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:

3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-h ydroxy-4-methoxyphenyl)- penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolizin]-2-one

3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(4-h ydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2' -pyrrolidin]-2-one

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

5-chloro-3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hy droxy-5-(3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2' -pyrrolidin]-2-one

3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-h ydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methyl-5-nitrophenylspiro[indoline-3,2'-pyrrolidin]-

2-one

H ₃ CO

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

3'-(4-hydroxy-3-methoxyphenyl)-4'-((2Z,4£)-3-hydroxy-5-(3-h ydroxy-4- methoxyp enyl)penta-2,4-dienoyl)-5'-phenylspiro[indene-2,2'-pyrrolidi ne]-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

(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

(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-hydroxyacryl oyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-on e

(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

(2)-4'-(3-hydroxy-3-(4'-(3-hydroxy-4-methoxyphenyl)-5-nitro- 2-oxo-5'- phenylspiro[indoline-3,2'-pyrrolidine]-3'-yl)-3-hydroxyacryl oyl)-3'-(4-hydroxy-3- methoxyphenyl)-5-nitro-5'-phenylspiro[indoline-3,2'-pyrrolid in]-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

(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-hydroxyacrylo yl)-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-d ienoyl)-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-hy droxy-4- methoxyphenyl)-penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolizin]-2-one compound represented by the formula

Chemical Formula: C ₃₁ H3oN ₂ 0 ₇

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-h ydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2' -pyrrolidin]-2-one compound represented by the formula

Chemical Formula: C ₃ 6H ₃₂ 207

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-hydro xy-5-(3- hydroxy-4-methoxyphenyl)penta-2,4-dienoyl)-1 -methylspiro[indoline-3,2'-pyrrolidin]-2- one compound represented by the formula

Chemical Formula: C ₃₁ H2 ₉ CIN ₂ 0 ₇

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-hydro xy-5-(3- methoxyphenyl)penta-2,4-dienoyl)-5-phenylspiro[indoline-3,2' -pyrrolidin]-2-one compound represented by the formula

Chemical Formula: C ₃₆ H ₃₁ CIN206

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-h ydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methyl-5-nitrospiro[indoline-3,2'-pyrrolidin]-2-one compound represented by the formula

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-h ydroxyl-3- methoxyphenyl)penta-2,4-dienoyl)-5-nitro-5-phenylspiro[indol ine-3,2'-pyrrolidin]-2-one compound represented by the formula

Chemical Formula: C ₃₆ H ₃₁ N ₃ 0 ₉

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-h ydroxyl-4- methoxyphenyl)penta-2,4-dienoyl)-1 '-methylspiro[indene-2,2'-pyrrolidine]-1 ,3(3aH,7aH)- dione compound represented by the formula

Chemical Formula: C ₃ 2H ₃₁ N08

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

Chemical Formula: C ₃₇ H3 ₃ NO8

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

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

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

Chemical Formula: C ₄ iH ₃₈ Cl2N ₄ 0 ₈

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-hydroxyacryl oyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-on e compound represented by the formula

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-on e compound represented by the formula

Chemical Formula: C4iH ₃ 8N ₆ 0i2

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-hydroxyacryl oyl)-3'-(4-hydroxy-3- methoxyphenyl)-5-nitro-5'-phenylspiro[indoline-3,2'-pyrrolid in]-2-one compound represented by the formula

Chemical Formula: C5iH ₄₂ N ₆ 0i2

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

Chemical Formula: C ₄ 3H38N2O ₁₀

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-hydroxyacr yloyl)-3'-(4-hydroxy-3- methoxyphenyl)-5'-phenylspiro[indene-2,2'-pyrrolidine]-1 ,3-dione compound represented by the formula

Chemical Formula: C53H ₄ 2N ₂ Oio

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.