WO2012099454A1 - Curcumin compounds and their preparations thereof - Google Patents

Curcumin compounds and their preparations thereof Download PDF

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WO2012099454A1
WO2012099454A1 PCT/MY2011/000177 MY2011000177W WO2012099454A1 WO 2012099454 A1 WO2012099454 A1 WO 2012099454A1 MY 2011000177 W MY2011000177 W MY 2011000177W WO 2012099454 A1 WO2012099454 A1 WO 2012099454A1
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hydroxy
methoxyphenyl
indoline
mmol
compound represented
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PCT/MY2011/000177
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French (fr)
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Rusli Ismail
Mohamed Ashraf Ali
Soo Choon Tan
Keng Yoon YEONG
Chee Wei Ang
Raju SURESH KUMAR
Hasnah OSMAN
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Universiti Sains Malaysia
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring 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 present invention relates to compounds for treatment of human immunodeficiency virus (HIV), tuberculosis (TB), Alzheimer or anti-cancer and the processes thereof, particularly curcumin compounds and processes for their preparation.
  • HAV human immunodeficiency virus
  • TB tuberculosis
  • Alzheimer or anti-cancer the processes thereof, particularly curcumin compounds and processes for their preparation.
  • heterocycles are a research area of ever-increasing importance, as heterocycles are widely prevalent in nature and play a pivotal role in the pharmaceutical and drug industry. Because of their ability to mimic the structure of peptides and binding to proteins, functionalized heterocycles are interesting scaffolds for the preparation of diversity-oriented compound libraries for medicinal and pharmaceutical applications.
  • Curcumin a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-HIV, anti-TB, antioxidant, antiproliferative and alzheimer diseases. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability.
  • curcumin Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination.
  • approaches involve, first, the use of adjuvant like piperdine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin like indolizine with isatin.
  • curcumin Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented.
  • curcumin compounds with enhanced bioavailability for the treatment of anti-HIV, anti-TB, anti-Alzheimer, and anti-cancer.
  • the curcumin compounds would have enhanced bioavailability and stability. Besides that, these curcumin compounds are soluble in water.
  • the invention discloses compounds with enhanced bioavailability for the prevention and treatment of anti-human immunodeficiency virus (HIV), antituberculosis (TB), anti-Alzheimer or anti-cancer, with the following formulas:
  • HIV anti-human immunodeficiency virus
  • TB antituberculosis
  • anti-Alzheimer anti-cancer
  • the invention also discloses the method in synthesizing these compounds wherein the steps includes mixing curcumin, isatin derivatives or ninhydrin and sarcosine or phenyl glycine in 20 mL methanol. The mixture was then refluxed with a solvent on a water bath and excess solvent was removed under vacuum. The residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. The ratio for curcumin: isatin derivative/ninhydrin: sarcosine/phenyl glycine is 1 :1 :2 and 1 :2:4. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides compounds with enhanced bioavailability for the prevention and treatment of anti-human immunodeficiency virus (HIV), anti-tuberculosis (TB), anti-Alzheimer or anti-cancer.
  • HIV anti-human immunodeficiency virus
  • TB anti-tuberculosis
  • anti-Alzheimer or anti-cancer anti-cancer.
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of sarcosine or phenylglycine in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of ninhydrin and 2 mmol of sarcosine or phenylglycine in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of isatin derivative and 4 mmol of sarcosine and phenylglycine in 20 ml. of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of ninhydrin and 4 mmol of sarcosine or phenylglycine in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
  • TLC thin layer chromatography

Abstract

Accordingly, the invention discloses compounds with enhanced bioavailability for the prevention and treatment of anti-human immunodeficiency virus (HIV), anti-tuberculosis (TB), anti-Alzheimer or anti-cancer, with the following formulas: The invention also discloses the method in synthesizing these compounds wherein the steps includes mixing curcumin, isatin derivatives or ninhydrin and sarcosine or phenyl glycine in 20 mL methanol. The mixture was then refluxed with a solvent on a water bath and excess solvent was removed under vacuum. The residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. The ratio for curcumin:isatin derivative/ninhydrin:sarcosine/phenyl glycine is 1:1:2 and 1:2:4.

Description

CURCUMIN COMPOUNDS AND THEIR PREPARATIONS THEREOF
FIELD OF THE INVENTION
The present invention relates to compounds for treatment of human immunodeficiency virus (HIV), tuberculosis (TB), Alzheimer or anti-cancer and the processes thereof, particularly curcumin compounds and processes for their preparation.
BACKGROUND OF THE INVENTION
Synthesis of heterocycles is a research area of ever-increasing importance, as heterocycles are widely prevalent in nature and play a pivotal role in the pharmaceutical and drug industry. Because of their ability to mimic the structure of peptides and binding to proteins, functionalized heterocycles are interesting scaffolds for the preparation of diversity-oriented compound libraries for medicinal and pharmaceutical applications. Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-HIV, anti-TB, antioxidant, antiproliferative and alzheimer diseases. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperdine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin like indolizine with isatin. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented.
However, there is the need for better curcumin compounds with enhanced bioavailability for the treatment of anti-HIV, anti-TB, anti-Alzheimer, and anti-cancer. The curcumin compounds would have enhanced bioavailability and stability. Besides that, these curcumin compounds are soluble in water.
SUMMARY OF THE INVENTION
Accordingly, the invention discloses compounds with enhanced bioavailability for the prevention and treatment of anti-human immunodeficiency virus (HIV), antituberculosis (TB), anti-Alzheimer or anti-cancer, with the following formulas:
Figure imgf000003_0001
3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4-methoxyphenyl)- penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolizin]-2-one
Figure imgf000003_0002
3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'-pyrrolidin]-2-one
Figure imgf000004_0001
5-chloro-3'-(4-hydroxy-3-methoxyp enyl)-4,-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolidin]-2-one
Figure imgf000004_0002
5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'-pyrrolidin]-2-one
Figure imgf000004_0003
3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methyl-5-nitrophenylspiro[indoline-3,2'-pyrrolidin]-
2-one
H3CO
3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]-1 ,3(3aH,7aW)- dione
Figure imgf000005_0001
3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4- methoxyp enyl)penta-2,4-dienoyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]-1 ,3(3aH,7aH)- dione
(Z)-4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-2-oxospiro[indoline-3,2'-pyrrolidine]-3'- yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-1 '-methylspiro[indoline-3,2,-pyrrolidin]-2-one
Figure imgf000006_0001
(2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'-phenylspiro[indoline-3,2'- pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-5'-phenylspiro[indoline-3,2'- pyrrolidin]-2-one
Figure imgf000006_0002
(2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indoline-3,2'-pyrrolidin]-2-one
A (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one
Figure imgf000007_0001
(Z)-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-5-nitro-2-oxospiro[indoline- 3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-5'- phenylspiro[indoline-3,2'-pyrrolidin]-2-one
Figure imgf000007_0002
(2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-5-nitro-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5-nitro-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one
(2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-1 ,3-dioxo-1 ,3- dihydrospiro[indene-2,2,-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione
Figure imgf000008_0001
(2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 ,3-dioxo-5,-phenyl-1 ,3- dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione
The invention also discloses the method in synthesizing these compounds wherein the steps includes mixing curcumin, isatin derivatives or ninhydrin and sarcosine or phenyl glycine in 20 mL methanol. The mixture was then refluxed with a solvent on a water bath and excess solvent was removed under vacuum. The residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. The ratio for curcumin: isatin derivative/ninhydrin: sarcosine/phenyl glycine is 1 :1 :2 and 1 :2:4. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds with enhanced bioavailability for the prevention and treatment of anti-human immunodeficiency virus (HIV), anti-tuberculosis (TB), anti-Alzheimer or anti-cancer. 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.
General procedure for synthesis of substituted 3'-(4-hvdroxy-3-methoxyphenyl)-4'-
(2Z.4E)-3-hvdroxy-5-(3-hvdroxy-4-methoxyphenvn-penta-2.4-dienoyl)-1 - methylspirofindoline-3.2'-pyrrolizinl-2-one
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of sarcosine or phenylglycine in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
General procedure for synthesis of substituted 3'-(4-hvdroxy-3-methoxyphenyl)-4'- ((2Z.4E)-3-hydroxy-5-(3-hvdroxyl-4-methoxyphenyl)penta-2.4-dienoyl)-1 '- methylspirofindene-2.2'-pyrrolidine1-1.3(3aH.7aH)-dione
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of ninhydrin and 2 mmol of sarcosine or phenylglycine in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. General procedure for synthesis of substituted (Z)-4'-(3-hvdroxy-4-methoxyDhenyl)-1'- methyl-2-oxospirofindoline-3.2'-pyrrolidine1-3'-yl)acryloyl)-3'-(4-hvdroxy-3- methoxyphenyl)-1 '-methylspirofindoline-3.2'-pyrrolidinl-2-one
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of isatin derivative and 4 mmol of sarcosine and phenylglycine in 20 ml. of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
General procedure for synthesis of (Z '-(3-hvdroxy-3-(4'-(3-hvdroxy-4-methoxyphenvD- 1 '-methyl-1 ,3-dioxo-1.3-dihvdrospirorindene-2.2'-pyrrolidinel-3'-yl)-3-hvdroxyacryloyl)-3'- (4-hvdroxy-3-methoxyphenyl)-1 '-methylspirofindene-2.2'-pyrrolidinel-1.3-dione
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of ninhydrin and 4 mmol of sarcosine or phenylglycine in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. EXAMPLES
Example 1
Synthesis of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4E)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)-penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolizin]-2-one compound represented by the formula
Figure imgf000011_0001
Chemical Formula: C31H3oN207
Exact Mass: 542.21
Molecular Weight: 542.58
m/z: 542.21 (100.0%), 543.21 (34.1 %), 544.21 (7.3%)
Elemental Analysis: C, 68.62; H, 5.57; N, 5.16; O, 20.64
A mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of sarcosine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. Example 2
Synthesis of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000012_0001
Chemical Formula: C36H32 207
Exact Mass: 604.22
Molecular Weight: 604.65
m/z: 604.22 (100.0%), 605.22 (39.7%), 606.23 (9.1 %), 607.23 (1.5%)
Elemental Analysis: C, 71.51 ; H, 5.33; N, 4.63; 0, 18.52
A mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of phenylglycine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 3
Synthesis of 5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3- hydroxy-4-methoxyphenyl)penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolidin]-2- one compound represented by the formula
Figure imgf000012_0002
Chemical Formula: C31 H29CIN207
Exact Mass: 576.16
Molecular Weight: 577.02
m/z: 576.17 (100.0%), 577.17 (34.1%), 578.16 (32.0%), 579.17 (1 1.4%), 578.17 (7.2%), 580.17 (2.3%)
Elemental Analysis: C, 64.53; H, 5.07; CI, 6.14; N, 4.85; O, 19.41
A mixture of 1 mmol of curcumin, 1 mmol of chloroisatin derivative and 2 mmol of sarcosine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 4
Synthesis of 5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000013_0001
Chemical Formula: C36H31CIN206
Exact Mass: 622.19
Molecular Weight: 623.09 m/z: 622.19 (100.0%), 623.19 (39.5%), 624.18 (32.0%), 625.19 (13.2%), 624.19 (9.0%), 626.19 (2.8%)
Elemental Analysis: C, 69.39; H, 5.07; CI, 5.69; N, 4. 50; 0, 15.41 A mixture of 1 mmol of curcumin, 1 mmol of chloroisatin derivative and 2 mmol of phenylglycine in 20 ml_ of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 5
Synthesis of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methyl-5-nitrospiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000014_0001
Chemical Formula: C31 H29C3O9
Exact Mass: 587.19
Molecular Weight: 587.58
m/z: 587.19 (100.0%), 588.19 (35.0%), 589.20 (5.7%), 589.19 (2.2%), 590.20 (1.2%) Elemental Analysis: C, 63.37; H, 4.97; N, 7.15; O, 24.51 A mixture of 1 mmol of curcumin, 1 mmol of nitroisatin derivative and 2 mmol of sarcosine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 6
Synthesis of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(4-hydroxyl-3- methoxyphenyl)penta-2,4-dienoyl)-5-nitro-5-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000015_0001
Chemical Formula: C36H31N309
Exact Mass: 649.21
Molecular Weight: 649.65
m/z: 649.21 ( 00.0%), 650.21 (39.6%), 651.21 (9.8%), 650.20 (1.1 %)
Elemental Analysis: C, 66.56; H, 4.81 ; N, 6.47; O, 22.17
A mixture of 1 mmol of curcumin, 1 mmol of nitroisatin derivative and 2 mmol of phenylglycine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography usi g petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 7
Synthesis of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]-1 ,3(3aH,7aH)- dione compound represented by the formula
Figure imgf000016_0001
Chemical Formula: C32H31N08
Exact Mass: 557.2
Molecular Weight: 557.59
m/z: 557.20 (100.0%), 558.21 (35.3%), 559.21 (7.8%)
Elemental Analysis: C, 68.93; H, 5.60; N, 2.51 ; O, 22.96
A mixture of 1 mmol of curcumin, 1 mmol of ninhydrin derivative and 2 mmol of sarcosine in 20 mL of methanol which were refiuxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 8
Synthesis of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4-r)-3-hyclroxy-5-(3-hyclroxy-4- methoxyphenyl)penta-2,4-dienoyl)-5'-phenylspiro[indene-2,2,-pyrrolidine]-1 ,3(3aH,7aAV)- dione compound represented by the formula
Figure imgf000017_0001
Chemical Formula: C37H33NO8
Exact Mass: 619.22
Molecular Weight: 619.66
m/z: 619.22 (100.0%), 620.22 (40.7%), 621.23 (8.1 %), 621.22 (1.8%), 622.23 (1.7%) Elemental Analysis: C, 71.72; H, 5.37; N, 2.26; O, 20.66
A mixture of 1 mmol of curcumin, 1 mmol of ninhydrin derivative and 2 mmol of phenylglycine in 20 ml. of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 9
Synthesis of (2)-4'-(3-hydroxy-4-methoxyphenyl)- -methyl-2-oxospiro[indoline-3,2'- pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-1 '-methylspiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000018_0001
Chemical Formula: C 1H40N4O8
Exact Mass: 716.28
Molecular Weight: 716.78
m/z: 716.28 (100.0%), 717.29 (45.1%), 718.29 (12.2%), 719.29 (2.3%), 717.28 (1.5%) Elemental Analysis: C, 68.70; H, 5.62; N, 7.82; 0, 17.86
A mixture of 1 mmol of curcumin, 2 mmol of isatin derivative and 4 mmol of sarcosine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by Thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. Example 10
Synthesis of (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-5'- phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000018_0002
Chemical Formula: C51H44 4O8
Exact Mass: 840.32
Molecular Weight: 840.92
m/z: 840.32 (100.0%), 841.32 (56.0%), 842.32 (17.6%), 843.33 (2.8%), 841.31 (1.5%), 843.32 (1.2%)
Elemental Analysis: C, 72.84; H, 5.27; N, 6.66; 0, 15.22
A mixture of 1 mmol of curcumin, 2 mmol of isatin derivative and 4 mmol of phenylglycine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by Thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 1 1
Synthesis of (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000019_0001
Chemical Formula: C4iH38Cl2N408
Exact Mass: 784.21
Molecular Weight: 785.67 m/z: 784.21 (100.0%), 786.20 (63.9%), 785.21 (45.1 %), 787.21 (29.7%), 786.21 (12.0 %), 788.20 (10.6%), 788.21 (7.4%), 789.20 (4.7%), 789.21 (1.5%), 787.22 (1.4%), 790.21 (1.3%)
Elemental Analysis: C, 62.68; H, 4.88; CI, 9.02; N, 7.13; O, 16.29
A mixture of 1 mmol of curcumin, 2 mmol of chloroisatin derivative and 4 mmol of sarcosine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 2
Synthesis of (Z)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000020_0001
Chemical Formula: C41 H42CI2N4O8
Exact Mass: 908.24
Molecular Weight: 909.81
m/z: 908.24 (100.0%), 910.24 (81.3%), 909.24 (57.4%), 91 1.24 (36.0%), 912.24 (1 1.4 %), 912.23 (10.2%), 913.24 (6.5%), 91 1.25 (3.7%), 913.25 (1.9%), 914.24 (1.8%) Elemental Analysis: C, 67.33; H, 4.65; CI, 7.79; N, 6.16; 0, 14.07
A mixture of 1 mmol of curcumin, 2 mmol of chloroisatin derivative and 4 mmol of phenylglycine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 13
Synthesis of (2)-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-5-nitro-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000021_0001
Chemical Formula: C4iH38N60i2
Exact Mass: 806.25
Molecular Weight: 806.77
m/z: 806.25 (100.0%), 807.26 (45.2%), 808.26 (13.5%), 809.26 (2.7%), 807.25 (2.2%) Elemental Analysis: C, 61.04; H, 4.75; N, 10.42; O, 23.80 A mixture of 1 mmol of curcumin, 2 mmol of nitroisatin derivative and 4 mmol of sarcosine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 14
Synthesis of (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-5-nitro-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5-nitro-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000022_0001
Chemical Formula: C5iH42N60i2
Exact Mass: 930.29
Molecular Weight: 930.91
m/z: 930.29 (100.0%), 931.29 (45.2%), 932.29 (18.9%), 933.30 (2.8%), 931.28 (2.2%), 933.29 (1.8%)
Elemental Analysis: C, 65.80; H, 4.55; N, 9.03; O, 20.62
A mixture of 1 mmol of curcumin, 2 mmol of nitroisatin derivative and 4 mmol of phenylglycine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 15
Synthesis of (Z)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-1 ,3-dioxo- 1 ,3-dihydrospiro[indene-2,2,-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula
Figure imgf000023_0001
Chemical Formula: C43H38N2O10
Exact Mass: 742.25
Molecular Weight: 742.77
m/z: 742.25 (100.0%), 743.26 (47.3%), 744.26 (13.0%), 745.26 (2.7%)
Elemental Analysis: C, 69.53; H, 5.16; N, 3.77; O, 21.54
A mixture of 1 mmol of curcumin, 2 mmol of ninhydrin derivative and 4 mmol of sarcosine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 16
Synthesis of (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 ,3-dioxo-5'-phenyl- 1 ,3-dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula
Figure imgf000024_0001
Chemical Formula: C53H42N2Oio
Exact Mass: 866.28
Molecular Weight: 866.91
m/z: 866.28 (100.0%), 867.29 (58.2%), 868.29 (18.7%), 869.29 (4.4%)
Elemental Analysis: C, 73.43; H, 4.88; N, 3.23; 0, 18.46
A mixture of 1 mmol of curcumin, 2 mmol of ninhydrin derivative and 4 mmol of phenylglycine in 20 mL of methanol which were refluxed on water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.

Claims

1. A 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)-penta-2,4-dienoyl)-1-methylspiro[indoline-3,2'-pyrrolizin]-2-one
Figure imgf000025_0001
A 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4f)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,
2'-pyrrolidin]-2- compound represented by the formula
Figure imgf000025_0002
3. A 5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)-1-methylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000025_0003
A 5-chloro-3'-(4-hydroxy-3-methoxyp enyl)-4'-((2Z,4£)-3-hydroxy-5-(3- methoxyphenyl)penta-2,
4-dienoyl)-5-phenylspiro[indoline-3,2'-pyrrolidin]-2- compound represented by the formula
Figure imgf000026_0001
5. A 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methyl-5-nitrospiro[ind
one compound represented by the formula
Figure imgf000026_0002
6. A 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(4-hydroxyl-3- methoxyphenyl)penta-2,4-dienoyl)-5-nitro-5-phenylspiro[indoline-3,2'-pyrrolidin]-2- one compound represented by the formula
Figure imgf000026_0003
7. A 3'-(4- ydroxy-3-methoxyp enyl)-4'-((2Z,4£)-3-hyclroxy-5-(3-hyclroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]- 1 ,3(3aAV,7aH)-dione compound represented by the formula
Figure imgf000027_0001
8. A 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]- 1 ,3(3aW,7aH)-dione compound represented by the formula
Figure imgf000027_0002
9. A (2)-4'-(3-hydroxy-4-methoxyphenyl)-1'-methyl-2-oxospiro[indoline-3,2'-pyrrolidine]- 3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-1 '-methylspiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000027_0003
10. A (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'^henylspiro[indoline- 3,2'-pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-5'- phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000028_0001
1 1. A (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000028_0002
12. A (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2,-pyrrolidin]-2-one compound represented by the formula
Figure imgf000029_0001
13. A (Z)-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-5-nitro-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000029_0002
14. A (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-5-nitro-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5-nitro-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000029_0003
15. A (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-1 ,3-dioxo-1 ,3- dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula
Figure imgf000030_0001
16. A (Z)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 ,3-dioxo-5'-phenyl-1 ,3- dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula
Figure imgf000030_0002
17. A use of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2 Z,4 £)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)-penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000031_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
18. A use of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2 Z,4 £)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)-penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000031_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
19. A use of 5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2 Z,4 £)-3-hydroxy-5-(3- hydroxy-4-methoxyphenyl)-penta-2,4-dienoyl)-1-methylspiro[indoline-3,2'-pyrrolidin]- 2-one compound represented by the formula
Figure imgf000031_0003
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
20. A use of 5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000032_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
21. A use of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3- hydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methyl-5-nitrospiro[indoline-3,2'-pyrrolidin]-2- one compound represented by the formula
Figure imgf000032_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
22. A use of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(4-hydroxyl-3- methoxyphenyl)penta-2,4-dienoyl)-5-nitro-5-phenylspiro[indolm^
one compound represented by the formula
Figure imgf000033_0001
tuberculosis, Alzheimer or cancer.
23. A use of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-hydroxyl-4 methoxyphenyl)penta-2,4-dienoyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]- 1 ,3(3aH,7aA/)-dione compound represented by the formula
Figure imgf000033_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
24. A use of 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4iE)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]- 1 ,3(3aW,7aH)-dione compound represented by the formula
Figure imgf000034_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
25. A use of (Z)-4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-2-oxospiro[indoline-3,2'- pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-1 '-methylspiro[indoline- 3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000034_0002
26. A use of (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)- 5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000035_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
27. A use of (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000035_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
28. A use of (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4-methoxyphenyl)-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000036_0001
29. A use of (2)-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-5-nitro-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000036_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
30. A use of (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-5-nitro-2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5-nitro-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000037_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
31. A use of (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '-methyl-1 ,3-dioxo- 1 ,3-dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula
Figure imgf000037_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
32. A use of (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 ,3-dioxo-5'-phenyl- 1 ,3-dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula
Figure imgf000038_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
33. A method of synthesizing 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5- (3-hydroxy-4-methoxyphenyl)-penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'- pyrrolizin]-2-one compound represented by the formula
Figure imgf000038_0002
wherein the method includes the steps of
a. mixing 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of sarcosine;
b. refluxing the mixture from step (a) with an organic solvent.
34. A method of synthesizing 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5- (4-hydroxy-3-methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000039_0001
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
35. A method of synthesizing 5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3- hydroxy-5-(3-hydroxy-4-methoxyphenyl)penta-2,4-dienoyl)-1 -methylspiro[indoline- 3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000039_0002
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 1 mmol of chloroisatin derivative and 2 mmol of sarcosine;
b) refluxing the mixture from step (a) with an organic solvent.
36. A method of synthesizing 5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3- hydroxy-5-(3-methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000040_0001
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 1 mmol of chloroisatin derivative and 2 mmol of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
37. A method of synthesizing 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5- (3-hydroxyl-4-methoxyphenyl)penta-2,4-dienoyl)-1 '-methyl-5-nitrospiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000040_0002
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 1 mmol of nitroisatin derivative and 2 mmol of sarcosine;
b) refluxing the mixture from step (a) with an organic solvent.
38. A method of synthesizing 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5- (4-hydroxyl-3-methoxyphenyl)penta-2,4-dienoyl)-5-nitro-5-phenylspiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000041_0001
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 1 mmol of nitroisatin derivative and 2 mmol of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
39. A method of synthesizing 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4E)-3-hydroxy-5- (3-hydroxyl-4-methoxyphenyl)penta-2,4-dienoyl)- -methylspiro[indene-2,2'- pyrrolidine]-1 ,3(3aH,7a/- )-dione compound represented by the formula
Figure imgf000041_0002
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 1 mmol of ninhydrin derivative and 2 mmol of sarcosine;
b) refluxing the mixture from step (a) with an organic solvent.
40. A method of synthesizing 3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5- (3-hydroxy-4-methoxyphenyl)penta-2,4-dienoyl)-5'-phenylspiro[indene-2,2'- pyrrolidine]-1 ,3(3aH,7aAV)-dione compound represented by the formula
Figure imgf000042_0001
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 1 mmol of ninhydrin derivative and 2 mmol of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
41. A method of synthesizing (2)-4'-(3-hydroxy-4-methoxyphenyl)-1'-methyl-2- oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-1 '- methylspiro[indoline-3,2'-pyrrolidin)-2-one compound represented by the formula
Figure imgf000042_0002
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 2 mmol of isatin derivative and 4 mmol of sarcosine;
b) refluxing the mixture from step (a) with an organic solvent.
42. A method of synthesizing (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-2- oxo-5'-phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)acryloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000043_0001
wherein the method includes the steps of
a) mixing 1 mmoi of curcumin, 2 mmoi of isatin derivative and 4 mmoi of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
A method of synthesizing (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4- methoxyphenyl)-1 '-methyl-2-oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3- hydroxyacryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-1 '-methylspiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000043_0002
wherein the method includes the steps of
a) mixing 1 mmoi of curcumin, 2 mmoi of chioroisatin derivative and 4 mmoi of sarcosine;
b) refluxing the mixture from step (a) with an organic solvent.
44. A method of synthesizing (2)-5-chloro-4'-(3-(5-chloro-4'-(3-hydroxy-4- methoxyphenyl)-2-oxo-5'-phenylspiro[indoline-3,2'-pyrrolidine)-3'-yl)-3- hydroxyacryloyl)-3'-(4-hydroxy-3-methoxyphenyl)-5'-phenylspiro[indoline-3,2'- pyrrolidin]-2-one compound represented by the formula
Figure imgf000044_0001
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 2 mmol of chloroisatin derivative and 4 mmol of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
45. A method of synthesizing (2)-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '- methyl-5-nitro-2-oxospiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4- hydroxy-3-methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000044_0002
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 2 mmol of nitroisatin derivative and 4 mmol of sarcosine; b) refluxing the mixture from step (a) with an organic solvent.
46. A method of synthesizing (Z)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-5- nitro-2-oxo-5'-phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'-(4- hydroxy-3-methoxyphenyl)-5-nitro-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula
Figure imgf000045_0001
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 2 mmol of nitroisatin derivative and 4 mmol of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
47. A method of synthesizing (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 '- methyl-1 ,3-dioxo-1 ,3-dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)- 3'-(4-hydroxy-3-methoxyphenyl)- -methylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented b the formula
Figure imgf000045_0002
wherein the method includes the steps of a) mixing 1 mmol of curcumin, 2 mmol of ninhydrin derivative and 4 mmol of sarcosine;
b) refluxing the mixture from step (a) with an organic solvent.+
48. A method of synthesizing (2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-1 ,3- dioxo-5'-phenyl-1 ,3-dihydrospiro[indene-2,2'-pyrrolidine]-3'-yl)-3-hydroxyacryloyl)-3'- (4-hydroxy-3-methoxyphenyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula
Figure imgf000046_0001
wherein the method includes the steps of
a) mixing 1 mmol of curcumin, 2 mmol of ninhydrin derivative and 4 mmol of phenylglycine;
b) refluxing the mixture from step (a) with an organic solvent.
49. The method as claimed in claims 33 to 48 wherein the organic solvent is preferably methanol.
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