WO2012057599A1 - Anti-mycobacterial agents - Google Patents

Anti-mycobacterial agents Download PDF

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Publication number
WO2012057599A1
WO2012057599A1 PCT/MY2010/000222 MY2010000222W WO2012057599A1 WO 2012057599 A1 WO2012057599 A1 WO 2012057599A1 MY 2010000222 W MY2010000222 W MY 2010000222W WO 2012057599 A1 WO2012057599 A1 WO 2012057599A1
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synthesizing
acid
bases
carboxylic acid
synthesis
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PCT/MY2010/000222
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French (fr)
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Rusli Ismail
Mohamed Ashraf Ali
Soo Choon Tan
Suresh Pandian
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Universiti Sains Malaysia
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Publication of WO2012057599A1 publication Critical patent/WO2012057599A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention provides compounds with anti-mycobacterial properties, in particular anti-tuberculosis properties.
  • Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis, a relatively slow-growing, aerobic, acid-fast bacillus.
  • Tuberculosis is a pulmonary disease, but disseminated and extra-pulmonary manifestations may also occur, especially in immuno-compromised persons.
  • Tuberculosis is transmitted person to person and is usually contracted by inhalation of M. tuberculosis droplet nuclei generated by an infectious person.
  • Tuberculosis has infected about one-third of the world's 5 billion people. In 1995, from this pool of infected people, about 3.3 million new active smear-positive cases were reported, along with an estimated 4 million other cases, which led to about 2-3 million deaths.
  • MDR-TB multi drug-resistant tuberculosis
  • MDR-TB The major barrier to MDR-TB treatment is the high cost of second-line drugs which are at least 300 times more expensive than first-line drugs based on Green Light Committee (GLC) prices and between 1000-3000 times more expensive when market prices are used. Globally, 400,000 new cases of MDR-TB occur each year. Currently, drug-sensitive TB can be treated with first-line drugs for 6 to 9 months, and 95% of patients can be cured with these regimens.
  • GLC Green Light Committee
  • Tuberculosis is an important cause of death in the world. Available treatments are costly, and they can cause other health problems, and are of varying effectiveness. For such reason the search for products particularly on those having anti-mycobacterial properties are essential as a sustainable alternative treatment.
  • the invention relates to novel compounds which act has anti-mycobacterial properties, in particular anti-tuberculosis.
  • the novel molecules are of substituted Mannich base and Schiff base which contains anti-tuberculosis properties.
  • the invention presents the method for preparation of compounds AM1 , AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM1 1 , AM 2, AM13, AM14 and AM15, wherein the steps includes: (a) synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid; (b) synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a); (c) synthesizing Schiff bases using the acid hydrazide derivative from step (b); and (d) synthesizing Mannich bases using the Schiff bases from step (c).
  • the present invention presents the method for preparation of compounds AS1 , AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS11 , AS12, AS13 and ASM, wherein the steps includes: (a) synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid; (b) synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a);and (c) synthesizing Mannich bases using the Schiff bases from step (b).
  • the present invention provides compounds of AM1 , AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM1 1 , AM12, AM13, AM14, AM15, AS1 , AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS1 1 , AS12, AS13 and ASM.
  • These compound present anti- mycobacterial properties, particularly in the use as an anti-tuberculosis agent in a therapeutic amount.
  • this specification will describe the present invention according to the preferred embodiments of the present invention. However, it is to be understood that limiting the description to the preferred embodiments of the invention is merely to facilitate discussion of the present invention and it is envisioned that those skilled in the art may devise various modifications and equivalents without departing from the scope of the appended claims.
  • the novel Mannich base and Schiff base were synthesized and in the preparation of these bases, acid hydrazide and aromatic ester were used as raw materials. These raw materials were used in the preparation of the novel compounds.
  • the aromatic ester derivative was prepared by the esterification of 0.4 mol aromatic carboxylic acid with 156 ml of 4 mol absolute alcohol in presence of 68 ml concentrated sulfuric acid (Con.H 2 S0 4 ). This provides an acidic medium and the mixture was refluxed for 4 hours. The product obtained was cooled and alkalinized using strong ammonia. The solution was divided into 25 ml portions and was extracted with ester. Anhydrous magnesium sulphate was used as the drying agent. The extracted liquid was evaporated and ether was removed by flash distillation.
  • Table 1 The structural compounds of AM1. AM2. AM3. AM4. AM5. AM6. AM7. AM8. AM9. AM10. A 11. AM12. AM13. A 14 and AM15.
  • Table 2 The structural compounds of AS1. AS2. AS3. AS4. AS5. AS6. AS7. AS8. AS9. AS10. AS1 1 . AS12. AS13 and ASM
  • the VERO cell cytotoxicity assay is done in parallel with the TB Dose Response assay. After 72 hours exposure, viability is assessed using Promega's Cell Titer Glo Luminescent Cell Viability Assay, a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present. Cytotoxicity is determined from the dose-response curve as the CC 50 using a curve fitting program. Ultimately, the CC 5 o is divided by the IC90 to calculate an SI (Selectivity Index) value. SI values of ⁇ 10 are considered for further testing.
  • SI Selectivity Index

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to novel compounds which act has anti-mycobacterial properties, in particular anti-tuberculosis. The novel molecules of AM1, AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM11, AM12, AM13, AM14, AM15, AS1, AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS11, AS12, AS13 and AS14 are of substituted Mannich base and Schiff base which contains anti-tuberculosis properties. The invention presents the method for preparation of compounds AM1, AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM11, AM12, AM13, AM14 and AM15, wherein the steps includes: (a) s synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid; (b) synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a); (c) synthesizing Schiff bases using the acid hydrazide derivative from step (b); and (d) synthesizing Mannich bases using the Schiff bases from step (c). The present invention presents the method for preparation of compounds AS1, AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS11, AS12, AS13 and AS14, wherein the steps includes: (a) synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid; (b) synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a);and (c) synthesizing Mannich bases using the Schiff bases from step (b).

Description

Anti-Mycobacterial Agents
Field of Invention
The invention provides compounds with anti-mycobacterial properties, in particular anti-tuberculosis properties.
Background of Invention
Tuberculosis (TB) is a bacterial disease caused by Mycobacterium tuberculosis, a relatively slow-growing, aerobic, acid-fast bacillus. Classically, tuberculosis is a pulmonary disease, but disseminated and extra-pulmonary manifestations may also occur, especially in immuno-compromised persons. Tuberculosis is transmitted person to person and is usually contracted by inhalation of M. tuberculosis droplet nuclei generated by an infectious person.
Tuberculosis (TB) has infected about one-third of the world's 5 billion people. In 1995, from this pool of infected people, about 3.3 million new active smear-positive cases were reported, along with an estimated 4 million other cases, which led to about 2-3 million deaths.
Currently TB a silent threat to industrialized people, the World Economic Forum (WEF) report found that nearly one third of over 1 1 ,000 business leaders from more than 130 developed and developing countries said they expected TB to affect their business in the next five years.
One out of every 10 said they expected the effect to be serious, particularly because three- quarters of those who fall sick or die of TB are people of prime working age, between 15 and
54 years. TB claims millions of lives every year with 1.6 million people dying of the disease in
2006, 98% of them developing countries.
Although the immediate tuberculosis threat is chiefly to people infected with the human immunodeficiency virus, which causes AIDS, participants at a meeting here expressed alarm that the spread of tuberculosis from such patients also threatened the health workers who care for them and ultimately healthy people who are not infected with human immunodeficiency virus (H.I. V.). Currently available regimens to treat multi drug-resistant tuberculosis (MDR-TB) are 4 to 10 times more likely to fail than standard therapy for patients with drug-susceptible organisms. After the introduction of Rifampicin, no worthwhile anti-tuberculosis drug with new mechanism(s) of action has been developed in over forty years. Along with HIV/AIDS, MDR- TB is the most important threat to TB control. Countries with a high MDR-TB prevalence generally have a history of poor TB control.
The major barrier to MDR-TB treatment is the high cost of second-line drugs which are at least 300 times more expensive than first-line drugs based on Green Light Committee (GLC) prices and between 1000-3000 times more expensive when market prices are used. Globally, 400,000 new cases of MDR-TB occur each year. Currently, drug-sensitive TB can be treated with first-line drugs for 6 to 9 months, and 95% of patients can be cured with these regimens.
Tuberculosis is an important cause of death in the world. Available treatments are costly, and they can cause other health problems, and are of varying effectiveness. For such reason the search for products particularly on those having anti-mycobacterial properties are essential as a sustainable alternative treatment.
Summary of Invention
The invention relates to novel compounds which act has anti-mycobacterial properties, in particular anti-tuberculosis. The novel molecules are of substituted Mannich base and Schiff base which contains anti-tuberculosis properties. The invention presents the method for preparation of compounds AM1 , AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM1 1 , AM 2, AM13, AM14 and AM15, wherein the steps includes: (a) synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid; (b) synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a); (c) synthesizing Schiff bases using the acid hydrazide derivative from step (b); and (d) synthesizing Mannich bases using the Schiff bases from step (c). The present invention presents the method for preparation of compounds AS1 , AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS11 , AS12, AS13 and ASM, wherein the steps includes: (a) synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid; (b) synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a);and (c) synthesizing Mannich bases using the Schiff bases from step (b).
Description of the Preferred Embodiments
The present invention provides compounds of AM1 , AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM1 1 , AM12, AM13, AM14, AM15, AS1 , AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS1 1 , AS12, AS13 and ASM. These compound present anti- mycobacterial properties, particularly in the use as an anti-tuberculosis agent in a therapeutic amount. Hereinafter, this specification will describe the present invention according to the preferred embodiments of the present invention. However, it is to be understood that limiting the description to the preferred embodiments of the invention is merely to facilitate discussion of the present invention and it is envisioned that those skilled in the art may devise various modifications and equivalents without departing from the scope of the appended claims.
The novel Mannich base and Schiff base were synthesized and in the preparation of these bases, acid hydrazide and aromatic ester were used as raw materials. These raw materials were used in the preparation of the novel compounds.
Synthesis of aromatic ester derivative
The aromatic ester derivative was prepared by the esterification of 0.4 mol aromatic carboxylic acid with 156 ml of 4 mol absolute alcohol in presence of 68 ml concentrated sulfuric acid (Con.H2S04 ). This provides an acidic medium and the mixture was refluxed for 4 hours. The product obtained was cooled and alkalinized using strong ammonia. The solution was divided into 25 ml portions and was extracted with ester. Anhydrous magnesium sulphate was used as the drying agent. The extracted liquid was evaporated and ether was removed by flash distillation.
Synthesis of acid hvdrazide derivatives
5.5 ml of 0.1 mol hydrazine hydrate was being condensed with 15.1 g of 0.1 mol aromatic ester in presence of 50 ml of alcohol. The reaction mixture was boiled on water bath for 4 hours. The reaction mixture was then added to cold water and the product mixture obtained was filtered. The product was recrystallized using ethanol after filtration.
Synthesis of compounds AM1. AM2. AM3. AM4. AM5. AM6. AM7. AM8, AM9. AM10. AM1 1. AM12. AM13. AM14 and AM15
Table 1 : The structural compounds of AM1. AM2. AM3. AM4. AM5. AM6. AM7. AM8. AM9. AM10. A 11. AM12. AM13. A 14 and AM15.
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
oxo-1 ,4-dihydroquinoline-3-carboxylic add
Figure imgf000009_0001
oxo-1 ,4-dihydroquinoline-3-carboxylic acid
Figure imgf000010_0001
dihydroquinoline-3-carboxylic acid
Figure imgf000011_0001
dihydroquinoline-3-carboxylic acid
Figure imgf000012_0001
Synthesis of Schiff base derivatives AM1 , AM2, AM3, AM4 and AM5 (I.M)
Isonicotinohydrazide was dissolved completely in 25 ml of glacial acetic acid and with 0.1 mol of appropriate isatin. The mixture was refluxed for 8 to 13 hours. The refluxed mixture was added to cold water and the residue obtained was filtered. The filtered residue was recrystallized using ethanol. Synthesis of Mannich base derivatives AM1 , AM2. AM3, AM4 and AM5
0.1 mol of the Schiff base derivatives AM,_5 (I.M) in 25 ml of ethanol was added to 0.1 mole of paraformaldehyde and 0.1 mol of 1 -cyclopropyl-7-[(1 S,6S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6- fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid or moxifloxacin. The mixture was stirred for 10 to 20 hours in an ice bath. The mixture was then subjected to evaporation using a solvent and the residue obtained was recrystallized from ethanol.
Synthesis of Schiff base derivatives AM6, AM7. AM8. AM9 and AM10 (I.M)
2-amino-9-((2-hydroxyethoxy)methyl)-1 H-purin-6(9H)-one was dissolved completely in 25 ml of glacial acetic acid and added to 0.1 mol of appropriate isatin. The mixture was refluxed for 8 to 13 hours. The mixture was then added to cold water and the residue obtained was filtered. The filtered residue was recrystallized using ethanol.
Synthesis of Mannich base derivatives AM6, AM7. AM8, AM9 and AM10
0.1 mol of the schiff base derivatives AM6. 0(I.M) in 25ml of ethanol was added into 0.1 mol of paraformaldehyde and 0.1 mol of 1 -cyclopropyl-7-[(1 S,6S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6- fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid or moxifloxacin. The mixture was stirred for 10 to 20 hours in an ice bath. The mixture was then subjected to evaporation using a solvent and the residue obtained was recrystallized from ethanol.
Synthesis of Schiff base derivatives AM11. AM12. AM13. AM14 and AM15 (I.M)
4-amino-1 -[(2R,5S)-2-(hydroxymethyl)-1 ,3-oxathiolan-5-yl]-1 ,2-dihydropyrimidin-2-one dissolve completely in 25 ml of glacial acetic acid and added into 0.1 mol of appropriate isatin. The mixture was refluxed for 8 to13 hours. The refluxed mixture was then added to cold water. The obtained residue was filtered and recrystallized from ethanol. Synthesis of Mannich base derivatives AM1 1. AM12, AM13. AM14 and AM15
0.1 mol of the schiff base derivatives AM .^l.M) in 25ml of ethanol was added into 0.1 mol of paraformaldehyde and 0.1 mol of 1-cyclopropyl-7-[(1 S,6S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6- fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid or moxifloxacin. The mixture was then stirred for 10 to 20 hours in an ice bath. The mixture was then subjected to evaporation using a solvent and the residue obtained was recrystallized from ethanol.
Synthesis of compounds AS1. AS2. AS3. AS4. AS5. AS6. AS7. AS8. AS9. AS10. AS11. AS12. AS 3 and AS14
Table 2: The structural compounds of AS1. AS2. AS3. AS4. AS5. AS6. AS7. AS8. AS9. AS10. AS1 1 . AS12. AS13 and ASM
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000018_0001
Figure imgf000019_0001
Synthesis of Mannich base derivatives AS1 , AS2. AS3. AS4, AS5, AS6 and AS7
0.1 mol of trimethoxy benzaldehyde was added to the solution of 0.1 mol of acid appropriate acid hydrazide in 20 ml of methanol. The mixture was stirred for 1 to 2 hours in an ice bath. The cold solution of 1.0 mol of 1 -cyclopropyl-7-[(1 S,6S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6- fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid or moxifloxacin was added drop wise to the mixture while stirring. The resulting mixture was refluxed for 5 to 8 hours on a steam bath. The refluxed mixture was then subjected to evaporation using a solvent and the residue obtained was recrystallized from ethanol.
Synthesis of Mannich base derivatives AS8. AS9. AS 0. AS 1. AS12. AS13 and ASM
0.1 mol of 2,6-dichloro benzaldehyde was added into 0.1 mol of acid appropriate acid hydrazide in 20 ml of methanol. The mixture was stirred for 1 to 2 hours in an ice bath. 0.1 mol of cold 1 -cyclopropyl-6-f luoro-8-methoxy-7-(3-methylpiperazin-1 -yl)-4-oxo-quinoline-3- carboxylic acid or gatifloxacin solution was added drop wise into the mixture while stirring. The resulting mixture was refluxed for 5 to 8 hours on a steam bath. The refluxed mixture was then subjected to evaporation using a solvent and the residue obtained was recrystallized from ethanol. Primary Screen (Dose Response): Determination of a 90% Inhibitory Concentration (ICon) The initial screen is conducted against Mycobacterium tuberculosis H37Rv (ATCC 27294) in BACTEC 12B medium using the Microplate Alamar Blue Assay (MABA). Compounds are tested in ten 2-fold dilutions, typically from 100 g/mL to 0.19 g/mL The IC90 is defined as the concentration effecting a reduction in fluorescence of 90% relative to controls. This value is determined from the dose-response curve using a curve-fitting program.
Table 1 : Antimycobacterial and recent dose-response activity of novel mannich base and
Schiff base
Figure imgf000020_0001
416730 AM14 MABA H37Rv 3.200 2.891 Active
416724 AM8 MABA H37Rv 4.681 3.139 Active
416719 AM3 MABA H37Rv 4.911 3.754 Active
416723 AM7 MABA H37Rv 5.186 3.879 Active
416726 AM10 MABA H37Rv 5.643 4.696 Active
416725 AM9 MABA H37Rv 6.217 5.1 14 Active
416731 AM15 MABA H37Rv 9.31 1 7.284 Active
416727 AM11 MABA H37Rv 11.542 8.953 Weakly Active
416720 AM4 MABA H37Rv 15.156 10.893 Weakly Active
415353 AS7 MABA H37Rv 15.838 10.477 Weakly Active
415358 AS12 MABA H37Rv 22.377 15.528 Weakly Active
415352 AS6 MABA H37Rv 25.87 23.163 Weakly Active
415351 AS5 MABA H37Rv 37.914 25.388 Weakly Active
415354 AS8 MABA H37Rv >100.000 >100.000 Inactive
Secondary Screen: Determination of Mammalian Cell Cytotoxicity (CCRn)
The VERO cell cytotoxicity assay is done in parallel with the TB Dose Response assay. After 72 hours exposure, viability is assessed using Promega's Cell Titer Glo Luminescent Cell Viability Assay, a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present. Cytotoxicity is determined from the dose-response curve as the CC50 using a curve fitting program. Ultimately, the CC5o is divided by the IC90 to calculate an SI (Selectivity Index) value. SI values of≥ 10 are considered for further testing.
Table 2: Cell cytotoxicity activity of novel mannich base and Schiff base
Figure imgf000022_0001

Claims

Claims
1. A method of synthesizing an anti-mycobacterial agent for treating tuberculosis comprising a therapeutic amount of compound referred as AM1 , AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM11 , AM12, AM13, AM14 and AM15 wherein the steps includes:
a. synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid;
b. synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a);
c. synthesizing Schiff bases using the acid hydrazide derivative from step (b); and d. synthesizing Mannich bases using the Schiff bases from step (c).
2. The method as claimed in claim 1 wherein isatin is used in the synthesis of Schiff bases.
3. The method as claimed in claim 1 wherein the acid hydrazide is of isonicotinohydrazide, 2-amino-9-((2-hydroxyethoxy)methyl)-1 H-purin-6(9H)-one and 4- amino-1 -[(2R,5S)-2-(hydroxymethyl)-1 ,3-oxathiolan-5-yl]-1 ,2-dihydropyrimidin-2-one dissolved in glacial acetic acid.
4. The method as claimed in claim 1 wherein 1 -cyclopropyl-7-[(1 S,6S)-2,8- diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid is used in the synthesis of Mannich bases. 5. A use of compounds AM1 , AM2, AM3, AM4, AM5, AM6, AM7, AM8, A 9, AM10,
AM1 1 , AM12, AM13, AM14, AM15 or a combination thereof in a therapeutic amount for the manufacture of a medicament for treating tuberculosis.
The use as claimed in claim 5 wherein the compounds are of substituted Schiff bases and Mannich bases.
The use as claimed in claim 6 wherein the Schiff bases are synthesized using an acid hydrazide derivative in glacial acetic acid and isatin.
8. The use as claimed in claim 6 wherein the Mannich bases are synthesized using Schiff bases, paraformaldehyde and 1 -cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo[4.3.0]non-8- yl]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid.
9. The use as claimed in claim 7 wherein the acid hydrazide used is selected from one or more from the group of isonicotinohydrazide, 2-amino-9-((2-hydroxyethoxy)methyl)- 1 H-purin-6(9H)-one and 4-amino-1 -[(2R,5S)-2-(hydroxymethyl)-1 ,3-oxathiolan-5-yl]- 1 ,2-dihydropyrimidin-2-one dissolved in glacial acetic acid.
10. A method of synthesizing an anti-mycobacterial agent for treating tuberculosis comprising a therapeutic amount of the compound referred as AS1 , AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS1 1 , AS12, AS13 and AS14 wherein the steps includes:
a. synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid;
b. synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a); and
c. synthesizing Mannich bases using the acid hydrazide derivative from step (c).
1 1. The method as claimed in claim 10 wherein trimethoxy benzaldehyde and 2,6-dichloro benzaldehyde are used in the synthesis of the Mannich bases.
12. The method as claimed in claim 10 where in 1 -cyclopropyl-7-[(1 S,6S)-2,8- diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid and 1 -cyclopropyl-6-f luoro- 8-methoxy-7-(3-methylpiperazin-1 -yl)- 4-oxo-quinoline-3- carboxylic acid are used in the synthesis of Mannich.
13. A use of compounds AS1 , AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS1 1 , AS12, AS13 or ASH or a combination thereof in the manufacture of a medicament for treating tuberculosis.
14. The use as claimed in claim 13 wherein the compounds are of substituted Mannich bases.
15. The use as claimed in claim 14 wherein trimethoxy benzaldehyde and 2,6-dichloro benzaldehyde are used in the synthesis of the Mannich bases.
16. The use as claimed in claim 14 wherein 1 -cyclopropyl-7-[(1 S,6S)-2,8- diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid and 1 -cyclopropyl-6-fluoro- 8-methoxy-7-(3-methylpiperazin-1 -yl)- 4-oxo-quinoline-3- carboxylic acid are used in the synthesis of Mannich bases.
17. A use of AM1 , AM2, AM3, AM4, AM5, AM6, AM7, AM8, AM9, AM10, AM11 , AM12, AM13, AM14, AM15, AS1 , AS2, AS3, AS4, AS5, AS6, AS7, AS8, AS9, AS10, AS11 , AS12, AS13, AS14 or a combination thereof in a therapeutic amount for the manufacture of a medicament for treating tuberculosis.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102687719A (en) * 2012-06-04 2012-09-26 陕西海安实业有限责任公司 Novel high-efficiency fungicide for oil fields and method for preparing same
CN106928088A (en) * 2017-03-10 2017-07-07 李亚杉 A kind of synthetic method of o-chlorobenzoyl hydrazine
CN107188827A (en) * 2017-05-04 2017-09-22 重庆锦杉科技有限公司 The preparation method of o-chlorobenzoyl hydrazine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010003533A2 (en) * 2008-06-17 2010-01-14 Institut Pasteur Korea Anti-infective compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010003533A2 (en) * 2008-06-17 2010-01-14 Institut Pasteur Korea Anti-infective compounds

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALI, M. A. ET AL.: "Oxadiazole Mannich Bases: Synthesis and Antimycobacterial Activity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 12, 2007, pages 3314 - 3316 *
SRIRAM, D. ET AL.: "Gatifloxacin Derivatives: Synthesis, Antimicrobail Activities and Inhibition of Mycobacterium tuberculosis DNA Gyrase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, no. 11, 2006, pages 2982 - 2985 *
SRIRAM, D. ET AL.: "Synthesis, anti-HIV and Antitubercular Activities of Lamivudine Prodrugs", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 2, 2005, pages 1373 - 1376 *
UMAR, M. ET AL.: "Synthesis of some Isoniazide Derivatives and Related Compounds", INDIAN CHEMICAL JOURNAL, vol. 12, no. 12, 1978, pages 16 - 19 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102687719A (en) * 2012-06-04 2012-09-26 陕西海安实业有限责任公司 Novel high-efficiency fungicide for oil fields and method for preparing same
CN106928088A (en) * 2017-03-10 2017-07-07 李亚杉 A kind of synthetic method of o-chlorobenzoyl hydrazine
CN107188827A (en) * 2017-05-04 2017-09-22 重庆锦杉科技有限公司 The preparation method of o-chlorobenzoyl hydrazine

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