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Quinoline-Based Hybrid Compounds with Antimalarial Activity

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Quinoline-Based Hybrid Compounds with Antimalarial Activity molecules Review Quinoline-Based Hybrid Compounds with Antimalarial Activity Xhamla Nqoro, Naki Tobeka and Blessing A. Aderibigbe * Department of Chemistry, University of Fort Hare, Alice Campus, Alice 5700, Eastern Cape, South Africa; [email protected] (X.N.); [email protected] (N.T.) * Correspondence: [email protected] Received: 7 November 2017; Accepted: 11 December 2017; Published: 19 December 2017 Abstract: The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by drug-drug interactions. In order to overcome the aforementioned factors, several researchers have reported hybrid compounds prepared by reacting quinoline-based compounds with other compounds via selected functionalities. This review will focus on the currently reported quinoline-based hybrid compounds and their preclinical studies. Keywords: 4-aminoquinoline; 8-aminoquinoline; malaria; infectious disease; hybrid compound 1. Introduction Malaria is a parasitic infectious disease that is a threat to approximately half of the world’s population. This parasitic disease is transmitted to humans by a female Anopheles mosquito when it takes a blood meal. Pregnant women and young children in the sub-tropical regions are more prone to malaria infection. In 2015, 214 million infections were reported, with approximately 438,000 deaths and the African region accounted for 90% of the deaths [1–3]. Malaria is caused by five parasites of the genus Plasmodium, but the majority of deaths are caused by Plasmodium falciparum and Plasmodium vivax [1,4–6]. Effective drugs to treat malaria have been developed and they include drugs such as quinine, quinoline, mefloquine, and artemisinin. Quinoline was the drug of choice for the treatment of malaria caused by Plasmodium falciparum. However, the parasite has developed resistance to the drug. To overcome drug resistance, different approaches which include combination therapy have been evaluated. More than a decade ago, the combination therapy which involves the combination of two or more antimalarials has been reported to be the future approach to overcome drug resistance of antimalarials. Hybridization approach has also been utilized, it involves the combination of two distinctive pharmacophoric features from new and known drugs to form a molecule with enhanced efficacy against most of the malaria stages [5,7]. Antimalarial drugs containing 4-aminoquinoline scaffolds are good precursors for hybridization with other antimalarials and metal-based compounds via selected functionalities [8]. Hybrid compounds are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects [9]. This review will be focused on the synthesis, in vitro and in vivo studies of hybrid compounds containing 4- and 8-aminoquinoline derivatives. 2. Classes of Antimalarial Drugs Antimalarials are classified based on their activities against the malaria life stages within the human host. This classification includes [10,11] (Figure1): The tissue schizontocidal drugs which can be classified as causal drugs and they hinder erythrocytic stages such as pyrimethamine 1 and Molecules 2017, 22, 2268; doi:10.3390/molecules22122268 www.mdpi.com/journal/molecules Molecules 20172017,, 2222,, 22682268 22 ofof 2220 be classified as causal drugs and they hinder erythrocytic stages such as pyrimethamine 1 and primaquineprimaquine 2,, which which also also prevent prevent a relapse a relapse caused caused by byhypnozoites hypnozoites of P. of vivaxP. vivax and andP. ovaleP. ovalein thein liver; the liver;hypnozoitocidal hypnozoitocidal drugs drugs act against act against exo-erythrocytic exo-erythrocytic hypnozoites hypnozoites of P. of P.vivax vivax andand P.P. ovale ovale such asas primaquine;primaquine; blood schizontocidal drugs act on the bloodblood formsforms ofof thethe parasiteparasite therebythereby eliminatingeliminating clinicalclinical attacksattacks of malaria. These include halofantrine ( 3), quinine ( 4), chloroquine chloroquine ( 5), mefloquine mefloquine ( 6), pyrimethamine,pyrimethamine, sulfones, sulfadoxine (7)) tetracyclinetetracycline ((88).). Gametocytocides such such as primaquine, chloroquinechloroquine andand quinine quinine prevent prevent gametocyte gametocyte forms form in thes in blood, the blood, thereby thereby hindering hindering mosquito mosquito infection andinfection sporontocides and sporontocides such as primaquine, such as primaquine, chloroguanide chloroguanide (9) and pyrimethamine (9) and pyrimethamine hinder the development hinder the ofdevelopment oocyst and multiplicationof oocyst and multiplication of the parasites of in the the parasites mosquito in gutthe whenmosquito it takes gut awhen blood it meal takes from a blood the humanmeal from host. the human host. Cl NH2 HN N HO N N H2N N NH2 O 1 2 Cl F F F N HN 3 HO Cl N H O OH O OH O O Cl N OH 5 NH2 N 4 OH HO H H F N F F 8 F F N Cl F NH NH O O H O H N S N N N N H 2 H H H N H OH O 9 7 6 Figure 1. Examples of antimalarials classifiedclassified based on their activity againstagainst malariamalaria lifelife stage.stage. Antimalarial drugs are also classified based on their structures into groups such as 4- Antimalarial drugs are also classified based on their structures into groups such as aminoquinolines, like chloroquine and amodiaquine (10); 8-aminoquinolines such as primaquine; 4- 4-aminoquinolines, like chloroquine and amodiaquine (10); 8-aminoquinolines such as primaquine; quinolinemethanols, e.g., mefloquine; quinoline-containing cinchona alkaloids, e.g., quinine and 4-quinolinemethanols, e.g., mefloquine; quinoline-containing cinchona alkaloids, e.g., quinine and quinidine (11); hydroxynaphthoquinones, e.g., atovaquone (12); diaminopyrimidines such as quinidine (11); hydroxynaphthoquinones, e.g., atovaquone (12); diaminopyrimidines such as pyrimethamine; sesquiterpene-lactones such as artemisinin (13), arteether, artemether; sulfonamides, pyrimethamine; sesquiterpene-lactones such as artemisinin (13), arteether, artemether; sulfonamides, e.g., sulfalene (14), sulfadoxine, dapsone; biguanides such as proguanil, chlorproguanil and e.g., sulfalene (14), sulfadoxine, dapsone; biguanides such as proguanil, chlorproguanil cycloguanil (15); antibiotics such as tetracycline, azithromycin and doxycycline and phenanthrene- and cycloguanil (15); antibiotics such as tetracycline, azithromycin and doxycycline and methanols such as lumefantrine (16) [11,12] (Figure 2). Each of these classes has its own unique mode phenanthrene-methanols such as lumefantrine (16)[11,12] (Figure2). Each of these classes has its own of action and mechanism of resistance against the malaria parasite. unique mode of action and mechanism of resistance against the malaria parasite. Molecules 2017, 22, 2268 3 of 22 Molecules 2017, 22, 2268 3 of 20 O HO H N HO HN N H O O Cl N N Cl 12 N OH Cl 10 11 O O Cl H Cl NH S NH N 2 OO O N N H N H2N H O 14 Cl 15 O 16 13 Figure 2. ExamplesExamples of of antimalarials antimalarials classified classified based on their structure. 3. Mechanism of Antimalarial Drug Resistance 3. Mechanism of Antimalarial Drug Resistance 3.1. Mechanism Mechanism of Resistance in Quinolines The mechanism mechanism of of resistance resistance in inquinolines quinolines such such as chloroquine as chloroquine is not is well not understood. well understood. Many researchersMany researchers have tried have to explain tried to the explain possible the mechanisms possible mechanisms of resistance of in resistancequinolones. in Chloroquine quinolones. inChloroquine an uncharged in anform uncharged diffuses fr formeely into diffuses the erythrocyte freely into onto the erythrocyte the digestive onto vacuole the digestivewhere it becomes vacuole protonated.where it becomes In the protonated.digestive vacuole, In the it digestive binds to vacuole,the haematin, it binds a toxic to the byproduct haematin, of a the toxic haemoglobin byproduct proteolysisof the haemoglobin [13]. Chloroquine proteolysis accumulates [13]. Chloroquine significan accumulatestly in chloroquine significantly sensitive in chloroquine parasites compared sensitive toparasites the chloroquine compared resistant to the chloroquine strains [13]. resistant The resistan strainsce [of13 ].chloroquine The resistance is associated of chloroquine with an is associatedincreased levelwith anof drug increased efflux. level Chloroquine of drug efflux. resistant Chloroquine strains ha resistantve been strains reported have to beenrelease reported the drug to releaseat a faster the ratedrug compared at a faster rateto the compared chloroquine to the sensitive chloroquine parasites, sensitive resulting parasites, in resultingdrug resistance in drug [14]. resistance Reduced [14]. affinityReduced of affinity chloroquine of chloroquine for heme for hemeresulting resulting in reduced in reduced chloroquine chloroquine uptake uptake also also contribute contribute to chloroquine resistanceresistance [[15].15]. P.P. falciparumfalciparumchloroquine chloroquine resistance resistance transporter transporter (PfCRT) (PfCRT) also also contributes contributes to tothe the resistance resistance of of parasite parasite to chloroquineto chloroquine drug drug [16 [16].]. 3.2. Mechanism Mechanism of Resistance in Artemisinins The resistance of plasmodium parasites to artemisinin
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