WO2018142288A1 - Acétate de mukaadial isolé à partir de warburgia salutaris et son utilisation comme antipaludéenne - Google Patents

Acétate de mukaadial isolé à partir de warburgia salutaris et son utilisation comme antipaludéenne Download PDF

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Publication number
WO2018142288A1
WO2018142288A1 PCT/IB2018/050583 IB2018050583W WO2018142288A1 WO 2018142288 A1 WO2018142288 A1 WO 2018142288A1 IB 2018050583 W IB2018050583 W IB 2018050583W WO 2018142288 A1 WO2018142288 A1 WO 2018142288A1
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Prior art keywords
compound
subject
mukaadial
malaria infection
salutaris
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PCT/IB2018/050583
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English (en)
Inventor
Francis Oluwole Shode
Mthokozisi Blessing Cedric SIMELANE
Zoxolo Nokulunga NYABA
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University Of Kwazulu-Natal
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Publication of WO2018142288A1 publication Critical patent/WO2018142288A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compounds and pharmaceutical compositions for the treatment of a malaria infection.
  • the invention also provides for uses and methods of treating a malaria infection in a subject using the compounds and pharmaceutical compositions described.
  • the invention also relates to methods of preparing the compounds described from plant material of Warburgia salutaris.
  • Malaria is a disease caused by parasitic protozoans of the genus Plasmodium. It is transmitted by an infected female Anopheles mosquito and results in fever and sickness. In 2013, about 584,000 people died from malaria worldwide, with 90% of these deaths occurring in Africa. Despite the advances that have been made in the treatment of this disease, it remains a burden as some species have become resistant to the currently available drugs. Approximately 80% of the rural African population is mainly dependent on traditional medicine to treat diseases including malaria. Historically, the majority of antimalarial drugs have been derived from plants. UNESCO encourages research into local medicinal plants with the hope of finding antimalarial drugs that are more efficient and could combat the artemisinin resistant malaria parasite. A pentacyclic triterpene, ursolic acid (UA), isolated from M. caffra has been reported to exhibit potent antimalarial activity.
  • U ursolic acid
  • Warburgia salutaris (pepper-bark tree) is an evergreen medium-sized tree that can grow up to 10 metres in height. It is found in the Southern African region, where it is used in traditional medicine. Most traditional concoctions are prepared from the inner bark of this tree. W. salutaris is widely used in traditional medicine for the treatment of several diseases. Tablet forms of W. salutaris are available in the market for the treatment of bronchitis, chest infections and ulcers; the leaf tablet form is a natural antibiotic, effective against oesophageal and oral thrush. Traditional use of the roots, bark and leaves is common in the treatment of venereal diseases, fever influenza, abdominal pain, ulcers, respiratory complaints and malaria. There has been no scientific proof of this plants' antimalarial activity to date, the antimalarial activity is unvalidated and potential antimalarial components are unknown.
  • Some drimane-type sesquiterpenes have been isolated from this plant; these include: warburganal, found to possess molluscicidal, antifungal and antibacterial activity; polygodial, with antifungal and antibacterial activity; salutarisolide and muzigadial, which possess antimicrobial and antifungal activity; ugandensidial; isopolygodial; and mukaadial, an 1 1 a-hydroxycinnamosmolide with anti- mycobacterial activity.
  • the present invention relates to compounds and pharmaceutical compositions for use in treating malaria infections.
  • the invention further relates to uses and methods of treating a malaria infection in a subject using the compounds and pharmaceutical compositions described.
  • the invention also relates to methods of preparing the disclosed compounds from plant material of Warburgia salutaris.
  • composition comprising a compound of the formula (I):
  • the compound or pharmaceutical composition of formula (I) may be used in the treatment of a malaria infection in a subject, preferably a human.
  • a third aspect of the invention there is provided for the use of the compound of formula (I) in the manufacture of a medicament for use in treating a malaria infection in a subject, preferably the subject is a human.
  • the malaria infection may be caused by a Plasmodium spp protozoan, preferably drug-resistant Plasmodium spp, transmitted by an Anopheles mosquito.
  • the compound, pharmaceutical composition or medicament comprises additional anti-parasitic agents.
  • the method may further comprise administering the compound in combination with other anti-parasitic agents.
  • Figure 1 X-ray structure of mukaadial acetate.
  • Figure 2 Single mass analysis of compound NN-01 DNA (identified as mukaadial acetate).
  • Figure 3 Three-dimensional structure of P HGXPRT protein with mukaadial acetate bound to the active site.
  • Figure 4 Predicted binding modes of mukaadial acetate in three dimensional
  • Figure 5 Predicted binding modes of mukaadial acetate showing generated intermolecular interactions within the P HGXPRT binding pocket.
  • Warburgia salutaris is a traditional medicinal plant used in malaria treatment by Zulu traditional healers.
  • the applicant has been involved in research to scientifically validate the use of W. salutaris in traditional medicine against malaria, and to also assess the binding mode of mukaadial acetate, a new compound isolated from W. salutaris, into P/HGXPRT protein.
  • the applicants have scientifically validated the use of W. salutaris for treating malaria in Zulu traditional medicine.
  • the applicants were able to identify the active constituent in the plant extract.
  • the molecular docking of the pure isolated compound was also investigated to examine the binding mode and conformation of the pure isolate to P/HGXPRT protein as one of the antimalarial target enzymes.
  • the bioassay guided separation of the DCM crude extract of W. salutaris led to the isolation and characterization of mukaadial acetate. This is the first time that this compound is isolated from the plant, and it is the first time its antimalarial activity is being reported.
  • the applicants have shown that W.
  • Drimane-type sesquiterpenes have previously been isolated from W. salutaris; including: warburganal, polygodial, salutarisolide, muzigadial, ugandensidial; isopolygodial; and mukaadial. Many of these have been shown to have antimicrobial and/or antifungal activity, However, this is the first time this specific compound, mukaadial acetate, has been isolated from W. salutaris.
  • Ugandensidial is a stereoisomer of mukaadial acetate.
  • enantiomers or stereoisomers do not always have identical pharmacokinetic and pharmacodynamic properties.
  • Pharmacokinetic differences resulting out of stereoisomerism can be in the absorption of the compound, for example, Esomeprazole is more bioavailable than racemic omeprazole.
  • Steroisomers may also differ in distribution and in metabolism, for example, S-Warfarin is more extensively bound to albumin than R-Warfarin, resulting in lower volume of distribution, and is also more potent and has a longer half-life due to differences in metabolism.
  • Pharmacodynamic differences resulting from stereoisomerism can be in pharmacological activity and potency.
  • Labetalol is formulated as a racemic mixture of four isomers, two of which are relatively inactive, a third isomer is a potent alpha-blocker and the fourth isomer is a potent beta-blocker.
  • isolating a chiral compound from a racemic mixture may present significant challenges.
  • the method of the present invention provides for isolation of mukaadial acetate predominantly, even when the stereoisomer is present in the crude extract.
  • malaria or “malaria infection” is meant any condition, disease or disorder that has been correlated with the presence of an existing Plasmodium parasitic infection, preferably the Plasmodium parasitic infection is caused by the presence of one or more parasites of the genus Plasmodium. More preferably the parasite is Plasmodium falciparum, Plasmodium vibrax, Plasmodium ovale, Plasmodium knowlesi or Plasmodium malariae. Most preferably the malaria infection is caused by Plasmodium falciparum. Plasmodium parasites are most commonly transmitted by an infected Anopheles mosquito intermediary host.
  • compositions and compounds of the invention can be provided either alone or in combination with other compounds (for example, nucleic acid molecules, small molecules, peptides, or peptide analogues), in the presence of a liposome, an adjuvant, or any carrier, such as a pharmaceutically acceptable carrier and in a form suitable for administration to mammals, for example, humans.
  • suitable forms include tablets, capsules, tinctures, powers, inhalants and/or liquids
  • a "pharmaceutically acceptable carrier” or “excipient” includes any and all antibacterial and antifungal agents, coatings, dispersion media, solvents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • a “pharmaceutically acceptable carrier” may include a solid or liquid filler, diluent or encapsulating substance which may be safely used for the administration of the compounds or compositions to a subject.
  • the pharmaceutically acceptable carrier can be suitable for intramuscular, intraperitoneal, intravenous, oral or sublingual administration.
  • Pharmaceutically acceptable carriers include sterile solutions, dispersions and sterile powders for the preparation of sterile solutions.
  • the use of media and agents for the preparation of pharmaceutically active substances is well known in the art. Where any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is not contemplated.
  • the pharmaceutically acceptable carrier or excipient is preferably not water. Supplementary active compounds can also be incorporated into the compositions.
  • Suitable formulations or compositions to administer the compounds and compositions of the present invention to subjects fall within the scope of the invention.
  • Any appropriate route of administration may be employed, such as, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, intracistemal, intraperitoneal, intranasal, aerosol, topical, or oral administration.
  • the compounds and compositions of the present invention can be converted to a pharmaceutically acceptable salt thereof according to a usual method, as necessary.
  • a salt may be presented as an acid addition salt or a salt with a base.
  • the acid addition salt include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like.
  • Examples of the salt with a base include salts with inorganic bases, such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt and the like, and salts with organic bases or the like such as piperidine, morpholine, pyrrolidine, arginine, lysine and the like.
  • inorganic bases such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt and the like
  • organic bases or the like such as piperidine, morpholine, pyrrolidine, arginine, lysine and the like.
  • compositions of the present invention or pharmaceutically acceptable salts thereof also encompass hydrates, and solvates with pharmaceutically acceptable solvents such as ethanol and the like.
  • the term "subject” includes a mammal, preferably a human or animal subject, but most preferably the subject is a human subject.
  • an effective amount of the compounds of the present invention can be provided, either alone or in combination with other compounds, or they may be linked with suitable carriers and/or other molecules, such as lipophilic cages.
  • suitable carriers and/or other molecules such as lipophilic cages.
  • lipophilic cages may assist in enhancing transport of the compounds to the cytoplasm of the cell in order to deliver them to the target proteins.
  • the pharmaceutical compositions or compounds according to the invention may be provided in a kit, optionally with a carrier and/or an adjuvant, together with instructions for use.
  • an “effective amount” of a compound according to the invention includes a prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as treatment of an infection or a condition associated with such infection. The outcome of the treatment may, for example, be measured by a decrease in parasite count, inhibition of target metabolic pathways, delay in development of a pathology associated with malaria infection, or any other method of determining a therapeutic benefit.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • An effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • the dosage of the compounds or compositions of the present invention will vary depending on the symptoms, age and body weight of the subject, the nature and severity of the disorder to be prevented, the route of administration, and the form of the composition. Any of the compositions of the invention may be administered in a single dose or in multiple doses. The dosages of the compositions of the invention may be readily determined by techniques known to those of skill in the art or as taught herein.
  • compositions of the invention may be administered in a single dose or in multiple doses.
  • dosages of the compositions of the invention may be readily determined by techniques known to those of skill in the art or as taught herein.
  • Dosage values may vary and be adjusted over time according to the individual need and the judgment of the person administering or supervising the administration of the pharmaceutical compositions or compounds of the invention. It may be advantageous to formulate the compositions in dosage unit forms for ease of administration and uniformity of dosage. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum response. For example, a single dose may be administered, or multiple doses may be administered over time. It may be advantageous to formulate the compositions in dosage unit forms for ease of administration and uniformity of dosage.
  • preventing when used in relation to an infectious disease, or other medical disease or condition, is well understood in the art, and includes administration of a composition which reduces the frequency of or delays the onset of symptoms of a condition in a subject relative to a subject which does not receive the composition.
  • Prevention of a disease includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population.
  • prophylactic or therapeutic treatment is well known to those of skill in the art and includes administration to a subject of one or more of the compounds or compositions of the invention. If the composition is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic.
  • unwanted condition e.g., disease or other unwanted state of the subject
  • the compounds and compositions of the present invention may be used in combination with other anti-parasitic agents, including sesquiterpene, artemisinin, artemether, artesunate, dihydroartemisinin, arteether, chloroquine, dihydroartemisinin, piperaquine, amodiaquine, lumefantrine, mefloquine, sulfadoxine, sulfamethoxypyridazineor, pyrimethamine, tafenoquine, quinine, mefloquine, proguanil (chloroguanide), atovaquone, primaquine, clindamycin, halofantrine, lumefantrine, or doxycycline.
  • the compounds and compositions of the invention may be administered in combination with, prior to, concurrent with, or subsequent to the other anti-parasitic agents.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds. It is to be noted that racemates, diastereomers, geometric isomers and individual isomers of these compounds are not intended to be encompassed within the scope of the present invention.
  • Toxicity and therapeutic efficacy of compositions of the invention may be determined by standard pharmaceutical procedures in cell culture or using experimental animals, such as by determining the LD 50 and the ED 50 . Data obtained from the cell cultures and/or animal studies may be used to formulating a dosage range for use in a subject.
  • the dosage of any composition of the invention lies preferably within a range of circulating concentrations that include the ED 50 but which has little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the stem bark of Warburgia salutaris (Bertol. f.) Chiov. was collected in March 2016 from plants in the Botanical gardens of the University of KwaZulu-Natal, Pietermaritzburg Campus, KwaZulu -Natal, South Africa (29° 37' 30" S, 30° 24' 14" E).
  • the plant was identified by the horticulturist, and then a voucher specimen was prepared (voucher number: NU0043932) at the UKZN, PMB herbarium.
  • the stem bark was dried under the sun for five days and then crushed into a fine powder.
  • the fine stem bark powder (1 kg) was subjected to extraction using dichloromethane (1 :5w/v) for three days with periodic shaking.
  • the resulting extract was filtered through Whatman (No. 1 ) filter paper and the filtrate was concentrated under reduced pressure at 45°C.
  • Silica gel column chromatography 60x1000mm; Merck silica gel, 60: 0.063-0.200mm was used to isolate the compound from the DCM extract.
  • the column was eluted with hexane: ethyl acetate gradient and the ratio 8:2 yielded 35 fractions.
  • the fractions were grouped according to the Thin Layer Chromatography (silica gel 60 aluminium sheets, F 254 — Merck, Whitehouse Station, New Jersey, USA) profiles, into 7 combined fractions (Cfrs).
  • the spots were fixed on the TLC plates with a 20% H 2 S0 4 in methanol mixture and viewed under UV light (254nm).
  • the combined fractions were then dried under a fume-hood overnight; Cfrs 2-4 produced a white amorphous powder (NN-01 ).
  • compound NN-01 was determined using spectroscopic analysis; nuclear magnetic resolution (NMR) techniques ( 1 H, 13 C, COSY, DEPT, NOESY, HMBC and, HSQC); infrared (IR) spectra and x-ray crystallography.
  • NMR nuclear magnetic resolution
  • IR infrared
  • Compound NN-01 was confirmed by comparing the compound's spectra with reported literature (Table 1 ) and was identified as mukaadial acetate ( Figure 1 ), having the structural formula:
  • Mukaadial acetate is a novel compound and this is the first time it has been isolated from this plant and any higher plant species.
  • Figure 2 shows the single mass spectra of the compound.
  • Table 1 1 H- and 13 C-NMR chemical shifts ( ⁇ , ppm) of mukaadial acetate
  • the University of the Witwatersrand, Medical school, Antiviral Gene Therapy Unit, SA provided the HEK293 (Human embryonic kidney) cells, while the HepG2 (liver hepatocellular carcinoma) cells were obtained from the Highveld Biologicals (Pty) Ltd, Kelvin, SA.
  • the assay method was a modification of that described by Mosman (1983), it is used to calculate the cells metabolic activity, via reducing MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) into formazan salt by the enzyme succinate-tetrazolium reductase within the cell.
  • the cells were developed to semiconfluent in the flasks for tissue culture (25 cm 2 ) in Eagle's minimal essential medium containing 100 U/ml penicillin, 100 pg/ml streptomycin as well as fetal bovine serum (10%). Cells were then prepared to a density of 21 x 10 3 cells in each well, with medium (100 ⁇ ) in a 96 well plate. A 24 hours incubation (37°C; 5% C0 2 ) followed, the old medium was then removed, while fresh medium (100 ⁇ ) was added. Varying concentrations (50 ⁇ g/ml, 100 ⁇ g/ml and 150 ⁇ g/ml) of the compound in triplicates were added onto the cells and were then further incubated (48 hours; 37°C). Cells without the experimental compound were used as the positive controls, which will show viability at 100%.
  • the compound was tested against a NF54 Plasmodium falciparum strain (chloroquine sensitive); the tests were done in triplicate. Continuous in vitro cultures of asexual erythrocytes stage of the parasite were maintained following the modified method of Trager and Jensen (1976). The viability of the parasite was evaluated by looking at the parasite lactate dehydrogenase activity, which was conducted following a modified method described by Makler et al (1993). Test sample was made to a stock solution of 20mg/ml in DMSO (100%). The stock solution was preserved at -20°C. Dilutions of the stock were made on the day of experimentation. Artesunate and chloroquine were the drugs of reference in the experiment.
  • IC 50 value concentrations at which 50% of parasitic growth is inhibited.
  • Primary compound concentration for the trial was at 100 ⁇ , thereafter the compound was successively diluted to a concentration of twice as much in the medium to produce ten measures with varying concentrations; with the minimum concentration being 0.2 g/ml.
  • Chloroquine initial concentration was at 1000 ng/ml.
  • a non-linear dose-response curve fitting analysis was used to calculate the IC 50 values, with the version 4.0 Graph Pad Prism software (Graph Pad Prism, Inc: San Diego, CA, USA, 1994-2003).
  • Table 2 The in vitro anti-plasmodial and cytotoxic activity of mukaadial acetate
  • Mukaadial acetate docking into P HGXPRT binding site was conducted using AutoDock Vina. Non-polar hydrogens, Garer charges, possible torsional degrees of motion and rotatable bonds of mukaadial acetate as well as Kollman charges for all atom types were assigned in AutoDock Tools interface. The Lamarckian Genetic Algorithm was applied to generate a docked conformation. Mukaadial acetate was docked using a gridbox size of 66x64x54 A which was generated to encapsulate the active site amino acid residues of the P HGXPRT structure. Coordinates of a docked mukaadial acetate- P/HGXPRT complex were saved for further molecular analyses conducted in UCSF Chimera and LigPlot.
  • the active site of the P/HGXPRT is subdivided into four functional regions namely; the purine, the phosphate, the ribose and the magnesium ion-pyrophosphate binding site.
  • Amino acid residues predominantly forming a purine binding site include; Ile146, Asp145, Phe197, Leu 203, Lys176 and Val198.
  • the phosphate binding site comprises Tyr1 16, Asp148, Thr149, Gly150 and Thr152.
  • the magnesium-pyrophosphate binding site is primarily constructed by residues Lys77, Gly78, Arg1 12, Ser1 15, Tyr1 16, Arg210 ( Figure 3).
  • the adopted docking calculation revealed that mukaadial acetate binds in the pyrophosphate and ribose binding sites of P HGXPRT protein with a docking score of -5.9 kcal/mol.
  • the predicted binding mode of mukaadial acetate to P HGXPRT binding site and interactions with residues inhabiting the binding site are depicted in Figure 4 and Figure 5.
  • the generated intermolecular interactions between mukaadial acetate and binding site residues predominantly included hydrogen bonding and hydrophobic interactions.
  • mukaadial acetate 0 3 and Gly78 nitrogen atom were also observed, and is attributed to steric forces generated between the two atoms, mukaadial acetate also formed hydrophobic interactions with residue Leu76, Lys77, Val1 13, Ser1 15, Tyr1 16, Glu144, Asp145, Ile146, Phe197 and Asp204.

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Abstract

L'invention concerne des composés et des compositions pharmaceutiques destinés à être utilisés dans le traitement d'infections paludéennes. L'invention concerne également des utilisations et des procédés de traitement d'une infection paludéenne chez un sujet à l'aide des composés et des compositions pharmaceutiques décrits. L'invention concerne en outre des procédés de préparation des composés décrits dans la description à partir de matière végétale de Warburgia salutaris.
PCT/IB2018/050583 2017-01-31 2018-01-31 Acétate de mukaadial isolé à partir de warburgia salutaris et son utilisation comme antipaludéenne WO2018142288A1 (fr)

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GBGB1701526.4A GB201701526D0 (en) 2017-01-31 2017-01-31 Antimalarial drimane sesquiterpene compound isolated from warburgia salutaris
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Non-Patent Citations (7)

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ABRAHAM ABEBE WUBE ET AL: "Sesquiterpenes from Warburgia ugandensis and their antimycobacterial activity", PHYTOCHEMISTRY, vol. 66, no. 19, 1 October 2005 (2005-10-01), GB, pages 2309 - 2315, XP055466345, ISSN: 0031-9422, DOI: 10.1016/j.phytochem.2005.07.018 *
ALFRED MAROYI: "The genus Warburgia : A review of its traditional uses and pharmacology", PHARMACEUTICAL BIOLOGY, vol. 52, no. 3, 5 November 2013 (2013-11-05), NL, pages 378 - 391, XP055466391, ISSN: 1388-0209, DOI: 10.3109/13880209.2013.837935 *
MAKLER, MT.; RIES, JM.; WILLIAMS, JA.; BANCROFT, JE.; PIPER, RC.; GIBBINS, BL.; HINRICHS, DJ.: "Parasite lactate dehydrogenase as an assay for Plasmodium failciparum drugs sensitivity", THE AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, vol. 48, 1993, pages 739 - 741
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VIRGINIE TREYVAUD AMIGUET ET AL: "Phytochemistry and Antifungal Properties of the Newly Discovered Tree Pleodendron c ostaricense1005", JOURNAL OF NATURAL PRODUCTS., vol. 69, no. 7, 1 July 2006 (2006-07-01), US, pages 1005 - 1009, XP055466478, ISSN: 0163-3864, DOI: 10.1021/np0504863 *

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