyl or substituted alkyl; aryl or heteroaryl groups can be optionally substituted with 1 to 5 substituents, where each substituent is independently selected from the alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonyl, benzene sulfonyl, benzene, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl, benzoyl carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfine, sulfa, sulfoamino, thiosulfo; “Alkyl”, which refers to a hydrocarbon radical (C1-C18) with a linear, branched or cyclic carbon chain, comprising methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl- 1-propyl (iso-butyl, -CH2CH (CH3) 2), 2-butyl (sec-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (tert-butyl, - C (CH3) 3 ), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl or 3,3-dimethyl-2-butyl; "Alkyl" can also be a substituent derived from divalent hydrocarbons such as alkylene; alkyl can be partially unsaturated providing an alkenyl or alkynyl; "Alkylene", which refers to a substituent derived from a saturated hydrocarbon of 1 to 18 carbon atoms in a linear, branched or cyclic carbon chain; alkylene has two monovalent radical centers derived from the removal of two hydrogen atoms from the same carbon atom or from different carbon atoms of a parent alkane; Typical alkylenes comprise, but are not limited to, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-); "Alkenylene" which refers to a substituent derived from an unsaturated hydrocarbon of 1-18 carbon atoms of a linear, branched or cyclic carbon chain; alkenylene has two monovalent radical centers derived from the removal of two hydrogen atoms from the same carbon atom or from different carbon atoms of a parent alkene; among alkenylenes, a typical, non-limiting example is 1,2-ethylene (-CH = CH-); alkyl, alkylene and alkenylene may have intercalating groups of chains and comprise oxide (-O-), thio (-S-), amino (-N (H) -), methylene dioxide (-OCH2O-), methylene oxide (- OCH2-), carbonyl (-C (= O) -), carboxy (-C (= O) O-), carbonyldioxy (-OC (= O) O-), carboxylate (-OC (= O) -), imino (-C = NH-), sulfinyl (SO) or sulfonyl (SO2); "Interleaving groups" indicates that one or more groups are inserted between two adjacent carbon atoms or between a carbon atom of an alkyl group and the carbon atom of the group to which the alkyl is attached; the insertion of the group results in a stable substance in which the valence of any atom is not exceeded; “Aryl” refers to an unsaturated aromatic carbocyclic group containing 6 to 20 carbons forming a single ring (eg, phenyl) or multiple fused rings in which at least one ring is aromatic (eg, naphthyl, dihydrophenanthrenyl, fluorenyl or anthryl); Aryl can optionally be a divalent substituent, in this case called arylene; “Carbocycle” refers to a saturated, unsaturated or aromatic ring containing 3 to 8 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 30 carbon atoms when polycyclic; Carbocycles comprise cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spirila and naphthyl; "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 20 carbon atoms; cycloalkyl can be a single cyclic ring or multiple fused rings - comprises the simple cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl ring, not limiting; and multiple adamantanyl rings, non-limiting; cycloalkyl may optionally be at least partially unsaturated, thereby providing a cycloalkenyl; cycloalkyl may optionally be a divalent substituent resulting in a cycloalkylene; "Heteroaryl" is defined as a mono, bi or polycyclic system containing one, two or three aromatic rings and at least one nitrogen, oxygen or sulfur atom in an aromatic ring; heteroaryl may optionally be a divalent substituent called heteroarylene; heteroaryl comprises 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nHcarbazolyl, acridinyl, benzo [b] thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo [b, d] furanyl, furanyl, furazil, furanil, furazan, furanil, furazil, furanil, furanil, furazil, furanil, furanil, furanil, furanil, furazil, furazil, imidazolidinila, imidazolinila, imidizolila, indazolila, indolisinila, indolyl, isobenzofuranila, isoindolila, isoquinolila, isoquinolinila, isotiazolila, isoxazolyl, naftiridinila, oxazolyl, fenantridinila, fenantrolinila, fenarsazinila, fenazinila, fenotiazinila, fenoxatinila, fenoxazinila, ftalazinila, naftilpiridinila, pteridinila, purinila, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinolinyl, quinolizinyl, quinoxalinyl, thiadiazolyl, thiantrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl and xant; “Heterocycle” refers to a partially unsaturated or saturated ring system containing at least one atom of oxygen, nitrogen and sulfur; Heterocycles can be monocyclic, bicyclic or polycyclic; The heterocycle may also contain an oxo group (= O) attached to the ring; Heterocycles comprise, but are not limited to, 1,3-dihydrobenzofuranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-dithianyl, 2H-pyranyl, 2-pyrazolinyl, 4Hpyranyl, chromanylil, imidazolidinyl, imidazolinyl, indolinyl, isochromalin, isoindolinyl, morpholinyl, piperazinyl, piperidinyl, piperidyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl and thiomorpholine; "Substituted" is used to indicate that one or more hydrogens in an atom has been replaced with a suitable group resulting in a stable substance in which no atom exceeds the valence; alkyl, alkylene, alkenylene, cycloalkyl and heterocycle can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino , nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxus, alkylthio, alkylsufinyl, alkylsulfonyl, cyano, acetamido, acetoxy, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonyl, benzene, benzoyl, benzene, benzene , benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanate, sulfamoyl, sulfinamoyl, sulfine, sulfa, sulfoamino, thiosulfo, NRXRY and / or COORX, where each RX and RY are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl or hydroxy; when the substituent is an oxo (= O) or thioxo (= S) group, two hydrogens are substituted; “Aloxy” refers to an alkyl-O- group, comprising methoxy, ethoxy, n-propoxy, iso-propoxy, nbutoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy, non-limiting, which can also be replaced; "Alkanoyl" refers to a C-alkyl (= O) - group, comprising methanoyl, ethanoyl, n-propanoyl, iso-propanoyl, n-butanoyl, tert-butanoyl, sec-butanoyl, n-pentanoyl, nhexanoyl and 1 , 2-dimethylbutanoyl, non-limiting, which can also be substituted; "Alkoxycarbonyl" refers to an alkyl-CO2- group, comprising methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, secbutoxycarbonyl, n-pentoxicarbonyl, n-hexoxycarbonyl, and 1,2-dimethylcarbonyl, and 1,2-dimethyl non-limiting, which can also be replaced; "Alkylamino" refers to –NR2, in which at least one R is an alkyl group and the second R is alkyl or hydrogen; "Acylamino" refers to N (R) C (= O) R, in which R is independently hydrogen, alkyl or aryl; "Halo" refers to fluorine, chlorine, bromine and iodine; "Haloalkyl" refers to an alkyl substituted by 1-4 the same or different halo groups comprising trifluoromethyl, 3-fluordodecyl, 2-bromooctyl and 3-bromo-6-chloroheptyl, non-limiting; “Carboxy” refers to –COOH; and pharmaceutically and pharmacologically acceptable excipients.

Use of the compounds, defined in claim 1, characterized by being for the manufacture of drugs for the treatment of malaria.

Use of the compositions defined in claim 2, characterized by being for the manufacture of drugs for the treatment of malaria.