Antimalarial potential of quinones isolated from plants: an integrative review Potencial antimalárico de quinonas isoladas de plantas: uma revisão integrativa Potencial antipalúdico de quinonas aislados de plantas: una revision integradora

Antimalarial treatment is often associated with the resistance developed by Plasmodium which generate ineffective drug treatment. Based on this, the search for therapeutic alternatives is necessary and urgent. This review intends to assess the antimalarial potential of quinones isolated from plants. The search for scientific articles was carried out on the CAPES Journal Portal (PPC), Virtual Health Library (VHL), PUBMED, NCBI and SCIELO, using the following descriptors: quinones and antimalarials. Inclusion criteria were adopted based on studies about quinones isolated from plants and tested against Plasmodium falciparum and Plasmodium berghei. The exclusion criteria were based mainly on articles that tested extracts, fractions and synthesis of quinones obtained from plants and other natural products. A total of 1344 publications were collected for screening (PPC = 5, VHL = 248, PUBMED = 525, NCBI = 462 and SCIELO = 94). From this total, 1280 articles were excluded, with only 64 articles selected for full reading. All benzoquinones were active against P. falciparum. Naphthoquinones were active, inactive and moderately active against the P. falciparum e P berghei. Anthraquinones and anthrones were active and moderately active against P. falciparum. The naphthoquinone 2-acetylnaphtho[2,3b] -furan-4,9-dione was the most active of all the molecules tested against Plasmodium. Whereas lapachol was the most studied naphthoquinone and structural changes do not seem to contribute to the activity. In summary, quinones are promising as antimalarials, however, need in vivo studies.


Introduction
About 3.3 billion people are exposed to malaria in endemic areas at risk of contracting the disease in more than 100 countries. In 2018 there were 228 million cases of malaria, with the African continent having the highest morbidity rate with 213 million cases, and almost 1 million deaths (WHO, 2019). In the Americas, 138 million people live in risk areas. The Venezuela, Brazil, Peru, Nicaragua and Colombia are the countries with the highest number of cases and deaths (OPAS, 2020).
The widespread increase in resistance to antimalarial drugs is one of the main problems in reducing the mortality caused by Plasmodium, which results in delay or failure of remission of blood forms, allowing the selection of resistant gametocytes. Resistance to antimalarials is associated with the irrational use of medicines, counterfeit drugs, long drug halflives, host immunity, parasite and environmental factors (Winstanley, 2001). In addition to quinine and chloroquine, resistance to primaquine, proguanil, atovacone, mefloquine and combined artemisinin therapy (Wongsrichanalai et al., 2002;Noeldl et al., 2008;Van Bong et al., 2014) has been reported.
Based on this, there is a search for new drugs that are more selective, less toxic and do not induce resistance in Plasmodium (Gamo et al., 2010;Penna-Coutinho et al., 2011;Aguiar et al., 2012;Coutinho et al., 2013;Souza et al., 2014).
One of the new strategies for creating antimalarial drugs is the characterization and isolation of compounds from medicinal plants, especially quinones such as naphthoquinones, with atovaquone as its main representative, a very active and less toxic naphthoquinone that acts by inhibiting purine biosynthesis in the parasite (Hage et al., 2009;Hughes et al., 2011).
The development of new therapeutic alternatives to treat malaria is necessary, mainly due to the drug resistance of the Plasmodium, therefore, metabolites such as quinones, isolated from medicinal plants have shown promising results as a potential drug in the treatment of infectious diseases such as malaria. The purpose of this literature review is to evaluate the antimalarial potential of quinones isolated from different plant species.

Methodology
In this integrative review, a research was carried out to select scientific articles available on the following platforms: CAPES Journal Portal (PPC), Virtual Health Library (VHL), PUBMED, NCBI and SCIELO, without limiting the publication year of articles.
The search period was between August and September 2020, and only articles in Portuguese, English and Spanish were adopted as inclusion criteria, and adaptation of the title to the theme and compatible summary as well.
The exclusion criteria adopted were articles that did not address the topic of study, papers in other languages, articles that tested extracts and fractions, quinones obtained through synthesis and other natural products, articles not available in full, duplicates and studies that have not been analyzed by experts.
The representative descriptors for searching the articles on platforms were quinones and antimalarials. Initially, 1344 were collected for screening (PPC = 5, VHL = 248, PUBMED = 525, NCBI = 462 and SCIELO = 94). However, after analyzing the title and abstract, 1,280 articles were excluded, with only 64 articles selected for full reading and likely inclusion in the integrative review.
The selection was based on the title and abstract, being carried out by three reviewers who took into account the inclusion and exclusion criteria. In cases of divergences during the selection analysis, a fourth reviewer was consulted to ensure compliance with the study requirements. After reading the articles, 38 were used in the results and 38 were used in the discussion of this review, with 24 articles excluded from the 64 initially included. In addition, to facilitate the organization and tabulation of the data, it was divided into two stages of analysis: first, a table with the title and summary was made. In the second stage, full reading and synthesis of the articles were carried out to produce the results and discussion.
The antimalarial activity of quinones in vitro was considered active when the IC50 was less than or equal to 10 µg.mL -1 against the plasmodium; moderately active with an IC50 greater than 10 µg.mL -1 and less than 100 µg.mL -1 and inactive with an IC50 greater than 100 µg/ml -1 .

Results and Discussion
As a causative agent of malaria, Plasmodium is responsible for approximately two million deaths worldwide. In almost all endemic populations, the parasite has developed resistance against drugs used in first-line treatment, such as chloroquine and its derivatives. An important area in antimalarial research is based on finding a potent and reliable antiparasitic medication capable of inhibiting Plasmodium infection and growth (Najera, 2001;Hyde, 2002). In this context, quinones have been increasingly studied, since the antimalarial activity of Atovaquone was described (Basco et al., 1995).
Quinones represent a wide and varied family of compounds found in nature, especially in plants, fungi, lichens and bacteria, and can be synthesized (Thomson, 1971). Based on their molecular structure, quinones can be classified according to the type of aromatic ring that supports the basic quinoid nucleus: benzoquinones (benzene ring), naphthoquinones (naphthalenic ring) and anthraquinones (linear or angular anthracene ring). These three types of quinones are the most frequently found in nature (Silva et al., 2003). When we analyzed the in vitro antimalarial activity of benzoquinones, we found few studies reporting the activity of these compounds against P. falciparum (Ichino et al., 2006;Tasdemir et al., 2006;Boonphong et al., 2007;Radwan et al., 2008).
One of the most studied naphthoquinones with great antimalarial potential is Atovaquone. It is even used as an alternative therapy in cases of resistance against first-line drugs, and for malaria prophylaxis. Due to the quinonic nature of the compounds evaluated in the present study, and the structural similarity of naphthoquinones with Atovaquone, the antimalarial activity of these compounds may be related to the inhibition of parasite's mitochondrial cytochrome bc1 complex, interrupting electron transport and consequently the synthesis of pyrimidines and, therefore, preventing the replication of the parasite's DNA (Birth et al., 2014). Just to clarify, a study showed that Atovaquone binds to the mitochondrial bc1 complex inhibiting the electron transport system in the apicoplast (Waller & McFadden, 2005).
In an antimicrobial and cytotoxicity study of Eleutherine bulbosa, a plant rich in quinones, identified activity of the extracts and fractions for Staphylococcus aureus, however the fractionation contributed to the increase in cytotoxicity (Borges et al., 2020). In a similar study, do Nascimento Brandão et al. (2020)  When we analyze the antimalarial activity of anthraquinones, we observe that it is the second most studied subclass of quinones. A total of 17 anthraquinones were evaluated to assess their antimalarial potential, from these 15 substances presented IC50 below 10 µg.mL -1 , therefore, they were considered active, and we can highlight the 3 most promising substances: Joziknipholone A, Joziknipholone B, Isoknipholone and Knipholoneanthrone that showed high activity against sensitive (3D7) and resistant (K1, D6 and W2) strains of P. falciparum with IC50 less than 1 µg.mL -1 (Table 1, Figure 1).
During the data analysis about anthrones, we found that only 8 molecules have been evaluated. However, 7 compounds have antimalarial potential, mainly because they showed activity against a chloroquine-resistant strain of P.

Conclusion
Quinones are promising as an antimalarial, however, there is a lack of in vivo studies for compounds belonging to the benzoquinone, anthraquinone and anthrax classes. In vitro studies, carried out with resistant P. falciparum clones, suggest that compounds belonging to these classes are promising antimalarials.
Regarding naphthoquinones, the compound 2-acetylnaphtho-[2,3b] -furan-4,9-dione presented the highest activity against Plasmodium berghei, and studies that aim to evaluate its safety should be prioritized. Without a doubt, the most studied naphthoquinone, promising as an antimalarial, is lapachol. For some biological activities, the lapachol ortho isomer (βlapachone) is the most active and most cytotoxic form. In the present study, lapachol appears to be more promising than βlapachone and α-lapachone.
The pharmacological therapies used to treat malaria are a source of free radicals to fight the parasite, since it is known that the Plasmodium sp. is highly sensitive to such molecules. Thus, studies on the generation of free radicals in the treatment and development of new drugs in malaria are necessary, especially those for the characterization and isolation of compounds from medicinal plants and their metabolites, both in vitro and in vivo.