i) Synthesis and structure-activity relationship of chalcones for antimalarial activity. . combination of artemisinin derivatives with other antimalarial agents also. STRUCTURE-ACTIVITY RELATIONSHIPS. 2-Substituted Research leading to the currently available antimalarial agents has been detailed in a number of. A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is presented. Consideration is given to the potential role of.
After the initial replication in the liver, the parasites undergo asexual multiplication in the erythrocytes erythrocytic stage. In every cycle, schizonts get ruptured with erythrocytes and releases new merozoites into the blood stream, which in turn again invade the new erythrocytes. Before this stage the infected individual may not have any symptoms, once RBCs get ruptured, the host immune system get exposed to parasite factors in turn stimulates to release cytokines and results in the symptoms like fever and chills.
Life cycle of malaria parasite Plasmodium falciparum. In case of P.
After a number of asexual life cycles, Some merozoites develop into sexual erythrocytic forms gametocytes. When an Anopheles mosquito ingests male and female gametocytes during a blood meal from an infected host, fertilization takes place in the gut of the mosquito forming zygotes.
The zygote s become elongated and invade the gut wall of the mosquito developing into oocysts. These oocysts grow, rupture, and release sporozoites. These invade the mosquito's salivary gland, and the mosquito is then ready to transmit the disease during the next blood meal [ 13 - 15 ]. Antimalarial agents are classified by the stages of the malaria life cycle that are targeted by the drug. Blood schizonticides acting on the asexual intraerythrocytic stages of the parasites.
Tissue schizonticides kill hepatic schizonts, and thus prevent the invasion of erythrocytes, acting in a causally prophylactic manner.
Hypnozoiticides kill persistent intrahepatic stages of P. Gametocytocides destroy intraerythrocytic sexual forms of the parasites and prevent transmission from human to mosquito.
4-aminoquinolines: An Overview of Antimalarial Chemotherapy | OMICS International
As there are no dormant liver stages in P. In cases of P. Chemotherapeutic Approaches Drug development directed against malaria is generally targeting blood schizonts. However, to prevent relapse tissue schizontocides are recommended to clean residual infection in the tissues.
In spite of the available drugs, malarial chemotherapy is still inadequate and therefore new strategies are being explored to fill the gaps. This review discusses the recent developments in new analogs of existing drugs, especially 4-aminoquinoline derived antimalarials.
Combination therapy Owing to rapid spreading of disease as well as emergence of resistance new strategies are being explored. Among various such approaches combination therapy offers several advantages. The combination therapy has also been recommended by World Health Organization WHO for the effective treatment of malaria.
As information on pharmacokinetics of antimalarials have become increasingly available, it is appropriate to reexamine current recommendations for effective treatment and prophylaxis. In addition, antimalarial formulations and dosage forms can be improved [ 16 ]. This approach is to optimize therapy with existing agents. New dosing regimens or formulations may optimize activity. Combination therapies, including newer agents e. The use of combination antimalarial therapy offers two important potential advantages.
First, the combination improves the antimalarial efficacy with additive or, preferably, synergistic effect. In the case of both the artemisinin derivatives and atovaquone, the new agents have had unacceptable failure rates when used as single agents to treat falciparum malaria but they have been highly effective in combination with other established antimalarials. Second, and probably most important in the use of combination therapy is slow down the progression of parasite resistance to the new agents.
This latter factor is a key consideration as we attempt to develop new therapies that will retain activity for a long period. Ideally, a combination regimen that prevents resistance development should include at least two agents against which parasite resistance has not yet developed and which have similar pharmacokinetics, so that low blood levels of a single agent will not be present.
Alternatively, the combination of a short-acting, highly potent compound and a longer-acting agent may prove effective, if the initial decrease in parasite burden is so great as to limit subsequent resistance development to the long-acting agent e. New analogs of existing drugs Improving upon the antimalarial chemotherapy profile of existing compounds by chemical modifications has been a rewarding approach. This approach does not require development of knowledge of the mechanism of action or the therapeutic target of the agents that used for combination therapy.
Indeed, this approach was responsible for optimizing the activity and selectivity of existing antimalarials even against resistant strains. For example, CQ, primaquine and mefloquine were discovered through chemical strategies to improve upon quinine [ 20 ].
More recently, 4-aminoquinoline derivatives that are closely related to CQ appear to offer the great potency even against CQresistant strains of parasites [ 2122 ].
A related compound, pyronaridine Figure 4was developed in China and is now undergoing extensive clinical trials in other areas [ 23 ]. An 8-aminoquinoline derivative, tafenoquine Figure 4offers improved activity against hepatic-stage parasites over that of the parent compound, primaquine [ 24 ], and is effective for antimalarial chemoprophylaxis [ 25 ]. New folate antagonists [ 27 ] and new endoperoxides related to artemisinin [ 2829 ] are also under study.
Development of Aminoquinolines Derived Antimalarials 4-Aminoquinolines derivatives were the first class of compounds used for the successful treatment of malaria and drugs of choice for the present time also. In the 18th century, the first attempt of successful treatment of malaria was made with use of the bark of cinchona trees [ 30 ].
The structure elucidation and different synthetic routes have come up in near 19th century. Inchemist William Henry Perkins set out to synthesize quinine. Paul Ehrlich noticed that methylene blue 1 was particularly effective in staining malaria parasites Figure 5.
He rationalized that this dye might also be selectively toxic to the parasite [ 30 ]. InEhrlich and Guttmann cured two malaria patients with methylene blue 1which became the first synthetic drug ever used in therapy. Although it was not used further at that time, methylene blue constituted the basis for the development of synthetic antimalarials.
In the s, chemists at Bayer in Germany started to modify the structure of methylene blue 1. A key modification was the replacement of one methyl by a dialkylaminoalkyl side chain to give compound 2. The dye methylene blue 1 is the predecessor of potent synthetic antimalarial drugs Subsequently, this side chain was connected with different heterocyclic systems such as the quinoline system, yielding the first synthetic antimalarial drug, plasmochin 3, also known as plasmoquine or pamaquine in the year However, under clinical evaluation, this drug displayed multiple side effects, and was therefore not widely used.
The congeneric primaquine 4introduced inwas better tolerated, making it the main representative of the class of 8-aminoquinoline derived anti-malarials.
Connection of the diethylaminoisopentylamino side chain with an acridine heterocycle yielded mepacrine 5, also known as quinacrinewhich was introduced in for prophylaxis and treatment of malaria [ 30 - 33 ]. A major success with the drug-design strategy was achieved in with the introduction of a diethylaminoisopentylamino side chain into position 4 of a 7- chloroquinoline, yielding a compound named resochin by the German inventors later known as chloroquine 6.
However, after initial trials, resochin was regarded as too toxic for use in humans and ignored for a decade. Inthe structurally closely related sontoquin 7, later known as nivaquine was prepared in the Bayer laboratories and tested in Germany. Resochin CQ was reevaluatedin and was found safe for human subjects.
A Medicinal Chemistry Perspective on 4-Aminoquinoline Antimalarial Drugs | BenthamScience
After the World War II, CQ became the foundation of malaria therapy for at least four decades [ 30 - 33 ] and most successful drug in clinical use till date [ 34 - 36 ]. Mode of action of 4-aminoquinoline derivatives Mode of action of 4- aminoquinoline classes of compounds is still a matter of debate despite the overwhelming importance. Various theories have been proposed and reviewed [ 137 - 39 ].
During its erythrocytic stages, the parasite consumes large quantities of haemoglobin from its host cell, either for the purpose of amino acid supply, or simply to create space inside the erythrocyte. Haemoglobin is shuttled by vesicles to a specialized organelle called digestive vacuole DV. A number of facts relating to the drugs action are now widely Accepted. Based on these facts several hypotheses have been raised. However, interaction of CQ with DNA does not explain the antimalarial activity and the selective toxicity of this compound.
Some other mechanisms have been proposed, but they would call for higher drug concentrations than what can be achievable in vivo and not generally regarded as convincing options [ 1 ]. These include inhibition of protein synthesis; inhibition of digestive vacuole DV lipase, and aspartic protease [ 137 - 39 ]. A clue to the mechanism of action of CQ came from the observation that it is active only against the erythrocytic stages of malaria parasites.
The next phase of research concentrated on the feeding process of the parasites, where CQ could able to inhibit the haemoglobin degradation. Uptake of haemoglobin and its metabolism by a series of proteases in food vacuole of the parasite strengthen the hypothesis [ 43 - 45 ].
4-aminoquinolines: An Overview of Antimalarial Chemotherapy
Thus, the 4-aminoquinoline derived drugs have been proposed that selectively target the haemoglobin degradation which is a specific to parasites [ 46 ]. The free heme, which is toxic to parasite, released from the haemoglobin degradation and a series of proteases involved were drawn more attention of the researchers Figure 6 [ 47 - 49 ].
The plasmodial enzymes involved in digestion of haemoglobin have attracted much attention as possible targets for antimalarial drug design. When hemereleased from haemoglobin get converted into ferric form, which is highly toxic to vacuolar proteases and damaging to parasite membranes. Interestingly, parasite has a unique non-enzymatic heme detoxification mechanism, in which heme released from parasite digestion is converted to an insoluble polymer, called hemozoin.
It is microscopically visible in the DV as malaria pigments [ 50 ]. Crystallographic information of the structure of the CQ—FP complex is not available. The precise mechanism by which this toxic effect is exerted remains to be elucidated [ 3554 ].
In these prematurely fused vesicles, haemoglobin is no longer properly degraded [ 55 ]. Since FPIX is a potential target for 4-aminoquinolines and related antimalarials, a number of studies have investigated the nature of FP binding to 4-aminoquinolines. Structure of heme, hemozoin and their structural similarity with synthetic FPIX have been well documented Figure 6. An important difference between monomeric heme including heme aggregates and hemozoin is their differential solubility in organic and aprotic solvents and in sodium dodecoyl sulphate SDS and mildly alkaline bicarbonate solutions.
Considerable evidence has accumulated in recent years that antimalarial drugs such as CQ act by forming complexes with FP, the hydroxo or aqua complex of Ferriprotoporphyrin IX Fe III FPderived from parasite proteolysis of host haemoglobin. Studies by Dorn et al. They have supported the enzymatic mechanism of hemepolymerization in vivo [ 56 - 60 ]. Considerable data supports the hypothesis that hematin is the target of 4-aminoquinoline class of compounds [ 61 ].
Recently Egan et al. As discussed earlier, UV, NMR, mass, crystallography and molecular modeling studies also support the complex formation [ 3651 ]. The isothermal titration calorimeter ITC is also used to explain the mechanism.
Mechanisms of resistance The indiscriminate use of CQ has led to the development of resistant malaria strains. They are almost spread over the entire malaria-endangered area. The need to understand the mechanisms of action of the 4-AQ antimalarials is urgent as levels of resistance to these drugs is on increase.
This information is also highly useful for the design and development of drugs against CQ-resistant strain of malaria. Resistance to CQ is more likely to involve more than one gene and altered drug transport rather than changes at site of drug action. In CQ-resistant strains, the drug is apparently removed from its putative locus of action, the digestive food vacuole Figure 7.
The main cause of CQ resistance is a matter of intense research and debate. Because there is not much else of significance inside the DV worthy transport, it has been proposed that the physiological role of this protein is the transport of amino acids or small peptides resulting from the degradation of haemoglobin into the cytoplasm [ 63 ]. All CQresistant strains have a threonine residue in place of lysine at position 76 of the protein.
In wild-type CRT, this positively charged side chain is thought to prevent access of the dicationic form of CQ to the substrate binding area of the transporter. The K76T mutation replaces the positively charged side chain by a neutral moiety, and thereby allows access of the CQ di-cation to the transporter, which then decreases the concentration of CQ in the DV considerably Figure 7.
The K76T mutation is accompanied by up to 14 more amino acid replacements, which are thought to restore the physiological function of the transporter, as, an engineered strain carrying only the K76T mutation is not viable [ 64 - 66 ].
Interestingly, a CQ-resistant strain kept under continuous drug pressure with halofantrine Figure 1 shows a SR mutation that renders this strain halofantrine resistant but restores susceptibility to CQ, most probably through re-emergence of the cation-repelling positive charge in the substrate binding area of the transporter [ 6467 ].
This is in agreement with the fact that CQ resistance can be reversed in vitro by several compounds of which verapamil 8 is the prototype Figure 8. The common molecular feature of these so-called CQ resistance reversers are two lipophilic aromatic residues and a basic aminoalkyl side chain.
It is believed that the aryl residues interact with a lipophilic pocket in the substrate binding site of the CRT, while the protonated amino group restores the positive charge that repels the CQ di-cation. The underlying molecular scaffold for CQ resistance reversers, resembles a variety of molecules including certain H1- antihistaminic agents chlorpheniramine 9 and neuroleptics [ 68 - 71 ].
A Medicinal Chemistry Perspective on 4-Aminoquinoline Antimalarial Drugs
Recent results suggest that this mutation plays a compensateory role in CQ-resistant isolates under CQ pressure and may also have some fine tuning effects on the degree of CQ resistance. Efforts to design new reversers of CQ resistance are underway [ 61 ]. Thus, although CQ appears to already have failed as a first-line antimalarial in most of the world, this inexpensive, rapid acting, well-tolerated antimalarial may be resurrected by combination with effective resistance reversers.
Structures of CQ resistant reversers. Considerably elevated glutathione levels are found in CQ- resistant strains, leading to the theory that a combination of CQ with a glutathione reductase inhibitor might overcome resistance. A dual drug consisting of a quinoline derivative [ 62 ] and a GR inhibitor 10 showed activity against various CQ-resistant strains that was superior to the parent quinoline, but failed to produce a radical cure in P.
The presumed role of glutathione in CQ resistance could also be the rationale behind the recently renewed interest in methylene blue 1which is known to inhibit GR [ 73 ]. A very challenging and timely endeavor.
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