Structure activity relationship of quinine

structure activity relationship of quinine

Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of Quinine · Clinical data. Some structure-activity relationships among the group of 48 hybrids are to Cinchona alkaloids (quinine, quinidine, cinchonine and cin-. This suggests that the activity of drug-dependent antibodies is dependent on different Quinine/immunology*; Stereoisomerism; Structure-Activity Relationship.

The bark is cheaper than bark of Cinchona. As it has an intense taste, it is used for making tonic water. The Spanish were aware of the medicinal properties of cinchona bark by the s or earlier: It was first used to treat malaria in Rome in During the 17th century, malaria was endemic to the swamps and marshes surrounding the city of Rome.

Malaria was responsible for the deaths of several popesmany cardinals and countless common Roman citizens. Most of the priests trained in Rome had seen malaria victims and were familiar with the shivering brought on by the febrile phase of the disease.

The Jesuit brother Agostino Salumbrino —[37] an apothecary by training who lived in Limaobserved the Quechua using the bark of the cinchona tree for that purpose. While its effect in treating malaria and malaria-induced shivering was unrelated to its effect in controlling shivering from rigorsit was a successful medicine against malaria. At the first opportunity, Salumbrino sent a small quantity to Rome for testing as a malaria treatment. Prior tothe bark was first dried, ground to a fine powder, and then mixed into a liquid commonly wine which was then drunk.

Large-scale use of quinine as a malaria prophylaxis started around In Paul Briquet published a brief history and discussion of the literature on "quinquina".

Quinine had been said to be the prime reason Africa ceased to be known as the "white man's grave". A historian has stated, "it was quinine's efficacy that gave colonists fresh opportunities to swarm into the Gold CoastNigeria and other parts of west Africa".

The Dutch government persisted in its attempts to smuggle the seeds, and in the late 19th century the Dutch grew the plants in Indonesian plantations. Soon they became the main suppliers of the plant, and in they set up the Kina Bureau, a cartel of cinchona producers charged with controlling price and production.

The effectiveness of an antimalarial drug depends, principally on the interactions between antimalarial drug and malaria parasite, i.

The ideal antimalarials are drugs which are selective and show curative activity without or minimal toxicity to the host [ 1112 ]. The development of new antimalarials requires prior knowledge of life cycle of the parasite and drug action of existing chemotherapy.

SAR of Acetylcholine (Explained with structures)

Interactions among the three components of malaria chemotherapy human host, malaria parasite, antimalarial drug. Malaria Life Cycle The life cycle of plasmodia has five stages that include both sexual and asexual mode of reproduction in two hosts, namely a mosquito and a human Figure 3. During a blood meal, a malaria-infected female Anopheles mosquito injects sporozoites into the human host.

These sporozoites then migrate to the liver where they transform, multiply, and mature into tissue schizonts, which eventually rupture, releasing merozoites into the blood stream.

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.

structure activity relationship of quinine

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.

4-aminoquinolines: An Overview of Antimalarial Chemotherapy | OMICS International

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.

structure activity relationship of quinine

Hypnozoiticides kill persistent intrahepatic stages of P. Gametocytocides destroy intraerythrocytic sexual forms of the parasites and prevent transmission from human to mosquito. 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.

4-aminoquinolines: An Overview of Antimalarial Chemotherapy

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 ].

structure activity relationship of quinine

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.

structure activity relationship of quinine

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. 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 ]. World Health Organization; The global distribution of clinical episodes of Plasmodium falciparum malaria.

Quinine,Quinidine And Gensenosides |authorSTREAM

Sustaining antimalarial drug development. Drug discovery for malaria: A very challenging and timely endeavor. Curr Opin Chem Biol ; Old and new approaches.

J Exp Biol ; From classical antimalarial drugs to new compounds based on the mechanism of action of artemisinin. Pure Appl Chem ; Selection of a trioxaquine as an antimalarial drug candidate. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P.

Antimicrob Agents Chemothe, ; Synthesis and antimalarial activity of Equinolinylbenzocycloalcanones. Eur J Med Chem ; Synthesis of quinolinyl chalcones and evaluation of their antimalarial activity.