Quinine structure activity relationship of methadone

Quinine - DrugBank

quinine structure activity relationship of methadone

Synergistic In Vitro Antimalarial Activity of Omeprazole and Quinine .. micellar properties of dextropropoxyphene hydrochloride and methadone hydrochloride. .. we have pursued a structure-activity relationship study, including vinyl group. In vitro activity of nicotinamide/antileishmanial drug combinations. an estimate of the functional structure of the dose-response relationship in silico, we propose an No Clinically Relevant Drug-Drug Interactions between Methadone or. Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of . The Spanish were aware of the medicinal properties of cinchona bark by the s or earlier: Nicolás Monardes () and Juan Fragoso () .

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 ].

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 ].

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 ]. However, very recent results showed that methylene blue and CQ are antagonistic in vitro [ 74 ]. In light of these results; it is not surprising that a clinical trial showed no advantage in using a combination of methylene blue and CQ over CQ monotherapy in an area with a high probability of CQ resistance.

Modifications of 4-aminoquinoline derived scaffold 4-aminoquinoline derived antimalarial constitute in major class of available antimalarial drugs broadly in clinical use. Much work has been invested in the structural modification on the 4-aminoquinoline scaffold, resulting in a large number of derivatives. Excellent reviews have described these efforts in depth. Three different structural modifications are able to overcome CQ resistance Figure 9: Figure 9 depicts the side chain modification on the 4-AQ and relative structure activity relationship.

Structural requirements of 4-AQs for antimalarial activity. For the sake of clarity, the discussion is organized as following sub headings a modification on 4-aminoquinoline-nucleus b modification on side chain analogs c modification on side chain dialkylaminomethyl-phenol and d Bisquinoline analogs.

Modifications on 4-aminoquinoline nucleus The core nucleus, 4-aminoquinoline is an essential for antimalarial activity and several attempts have been made on modifying the side chain on the quinoline ring. The reason being that intact 4-AQ is required in hematin binding and for antimalarial activity [ 75 ].

quinine structure activity relationship of methadone

Several studies report, the modification on the 4-AQ nucleus leads to loss of activity with the exceptions of chloroquine-N-oxide [ 76 ]. In literature it is evident that 7-halo substituted 4-aminoquinoline derivatives are more active than unsubstituted analogs [ 77 ]. Further Vippagunta et al. This evidence is further supported by Egan et al. Side chain modifications The diaminoalkyl side chain of 4-AQ derived antimalarials plays significant role in modulation of the activity.

It is considered that, side chain would provide and modulate the required pharmacokinetic properties for drug transport as well as basicity for accumulation in the DV. Thus several reports depict the alteration, or more importantly the shortening, of the dialkyl side chain for the activity against CQ resistant strains [ 7778 ]. A recently completed dose-dependent trial in healthy volunteers suggests that the adverse effects of AQ13 may not be different from those of CQ and that higher doses of AQ13 over CQ may be necessary to produce similar blood levels and AUC values [ 79 ].

Several options have come up with AQ13 success and variation have been made on the lateral amino group of the AQ These hits need to pass through pharmacology and toxicology filters to find the most promising candidates. In the same line various analogs 12 of AQ13 with potent antimalarial activities have been developed.

Extensive investigations were done by several research groups on the modification of side chain to determine the appropriate length and size. AQ13 11 and some of recently developed 4- aminoquinoline antimalarials Hybrid 4- aminoquinoline antimalarials The most effective analog Figures 10 and 15 shows that fold better activity than CQ [ 82 ].

Further, in one more study, they have synthesized N1 7-chloroquinyl -1,4-bis 3-aminopropyl piperazine derivatives and screened them against CQ resistant strain of P. In another series, eleven compounds displayed higher selectivity index than CQ, among these one of the compounds 17 cured mice infected by P.

Pyrrolizidinyl moiety at the pendent nitrogen 19 was recently reported by Sparatore et al. There are different research groups have reported potent antimalarial activity by introducing a aromatic group 20 in the side chain as well as lengthening the diaminoalkyl side chain of 4-aminoquinoliners Amodiaquine 65 and its congeners Congeners of amodiaquine All compounds were screened for in vitro antimalarial activity against chloroquine CQ -sensitive D6 and chloroquine CQ -resistant W2 strains of Plasmodium falciparum [ 86 ].

Generally hydrib derivatives showed roughly 1. Most active compounds found to be 34 and However, synthesized derivatives exhibited mild to moderate antimalarial activity with no toxicity signs [ 87 ]. All the synthesized derivatives were evaluated for antimalarial activity against NF 54 strain of P.

Further, methyl group on phenyl derivatives lead to corresponding compounds 49 and 50 with no antimalarial activity. Data analysis revealed that propyl linker was favorable for the antimalarial activity. All other derivatives were showed moderate antimalarial activity. Modifications on AQ side chain of dialkylaminomethylphenol Enhancement of lipophilicity of the side chain by the incorporation of an aromatic structure resulted in amodiaquine AQ Figure 14 ; 65 with certain degree of cross resistance to CQ activity.

However, the therapeutic value of amodiaquine is significantly decreased by the biotransformation of its p-aminophenol moiety into a quinonimine 66a severe hepatotoxic intermediate by complexing nucleophilic attack by thiol groups with proteins. Moreover, amodiaquineprotein complexes 67 are highly immunogenic, leading to lifethreatening agranulocytosis.

4-aminoquinolines: An Overview of Antimalarial Chemotherapy

To overcome these adverse effects, several anilinoquinolines have been developed to prevent the undesirable formation of toxic quinonimines and improved antimalarial activity. One of the modifications is the exchange of the positions of the hydroxy and diethylaminomethyl groups on the phenyl ring. The resulting isoquine 69 is not bioactivated and therefore does not lead to hepatotoxicity [ 85 ] with significantly improved activity against CQ-resistant strains.

Furthermore, to improve upon the rapid biotransformation by oxidative dealkylation in the body, tert-butylamino group is replaced the diethylamino moiety, resulting tert-butylisoquine It promises a new generation of affordable, well tolerated and effective antimalarial agents that is devoid of any cross-resistance to the chemically related CQ and amodiaquine.

From this study, they concluded that structural features of 4-anilinoquinoline, can help in circumventing cross resistance with CQ [ 62 ]. In continuation as mentioned earlier, they have synthesized prodrug of 4-anilinoquinolines derivatives Figures 8 and 10 in which metabolically labile ester linkage of GR inhibitor was combined to amino and hydroxy functionality of amodiaquine [ 72 ].

Bisquinoline analogs Bisquinolines were introduced to overcome CQ-resistance by connecting two 4-aminoquinoline moieties through linkers of various length and chemical nature.

The activity of such bisquinolines against CQ-resistant strains has been explained by their steric bulk, which prevents them from fitting into the substrate binding site of PfCRT. Alternatively, the bisquinolines may be more efficiently trapped in the acidic DV because of their four positive charges. On this basis bulky bisquinoline compounds were synthesized and evaluated for their antimalarial activity. The most advanced representative of the bisquinolines, piperaquine Figure 16 ; 74 was developed in s and heavily used in China.

Widespread resistance has developed in areas where piperaquine has been extensively used. However there are indications of cross-resistance with dihydroartemisinin Figure 1.

quinine structure activity relationship of methadone

This significant finding made to develop the combination of piperaquine and dihydroartemisinin named Euartekin and entered phase II clinical trails [ 89 ]. Of the several bisquinoline analogs developed, the compound WRFigure 16 ; 75 has shown potent in vivo activity against P.

quinine sulfate anhydrous,

For this reason, compound 75 underwent preclinical studies at Hoffmaan-LaRoche Ltd, and was found to be a good inhibitor of hematin polymerization, but its phototoxicity precluded its further development. However, these derivatives are extruded with difficulty by proteinaceous transporter with the aim of reducing CQ resistance. The results suggest that increased rigidity by cyclization, yields molecules that were not more active in CQ sensitive strains but very potent against resistant strains and were also non-toxic [ 91 ].

Piperaquine 74 and other bisquinoline analogs Compounds Active against Other Diseases A third approach to antimalarial chemotherapy is to identify agents that are developed or marketed as treatments for other diseases. These compounds might act against orthologs of their targets in other systems or by different mechanisms against malaria parasites.

The advantage of these compounds is that, whatever is the mechanism of action, they have already been developed for a human indication, so will be quite inexpensive to develop as antimalarials. Specific examples of this approach include the antimalarial screening of lead series of Histone-deacetylase inhibitors [ 92 ], which were originally developed for cancer chemotherapy, and cysteine protease inhibitors that are being developed for osteoporosis.

It should be noted that structure— activity relationships emerging from the parasite assays are unlikely to be the same as those observed for the original indication. It is therefore likely, that optimized clinical candidates emerging from this strategy will be disease-specific.

In many cases, however, drugs may be quite inexpensive to produce and may be available as inexpensive antimalarials, especially after patents have expired, as has been the case with some antibiotics. Folate antagonists, tetracyclines and other antibiotics were developed for their antibacterial properties and were later found to be active against malaria parasites [ 93 ].

Iron chelators, which are used to treat iron overload syndromes, have documented antimalarial efficacy [ 94 ]. These examples suggest that it is appropriate to screen new antimicrobial agents and other available compounds as antimalarial drugs. Quinine ethyl carbonate is tasteless and odourless, [28] but is available commercially only in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.

Mechanism of action[ edit ] Quinine is theorized to be toxic to the malarial pathogen, Plasmodium falciparumby interfering with the parasite's ability to dissolve and metabolize hemoglobin. This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. September Learn how and when to remove this template message The most widely accepted hypothesis of its action is based on the well-studied and closely related quinoline drug, chloroquine.

quinine structure activity relationship of methadone

This model involves the inhibition of hemozoin biocrystallization in Heme Detoxification pathway, which facilitates the aggregation of cytotoxic heme.

Free cytotoxic heme accumulates in the parasites, causing their deaths. However, under wartime pressure, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in by American chemists R.

The first synthetic organic dyemauveinewas discovered by William Henry Perkin in while he was attempting to synthesize quinine. Natural occurrence[ edit ] The bark of Remijia contains 0. The bark is cheaper than bark of Cinchona. As it has an intense taste, it is used for making tonic water.

quinine structure activity relationship of methadone

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.

beta-quinine drug combination: Topics by wagtailfarm.info

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".