AU2021104193A4 - A Novel Semisynthetic Derivate as a Potential Anti TB Agent - Google Patents
A Novel Semisynthetic Derivate as a Potential Anti TB Agent Download PDFInfo
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- AU2021104193A4 AU2021104193A4 AU2021104193A AU2021104193A AU2021104193A4 AU 2021104193 A4 AU2021104193 A4 AU 2021104193A4 AU 2021104193 A AU2021104193 A AU 2021104193A AU 2021104193 A AU2021104193 A AU 2021104193A AU 2021104193 A4 AU2021104193 A4 AU 2021104193A4
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- lupeol
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- 230000000694 effects Effects 0.000 claims abstract description 15
- 230000002365 anti-tubercular Effects 0.000 claims abstract description 11
- -1 nitrogen containing heterocyclic compounds Chemical class 0.000 claims abstract description 11
- 150000002656 lupeols Chemical class 0.000 claims abstract description 9
- 150000003219 pyrazolines Chemical class 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 27
- PKGKOZOYXQMJNG-UHFFFAOYSA-N lupeol Natural products CC(=C)C1CC2C(C)(CCC3C4(C)CCC5C(C)(C)C(O)CCC5(C)C4CCC23C)C1 PKGKOZOYXQMJNG-UHFFFAOYSA-N 0.000 claims description 24
- MQYXUWHLBZFQQO-QGTGJCAVSA-N lupeol Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C MQYXUWHLBZFQQO-QGTGJCAVSA-N 0.000 claims description 20
- 201000008827 tuberculosis Diseases 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 8
- 230000008018 melting Effects 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 238000004566 IR spectroscopy Methods 0.000 claims description 3
- 229930194542 Keto Natural products 0.000 claims description 3
- 238000005481 NMR spectroscopy Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 235000020071 rectified spirit Nutrition 0.000 claims description 3
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- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 3
- 150000002429 hydrazines Chemical class 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 238000004949 mass spectrometry Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims 1
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- 150000003505 terpenes Chemical class 0.000 abstract 2
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 238000011156 evaluation Methods 0.000 abstract 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
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- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 238000011282 treatment Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
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- 230000000144 pharmacologic effect Effects 0.000 description 4
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
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- 150000003648 triterpenes Chemical class 0.000 description 3
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- 241000221079 Euphorbia <genus> Species 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- RCQBVCISWCRYBO-SOYDKUNTSA-N Lupenone Natural products CC(=C)[C@@H]1CC[C@]2(C)CC[C@@H]3[C@H](CC[C@H]4[C@@]3(C)CC[C@H]5C(C)(C)C(=O)CC[C@]45C)[C@@H]12 RCQBVCISWCRYBO-SOYDKUNTSA-N 0.000 description 2
- GRBHNQFQFHLCHO-UHFFFAOYSA-N Lupenonq Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C GRBHNQFQFHLCHO-UHFFFAOYSA-N 0.000 description 2
- 229910018162 SeO2 Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
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- 238000007385 chemical modification Methods 0.000 description 2
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- 150000003222 pyridines Chemical class 0.000 description 2
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000000814 tuberculostatic agent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VCOPTHOUUNAYKQ-WBTCAYNUSA-N (3s)-3,6-diamino-n-[[(2s,5s,8e,11s,15s)-15-amino-11-[(6r)-2-amino-1,4,5,6-tetrahydropyrimidin-6-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide;(3s)-3,6-diamino-n-[[(2s,5s,8 Chemical compound N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](C)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1.N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1 VCOPTHOUUNAYKQ-WBTCAYNUSA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VKLOPQHLJNFYKK-UHFFFAOYSA-N 3-dodecylsulfanylpropanoic acid Chemical compound CCCCCCCCCCCCSCCC(O)=O VKLOPQHLJNFYKK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 101000578205 Arabidopsis thaliana Non-specific lipid-transfer protein 10 Proteins 0.000 description 1
- 108010065839 Capreomycin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 235000012043 Euphorbia helioscopia Nutrition 0.000 description 1
- 241001553772 Euphorbia radians Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 229910003556 H2 SO4 Inorganic materials 0.000 description 1
- 208000032420 Latent Infection Diseases 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 1
- 108700035964 Mycobacterium tuberculosis HsaD Proteins 0.000 description 1
- KGTSLTYUUFWZNW-PPJQWWMSSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(E)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate pyridine-4-carbohydrazide Chemical compound NNC(=O)c1ccncc1.CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c(O)c(\C=N\N4CCN(C)CC4)c(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C KGTSLTYUUFWZNW-PPJQWWMSSA-N 0.000 description 1
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 230000000398 anti-amebic effect Effects 0.000 description 1
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- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001355 anti-mycobacterial effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
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- 239000008280 blood Substances 0.000 description 1
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- 239000002034 butanolic fraction Substances 0.000 description 1
- 229960004602 capreomycin Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000002036 chloroform fraction Substances 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000036984 extensively drug-resistant tuberculosis Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002178 gastroprotective effect Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002044 hexane fraction Substances 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 125000003177 lupeol group Chemical group 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pulmonology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
In the present invention structural modification of terpenoids are performed and evaluation of
biological activities of natural terpenoids and their semisynthetic derivatives is evaluated. We
decided to perform some structural modifications in the natural diterpenes, various nitrogen
containing heterocyclic compounds such as pyrazolines, pyridazinones and pyrrolones have been
studied extensively for the development of pharmaceutically important antimicrobial agents.The
invention discloses novel lupeol derivatives, having anti tubercular activity, which can be, a
potential agent for the therapy of TB.
Description
Title of Invention
A Novel Semisynthetic Derivate as a Potential Anti TB Agent
The persistence of TB despite constant human endeavors has led to a renewed interest in the research and development of new effective drugs and treatment regimens. To develop a novel drug candidate, we set out to investigate the ability of lupeol and its pyrazoline and pyridine derivatives to inhibit the growth of M. tuberculosis in vitro. There was phenyl keto substituted derivative of lupeol was synthesized by the action of aromatic carbonyl compound and rectified spirit on lupeol aldehyde in the presence of alkali. The compound on further changes leads to various compounds which show activity against tuberculosis.
Pyrazoline derivatives were found to be the most potent compound of the series, but pyridine derivative also showed significant activity, thus, increasing its prospects for further development.
Background of Invention
Tuberculosis (TB) remains one of the world's deadliest communicable diseases. In 2019, an estimated 10 million people fell in TB worldwide, and 1.4 million died from the disease. Problematic issues in TB treatment include the increased incidence of multidrug-resistant TB (MDR-TB), which is a form of TB caused by bacteria that do not respond to isoniazid and rifampicin. Extensively drug-resistant TB (XDR-TB) is a more serious form of MDR-TB caused by bacteria that do not respond to the most effective second-line anti-TB drugs, often leaving patients without any further treatment options. The increasing emergence of drug resistance highlights the need to develop novel chemical entity of TB drugs. It is a fatal disease and one of the leading causes of the death all over the world especially in the developing countries like India. It is also believed to be the leading cause of death among HIV positive peoples. Present anti-tubercular drugs are quite effective in the treatment of TB but resistance to these drugs by M. tuberculosis strains is on the rise which is a growing concern among scientific community worldwide. New antitubercular compounds/structures are urgently needed in the present situation because very few agents belonging to first line (e.g. rifabutin) or second line drugs (e.g. capreomycin, levofloxacin) have become available for the treatment of this disease.. To solve these issues, there is an urgent need to develop novel alternative, safe and potent drugs with a broader spectrum of antimicrobial activity
. Natural products can be found in a wide plethora of living species, with many of them harnessing the potential to possess biological and therapeutic activity of high importance. The ever increasing demand for new drug molecules that act against current or new illnesses has led to greater interest in research conducted on secondary plant metabolites .The isolation of a new compound from its natural source and testing its bioactivity is one of the ways, but we wish to focus our research on another alternative; isolation of an already known biologically active compound and modifying key chemical moieties within the molecule to investigate any changes in its bioactivity. These chemical modifications could be performed through biotransformation, utilizing enzymes, or chemically, with the hope of using cheap and commercially available reagents. triiterpenes are a large class of natural compounds that exhibit a range of interesting biological activities such as antimicrobial anti-inflammatory gastroprotective , anti-spasmodic ,among others.
These nitrogen containing compounds have played an important role in drug discovery owing to their diverse pharmacological actions. Pyrazolines are even more special due to their marked physiological and pharmacological activity and distinct functions. Pyrazoline derivatives were reported to possess numerous prominent pharmacological activities; antimicrobial-antibacterial and antifungal, antiamoebic, anti-TB , anti-HIV, anticancer, antidepressant and anticonvulsant. Euphorbia diterpenes are of interest to chemists and biochemists regarding drug discovery from natural products due to their diverse therapeutic applications as well as their great structural diversity. Other chemical constituents such as triterpenoids have also been reported to possess various pharmacological properties, thus supporting the traditional uses of the Euphorbia species. These triterpenoids can provide potential leads that can be developed into pharmaceutical compounds for a wide range of medicinal applications. However, there are scattered scientific reports about the anticancer activities of these constituents.
Detailed Description Of The Invention
We invent herein the synthesis of six lupeol derivatives, three of which are new, generated through known organic chemistry reactions that allowed structural modification of the existing natural products lupeol and lupenone . The new compounds were fully characterized using high resolution mass spectrometry, infrared spectroscopy, lH. The present invention relates to new antitubercular drugs, more particularly to new derivatives of lupeol compounds. The most significant findings described in this patent for chemically diverse compounds as prospective anti-TB medications. Main points of emphasis include chemical classification, in vitro and in vivo activity
Salkowski Test - Few crystals of L-1 was dissolved in chloroform separately and a few drops of conc. H2 SO4 were added to the solution. The solutions turned blood red color.
Melting point is 214-216 °C.
Mass of Lupeol (L-1) showed molecular ion peak at m/z 426 (M+1) in its El mass spectrum with various other fragment peaks such 411, 218, 207, 189, 135, 109 & 95
IR spectrum showed hydroxyl group (3302.6 cm-1), Vinyldiene group 3068.1, 1636.8, 880 cm-) respectively.
In IH-NMR spectrum a pair of two singlets at 6 4.68 and 4.56 along with a singlet for 3 protons
at 61.68 is indicating for the presence of isoprenyl side chain present in the molecule. Six
singlets for 3 protons each and a muliplet for one proton at 6 3.23 is as according to the six methyl groups and H-3 proton connected with OH, present in Lupeol.
Chemical modification at C-30
Allylic oxidation of lupeol with SeO2 in moist dioxane under refluxing condition gave the aldehy de
SeO2 in moist dioxane H refluxing 12 hour H
HO - HO e - H S H
Traditional medicine is still the primary form of treating diseases of majority of people in developing countries including India; even among those to whom western medicine is available, the number of people using one form or another of complementary of alternative medicine is rapidly increasing worldwide
The present invention is concerned with novel lupeol and Lupenone derivatives of reduced toxicity and of correspondingly enhanced utility as antitubercular, and to the preparation there of.
Our invention is to explore and develop the novel molecules with improved potential for treating tuberculosis. The objectives of the present invention is to identify the (lupeol and lupenone) compounds and their derivatives present in the whole plant of Euphorbiatirucalliand to determine the antitubercular activity of their enriched fractions and isolated compounds. There are several reasons that justify the need to search for new drugs for anti- tubercular action, e.g. Improvement of current treatment by shortening its duration, to get efficient treatment for MDR TB and to eradicate the latent infection. So, the development of new drugs for shortening the duration of the treatment and to fight against multi drug resistant tuberculosis strains is urgent.
Embodiment
General experimental implementation:
IR spectra were recorded on PerkinElmer FT-IR Spectrometer
Electrospray Ionisation- MS were recorded on WATERS-Q-TOF Premier-HAB213 mass spectrometer.
Chromatographic separation was performed by using columns of various lengths and diameter, over silica gel (60-120 mesh) from Qualikems laboratory reagent (India).
Melting points in electrical heated melting point apparatus of Jindal, S.M. Scientific Instruments Pvt. Ltd., New Delhi.
IH-NMR spectrums were recorded on JEOL, JNM-ECS 400 MHz using Chloroform-D (CDCl 3
as solvent )
Experimental Procedure
1. Isolated the lupeol from the leaves of eurphorbiatiriccali. The green parts of Euphorbia Helioscopia were collected, and air-dried (500 g) were extracted with MeOH in soxhlet. methanoic extracts were extracted once with C6H14 Then extracted with CHCl3 and concentrated under vacuum to give 10.5 g. about 4gr were loaded on chromatographic column (2 cm diameter, 120 cm. long) over silica gel (230 - 400 mesh, ASTM). The column has been eluted successively with: nhexane (200 ml.), and: and n-hexane: ethyl acetate (10: 90, 200 ml.). Lupeol: was obtained from the latter fraction n-hexane: ethyl acetate (10: 90, 200 ml.), purified on preparative TLC by using mixture of n-hexane/ EtOAc (30: 70), to give (50 mg, the Rf= 0.45), it is a white powder solid, its melting point 212
2. Their purification was done by using column chromatography.
3. All the reactions were monitored by TLC using stationary phase as silica gel G from Merck Limited (India) and mobile phase as taking different solvent mixtures as n-hexane and EtOAc; Chloroform-EtOAc, etc. TLC Plates were visualized by iodine vapours or by heating the plates in oven (110°C). The plates were also visualised in UV light Chamber.
4. Melting points of compounds were measured in open capillaries in electrical heated melting point apparatus of Jindal, S.M. Scientific Instruments Pvt. Ltd., New Delhi.
5. Synthesize derivatives of lupeol under the schemes.
6. IR spectra were recorded on PerkinElmer FT-IR Spectrometer Spectrum Two and values are expressed in wave numbers (cm-1).
7. 1H-NMR spectrums were recorded on JEOL, JNM-ECS 400 MHz using Chloroform-D (CDC 3) as solvent. Tetramethylsilane (TMS, 60.00 ppm) was used as internal standard in 1H NMR. Chemical shifts are expressed in descending order (from down field to upfield signals). 1H -NMR data is given in the manner for e.g. 61.75(t, 2H, J= 6. 7Hz, H) where alphabets s, d, t and m displays multiplicity of signals as singlet, doublet, triplet and multiplet respectively, secondaly the number of protons for particular signal, next is coupling constant for splitting, and finally the protons or carbon for which signal is assigned.
8. Electrospray Ionisation- MS were recorded on WATERS-Q-TOF Premier-HAB213 mass spectrometer.
Bioassay-guided fractionation of the EtOAc-soluble fraction resulted in the isolation of two lupane-type triterpenes, lupenone and lupeol as the active principles. Both the compounds isolated showed selective inhibitory activity against
n-Hexane fraction (21.308 g) when subjected to silica gel column chromatography eluted successively with stepwise gradients of n-hexane/ethyl acetate and chloroform/methanol afforded four main fractions (I-IV)
The n-butanol fraction (36.7 g) was subjected to column chromatography on silica gel and eluted with a gradient system of chloroform and chloroform/methanol leading to three main fractions I, II and III. The compounds were isolated from chloroform fraction through column chromatography using gradient elution technique. The progress of separation was monitored by TLC (silica gel G 60 F254 plates, Merck).
Fractions eluted with n-hexane and EtOAc (8:2) resulted an amorphous yellowish white residue which after crystallization with methanol provides colorless crystalline substance termed as Lupeol (L-1)
Two new series of pyrazolines were synthesized starting from lupeol evaluated for their antibacterial, antifungal and antitubercular activities. The results of antitubercular activity of the synthesized compounds against Mycobacterium tuberculosis H 37Rv by the agar microdilution method are quite promising. The antitubercular activity of compounds 4c, 4d & 4g (MIC 3.12 pg/mL) was found to be superior than that of the reference drug rifampicinwhich showed MIC equal to 6.25 pg/mL
Lupeol (1 gm, 2.35 mmol) was refluxed with selenium dioxide in dioxane with 3-4 drops of distilled water, for 8 hr. After consumption of all of lupeol, reaction mixture was passed through filter aid and treated with 2.5% aq. KOH, and further extracted with chloroform. Chloroform layer was washed with distilled water till it became neutral, it was dried using anhydrous sodium sulphate, and was evaporated in vacuum. This reaction mixture was chromatographed over column, packed in hexane, and was eluted with hexane, 5, 10, and 20 % ethyl acetate and hexane elution with 20 % ethyl acetate and hexane gave the required product lupeol aldehyde.
Various modifications have been done in the isopropenyl side chain of the lupeol and third position of hydroxyl gp
There was phenyl keto substituted derivative of lupeol was synthesized by the action of aromatic carbonyl compound and rectified spirit on lupeol aldehyde in the presence of alkali. The compound on further changes leads to various compounds which show activity against tuberculosis.
0 01\\ C C HO H H 0-hydroxyacetophenone
ethanol/ thionyl chloride
Second steps of this phenyl keto group crafted on lupeol aldehyde was converted to pyrazoline analogues. This was done by reaction of compound with hydrazine derivatives in the solvent ethanol. These reaction lead to the formation of compounds and. Formation of different compounds were confirmed by melting point, I.R. spectroscopy, NMR spectroscopy and MASS spectrometry.
0 N'N'R
H C HO -HO H HH RNHNH 2 HO_'
R= H; R= C 6 H 5
Tuberculosis has been a major health problem for developing countries including India. Due to increase in MDR and XDR strains of M. tuberculosis, there is an urgent need of finding newer anti-mycobacterial agents to combat this problem.Natural products and/or their semi-synthetic derivatives can lead to novel antimycobacterial drugs and may have important role in the chemotherapy of tuberculosis. Among the lupeol derivatives tested few have shown MIC at 8.50 pg/ml, 10 pg/ml, while other showed >25 pg/ml. The most active compound 4a, 4b. This clearly demonstrate that pyrazoline moiety in lupeol increases the activity. It is thus concluded that lupeol skeleton deserve further investigation for the development of more potent and nontoxic new agents for therapeutic use.
In vivo Activity of Derivatives as compared with Rifampicin
Sr. no. Compound no. Antitubercular activity against rifampicin
1 lupeol 64 ( g/ ml)
2 LTa >50 ( g/ ml)
3 LTb >50 ( g/ ml)
4 LT 2 >25.0 ([g/ ml)
LT 8.50([tg/ ml)
6 LTP 10 ( g/ ml)
7 LTPA >25.0 ( g/ ml)
Claims (1)
- ClaimsClaim 1We claim herein a lupeol derivatives, having anti tubercular activity, which can be, a potential agent for the therapy of TB.Claim 2The antitubercular activity of potential agent claimed in 1 are the compounds 4c, 4d & 4g (MIC 3.12 tg/mL) whichwere found to be superior than that of the reference drug rifampicin which showed MIC equal to 6.25 tg/mL.Claim 3We also claim the process to obtain the Two new series of pyrazolines starting from lupeolThere was phenyl keto substituted derivative of lupeol was synthesized by the action of aromatic carbonyl compound and rectified spirit on lupeol aldehyde in the presence of alkali. The compound on further changes leads to various compounds which show activity against tuberculosis.0 0" C C HO H H 0-hydroxyacetophenoneethanol/ thionyl chlordeHO 'N/ HOSecond steps of this phenyl keto group crafted on lupeol aldehyde was converted to pyrazoline analogues. This was done by reaction of compound with hydrazine derivatives in the solvent ethanol. These reaction lead to the formation of compounds and. Formation of different compounds were confirmed by melting point, I.R. spectroscopy, NMR spectroscopy and MASS spectrometry.0 N'N'RH C HO - HO CH RNHNH 2R= H; R= C 6H5
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