Invited reviewQuinolines and structurally related heterocycles as antimalarials
Graphical abstract
Introduction
Malaria is the most lethal human parasitic infection. At present, there are estimated 250 million cases of malaria worldwide. The vast majority of these cases (86%) are in the African region, followed by the South-East Asia (9%) and Eastern Mediterranean regions (3%). There were an estimated 0.881 million deaths worldwide in 2006, of which 90% were in the African region and 4% in each of the South-East Asia and the Eastern Mediterranean regions [1]. The individuals most at risk of significant morbidity and mortality owing to malaria are the children under the age of 5 years and the pregnant women [2], [3]. However, as a result of varying transmission intensity, population flux and trans-migration, adults lacking acquired immunity may also develop severe malaria.
Human malaria is caused by four species of protozoan parasites of the genus Plasmodium. These are Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae, each of which differs in geographical distribution, microscopic appearance, clinical features and potential for the development of resistance to the antimalarial drugs. Malaria prevention and treatment currently relies on the vector control and chemotherapy. The vector control is achieved by interrupting their life cycle, and creating a barrier between the human host and the mosquitoes. Currently there are only limited safe drugs for the treatment of the disease, however, reports of emerging resistance against existing drugs warrants the introduction of new drugs. A number of vaccine candidates are being clinically tested, which may become important tools for the treatment of malaria in the future. The chemotherapy of malaria basically involves killing of the asexual parasites and providing supportive therapy to the host to boost its immune system. Prior to the 2nd World War, quinine, pamaquine, chloroquine (CQ) and mepacrine were developed. These were followed by proguanil and amodiaquine (AQ) (1940s), primaquine (PQ) and pyrimethamine (1950s), sulfadoxine (1960s), and artemisinin (1970s). A number of drugs were introduced in the 1980s, which include mefloquine, halofantrine, aablaquine, pyronaridine, piperaquine, and the artemisinin derivatives, such as artemether, aretsunate and dihydroartemisinin (Fig. 1).
The quinoline scaffold is prevalent in a variety of pharmacologically active synthetic and natural compounds [4]. The quinolines are historically among the most important antimalarial drugs ever used. Throughout the 20th century, the immense use of chloroquine, the most famous drug of this group, provided well-founded hopes for the eradication of malaria. The other known drugs from this family include: amodiaquine, piperaquine, primaquine, quinine and mefloquine. The understanding of the mode of action of quinoline-based antimalarials has increased in the recent years, but remains incomplete [5], [6], [7], [8], [9]. The drugs from this group mostly act during the blood stages of the parasite’s life cycle but some target the hepatic stages as well [10], [11]. The quinolines are known to inhibit the polymerization of heme and prevent disposal of polymers from the food vacuole to the cytoplasm where hemozoin is formed. This leads to intraparasitic accumulation of free heme, which is highly toxic to the parasite. In addition to the important targets such as heme and phospholipids, several other targets have been postulated to be involved in the antimalarial action of quinolines such as tyrosine kinase [12], DNA [13], hemoglobin degrading proteases [14], [15], and phospholipases [14], [15]. In the present review, efforts have been made to provide a comprehensive literature compilation concerning the study of quinolines and structurally related heterocycles, which may be useful for treating malaria. The review covers advances made in the last ten years and provides discussion on the 4-aminoquinolines, 4-anilinoquinolines, 8-aminoquinolines, quinolines from nature, quinolones, isoquinolines, ring-modified quinolines, and miscellaneous quinolines. The discussion under the various headings covers the structure–activity relationship, biological activities and information pertaining to biochemical pathways.
Section snippets
4-Aminoquinolines
Chloroquine (CQ), a 4-aminoquinoline, was first chemically synthesized in 1934, as a substitute for quinine. CQ is selectively deposited in the food vacuole of the parasite, exerting its antimalarial effect by preventing the polymerization of the toxic heme. The use of CQ became prominent in the early 1950s, when the World Health Organization (WHO) declared a war on malaria. Quickly, CQ became a drug of choice for treating malaria. During its prime, CQ was considered a wonder drug, cured
4-Anilinoquinolines (Fig. 9)
Amodiaquine (AQ), belonging to 4-anilinoquinoline class of antimalarial drugs is not recommended for prophylaxis of malaria because of the side effects like, agranulocytosis and hepatitis. AQ toxicity has been explained due to its 4-hydroxyanilino moiety, which undergoes P-450 catalyzed oxidation to a reactive amodiaquine quinoneimine (AQQI), followed by the nucleophilic addition of glutathione. The formation of this conjugate in vivo, and its subsequent binding to the cytosol macromolecules
8-Aminoquinolines
In 1891, based upon the observation that methylene blue (57, Fig. 10) was selectively taken up by the parasites in microscopic specimens, Paul Ehrlich cured two patients suffering from malaria. This was the first time a synthetic drug was ever used in human. Today it is known that methylene blue inhibits glutathione reductase, thereby disturbing the redox homoeostasis of the parasite. By modifying the methylene blue structure, pamaquine (Fig. 1) was synthesized in 1925. This 8-aminoquinoline
Quinolines from nature (Fig. 12)
Jain et al. have recently provided an extensive review on antimalarial quinoline alkaloids isolated from natural sources [106]. More recently, Valentin et al. reported antimalarial and toxicological activities of the tetrahydroquinoline alkaloids from Galipea officinalis bark. Galipinine 70 yielded the best antimalarial effect (IC50 = 0.09–0.9 μg/mL) [107]. Strong activity against CQR P. falciparum has been reported for benz[g]isoquinoline-5,10-dione 71, isolated from Psychotria camponutans
Quinolones (Fig. 13)
The activity of quinolone and fluoroquinolone antibiotics against P. falciparum in vitro has been documented in literature [110], [111], [112], [113], [114]. It is well known that histone deacetylase (HDA) is a key nuclear enzyme involved in the transcriptional control. The continuous acetylation/deacetylation of the ε-amino group of specific histone lysine residues is required for this process, and the inhibition of the histone deacetylation interferes with the transcriptional control and thus
Isoquinolines and tetrahydroquinolines (Fig. 14)
Based on the isoquinoline sulfonamide, H-89 (81), a potent inhibitor of Pfmrk, one of the cyclin dependent protein kinases (CDKs) from P. falciparum, Panda et al. synthesized a series of isoquinoline sulfonamides for antimalarial efficacy [121]. Compounds containing a 4-ethylphenol (82a) or a 3-imidazol-1-yl-propyl (82b) group did not show good activity, while those containing a dichlorobenzyl ring exhibited better potency (82c, MIC = 2 μg/mL). Bringmann et al. synthesized a series of
Ring-modified quinolines (Figs. 15–17)
In the context of exploring the 9-aminoacridine scaffold of mepacrine (Fig. 1) to target the propagation of prions, Guy et al. re-investigated this class of compounds for antimalarial activity, particularly against CQR strains [126]. Six compounds exhibited potent EC50 values, best being 86a and 86b, displaying EC50 values <1 nM against both CQR and CQS strains. Campiani et al. evaluated N2-acrydinylhydrazones for antiplasmodial activity [52]. The most potent analogues 87a and 87b bearing an
Miscellaneous quinolines (Fig. 18)
Several quinoline ring containing chalcones have been reported to exhibit antimalarial activities. Earlier, Go et al. carried out an extensive study on the structure–activity relationship of chalcones and showed that alkoxylated chalcones with polar ring, in particular those substituted with electron-withdrawing groups or quinoline ring possessed good antimalarial activity [143]. In this direction, Charris et al. reported antimalarial activity of a series of quinolinyl chalcones 105. The
Conclusions
The increasing spread of malaria together with the emergence of resistance against conventional antimalarial drugs has put enormous pressure on the public health systems to introduce new therapeutics. Current treatment regimes rely to a large extent on the combination of artemisinin derivatives with a variety of drugs, of which some have already lost much of their efficacy as mono therapeutics (for example, chloroquine, amodiaquine, mefloquine, sulfadoxine, and pyrimethamine). The importance of
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