Lumefantrine structure activity relationship of salicylates

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lumefantrine structure activity relationship of salicylates

1 SALICYLIC ACID DERIVATIVES Salicylates not only possess antipyretic, analgesic, and Structure-Activity Relationship (SAR) of Salicylates 1. artemether-lumefantrine combination in rats was carried out by me in the department of The liver because of its unique metabolism and close relationship with the structure and or function may manifest as alteration in liver enzymes or .. Analgesic combinations, particularly those containing salicylates, caffeine. parasites bringing about loss of its function, and also binds to their .. include artemether – lumefantrine, artesunate – mefloquine and artesunate – SP .. British Pharmacopoeial assay of methyl salicylate and diethyl phthalate in surgical spirit) A mathematical relationship between and A (1%, 1cm) is shown below.

Individual response to Toxoplasma infection is determined by immune status, timing of infection, and the genetic composition of the host and the organism. Toxoplasma organisms have also been shown to impair learning and memory in mice and to produce behavioral changes in both mice and rats.

Of special interest are studies showing that Toxoplasma-infected rats become less neophobic, leading to the diminution of their natural aversion to the odor of cats. These behavioral changes 18 P increase the chances that the rat will be eaten by a cat, thus enabling Toxoplasma to complete its life cycle, an example of evolutionarily driven manipulation of host behavior by the parasite. In humans, toxoplasma is an important cause of abortions and stillbirths after primary infection in pregnant women.

The organism also can cross the placenta and infect the fetus. The symptoms of congenital toxoplasmosis include abnormal changes in head size hydrocephaly or microcephalyintracranial calcifications, deafness, seizures, cerebral palsy, damage to the retina, and mental retardation.

Some sequelae of congenital toxoplasmosis are not apparent at birth and may not become apparent until the second or third decade of life. Hydrocephalus, increased ventricular size, and cognitive impairment also have been noted in some persons with schizophrenia and other forms of psychosis.

Some cases of acute toxoplasmosis in adults are associated with psychiatric symptoms, such as delusions and hallucinations. Schizophrenia was first diagnosed in these patients, but later neurologic symptoms developed, which led to the correct diagnosis of Toxoplasma encephalitis.

These medications have become known as "neuroleptics" because, although effective in treating positive symptoms i. A new class of antipsychotics atypical antipsychotics was introduced after At clinically effective doses, no or very few of these neurological side effects, which often affect the extrapyramidal nerve tracts which control such things as muscular rigidity, painful spasms, restlessness, or tremors are observed. Its use is not associated with extrapyramidal side effects, but it does produce other side effects, including possible decrease in the number of white cells, so the blood needs to be monitored every week during the first 6 months of treatment and then every 2 weeks to catch this side effect 19 P early if it occurs.

The use of these medications has allowed successful treatment and release back to their homes and the community for many people suffering from schizophrenia. Methods of Treating Cancer Since the isolation of artemisinin, there has been a concerted effort by investigators to study other therapeutic applications of artemisinin and its derivatives.

Later anticancer studies that have been conducted on cell line panels consisting of 60 lines organized into nine, disease-related subpanels including leukemia, non-small-cell lung cancer, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers, further confirm that artemisinin displays modest anticancer activity.

While artemisinin and its related derivatives demonstrate zero to slight antiproliferative and antitumor activity, it has been discovered that a class of artemisinin dimer compounds exhibits antiproliferative and antitumor activities that are, in vitro, equivalent to or greater than known antiproliferative and antitumor agents U. Unfortunately, while the in vitro results of these artemisinin compounds are encouraging, these compounds do not appear to have as significant antitumor activity on the treatment of tumor cells in mice.

There is still a need, therefore, to develop stable artemisinin derivatives and structural analogs thereof having antimalarial, anticancer, antiproliferative, and 20 P antitumor activities that are equivalent to or greater than those of known antimalarial, anticancer, antiproliferative and antitumor agents, respectively.

For example, selected artemisinin-related dimers, e. Other artemisinin analogs, including trioxane dimers have been shown to exhibit anti-cancer activity. Accordingly, in some embodiments, the presently disclosed subject matter provides a method for treating cancer in a subject in need of such treatment, by administering to the subject a therapeutically effective amount of the presently disclosed compounds of Formula I.

The cancer can include leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma cancer, ovarian cancer, renal cancer, prostate cancer, and breast cancer.

Pharmaceutical Compositions and Administration In another aspect, the present disclosure provides a pharmaceutical composition including one or more compounds of Formula I alone or in combination with one or more additional therapeutic agents in admixture with a pharmaceutically acceptable excipient. One of skill in the art will recognize that the pharmaceutical compositions include the pharmaceutically acceptable salts of the compounds described above.

Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy 20th ed. The compounds according to the disclosure are effective over a wide dosage range.

lumefantrine structure activity relationship of salicylates

For example, in the treatment of adult humans, dosages from 0. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the 21 P compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

Other pharmaceutically acceptable salts may be found in, for example, Remington: Pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate embonatephosphate, salicylate, succinate, sulfate, or tartrate. Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage forms and administered systemically or locally.

The agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art.

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Techniques for formulation and administration may be found in Remington: Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra- articullar, intra -sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.

For injection, the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation.

lumefantrine structure activity relationship of salicylates

Such penetrants are generally known in the art. Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic 22 P administration is within the scope of the disclosure.

With proper choice of carrier and suitable manufacturing practice, the compositions of the present disclosure, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.

The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject e.

For nasal or inhalation delivery, the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, preservatives, such as benzyl alcohol, absorption promoters, and fluorocarbons. Pharmaceutical compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose.

Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.

The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions. Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dye- stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations that can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.

In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols PEGs. In addition, stabilizers may be added. Depending upon the particular condition, or disease state, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this disclosure.

For example, chemotherapeutic agents or other antiproliferative agents may be combined with the inhibitors of this disclosure to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

These additional agents may be administered separately, as part of a multiple dosage regimen, from the inhibitor-containing composition. Alternatively, these agents may be part of a single dosage form, mixed together with the inhibitor in a single composition. Definitions Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs.

lumefantrine structure activity relationship of salicylates

While the following terms in relation to compounds of Formula I are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. These definitions are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure.

The terms substituted, whether preceded by the term "optionally" or not, and substituent, as used herein, refer to the ability, as appreciated by one skilled in this art, to change one functional group for another functional group provided that the valency of all atoms is maintained.

lumefantrine structure activity relationship of salicylates

When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.

The substituents also may be further substituted e. Where substituent groups or linking groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e. For example, both Ri and R2 can be substituted alkyls, or Ri can be hydrogen and R2 can be a substituted alkyl, and the like. The terms "a," "an," or "a n ," when used in reference to a group of substituents herein, mean at least one.

Moreover, where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted. A named "R" or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein.

For the purposes of illustration, certain representative "R" groups as set forth above are defined below. Description of compounds of the present disclosure is limited by principles of chemical bonding known to those skilled in the art. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

lumefantrine structure activity relationship of salicylates

The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic.

Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, methoxy, diethylamino, and the like.

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In particular embodiments, the term "alkyl" refers to Co inclusive, linear i. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, iso-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n- undecyl, dodecyl, cyclohexyl, cyclohexyl methyl, cyclopropylmethyl, and homologs and isomers thereof.

In certain embodiments, "alkyl" refers, in particular, to C straight-chain alkyls. In other embodiments, "alkyl" refers, in particular, to C branched-chain alkyls. Alkyl groups can optionally be substituted a "substituted alkyl" with one or more alkyl group substituents, which can be the same or different. The term "alkyl group substituent" includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.

There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl also referred to herein as "alkylaminoalkyl"or aryl.

This is thought to be its mechanism of action in treating dermatitis herpetiformis. Discovery[ edit ] In the early 20th century, the German chemist Paul Ehrlich was developing theories of selective toxicity based largely on the ability of certain dyes to kill microbes. Gerhard Domagkwho would later win a Nobel Prize for his efforts, made a major breakthrough in with the discovery of the antibacterial prontosil red sulfonamidochrysoidine.

Further investigation into the involved chemicals opened the way to sulfa drug and sulfone therapyfirst with the discovery of sulfanilamidethe active agent of prontosil, by Daniel Bovet and his team at Pasteur Institute[49] then with that of dapsone independently by Ernest Fourneau [50] in France and Gladwin Buttle [51] in the United Kingdom.

Wittmann, [53] Proposed use in antimalarial drugs[ edit ] The spread of drug-resistant malaria in Africa has encouraged the development of new, low-cost antimalarial drugs.


Artemisininanother antimalarial drug, had been developed in the s but was too expensive for large-scale use. This led GlaxoSmithKline to develop Lapdapa combination drug consisting of chlorproguanil and dapsone. Lapdap was licensed in the United Kingdom starting in October Another was that by virtue of being of a combination drug, it was less likely to cause drug resistance. It was available in many African countries for four years before GlaxoSmithKline took it off the market in February For many years scientists attempted to develop a topical formulation of dapsone that would be as effective against acne as oral dapsone, but without the hemolysis side effect.

This was difficult to accomplish because dapsone is highly insoluble in aqueous solvents.