Design and synthesis of isatin analogues

By: Mateus A. da C. Púcuta Student number: 200968513

Supervisor: Dr. Renate H. HansCo-Supervisor: Mr. Petrus Shanika

Introduction According to the World Health Organization, approximately 80 % of the population in developing countries relies almost entirely on plants for medication (Farnsworth, Akerele, Bingel, Soejarto, & Guo, 1985).

Natural product present a consistent, valuable source of drug leads and provide greater structural diversity than compounds obtained through standard combinatorial synthesis.

Introduction cont…Isatin, is natural product scaffold selected for this study because of the following reasons:

It can be used as the starting material for the synthesis of a large variety of heterocyclic compounds.

As raw material it can used for drug synthesis (Abele, E. & Abele, R., 2003).

Isatin

N

H

O

O

Motivation Isatin and its derivatives reportedly display antiviral activity against SARS viruses.

Previous work reported the inhibitory activity of isatin-β-thiosemicarbazones and isatin derivatives against HIV replication (Banerjee, et al., 2011).

The synthetic modification of isatin and its derivatives may yield new and improved drugs with enhanced biological properties.

ObjectivesThe objectives of this study are to:

Design analogues modelled on isatin

Synthesize isatin analogues

Characterize the synthesized analogues

MethodologyDesign of target molecule

Triazole linker

Chalcone

R= H, ClX= Semicarbazide, ThiosemicarbazideY= H, OCH3

Y

O

X

O

N

N

NN

O

R

Design of target molecule cont…For designing of the target molecules, the

following reports were considered: The isatin is a scaffold which offers different sites for chemical modification.

1 2

34

5

67

7a

3a

N

O

O

H

Design of target molecule cont… Reference has been made to the broad spectrum of biological properties displayed by its derivatives and its synthetic versatility (Raghu, et al., 2013).

Schiff bases of isatin have been reported to possess anti-HIV, activities (Chegyuan, et al., 2014).

The 1,2,3-triazole are responsible for enhanced biological activities.

Moreover, 1,2,3-triazoles as a have become useful and important in constructing bioactive molecules (Kewal, Sunir, Luke, Mandeep , & Vipan, 2012).

Design of target molecule cont…

Chalcones are very important in drug discovery because of the diverse biological activities displayed by their derivatives as well as their simplicity.

Chalcones also for the systematic variation of substituents and or substitution patterns on the aromatic rings (Hans, Jiri, Rosenthal, & Chibale, 2010).

Chemical synthesis

Step 1:N-alkylation

Br

N

O

O

HN

O

O

Chemical synthesis cont…

Salicylaldehyde4-hydroxybenzaldehydeVanillin

Step 2NaN3

O-alkylationFunctional group interconversion

BrBr

O H

O

O

Br

O

O

O

N3

Chemical synthesis cont…

Aldol condensation

Step 3: O

O

N3

O

O

O

N3

Chemical synthesis cont…

Step 4:

Click reaction

N

O

O

NN

N

NO

O

O

O

O

O

N3

Results & DiscussionInterme

diateChemic

al Formul

a

m.p.(°C)

Rf value

Yield(%)

Novel /Known

21C11H7NO2

153(158-161)

0.79(EtOAc: Hex

1:1)

37Known

20aC9H9BrO2

125

(52-62)

0.27(EtOAc: Hex

3:7)27

Known

20bC9H9BrO2

119

(61-64)

0.77(EtOAc: Hex) 53

Known

20cC10H11BrO3

178

(b.p. 356)

0.73(EtOAc: Hex

3:1)33

Known

NO

O

OBr

O

O

O

Br

O

O

Br

OCH3

Results & Discussion cont…Intermed

iateChemi

cal Formul

a

m.p.(°C)

Rf value

Yield(%)

Novel /Known

19a

C17H15BrO2142-144

0.77(EtOAc: Hex

1:1) 95 Novel

19b

C17H15BrO2 176 0.81(EtOAc: Hex

1:1)

89 Novel

19c

C18H17BrO3 168

0.73(EtOAc: Hex

3:1) 61 Novel

O

Br

O

O

O

Br

O

O

Br

OCH3

Results & Discussion cont…Intermed

iateChemi

cal Formul

a

m.p.(°C)

Rf value

Yield(%)

Novel /Known

18a

C17H15N3O2

1450.80

(EtOAc: Hex 1:1)

76Novel

18b

C17H15N3O2 184 0.83(EtOAc: Hex

1:1)

76 Novel

18c

C18H17N3O3

169

0.74(EtOAc: Hex

1:1)

96 Novel

O

O

N3

O

O

N3

O

O

OCH3

N3

Results & Discussion cont…Target

MoleculeChemi

cal Formul

a

m.p.(°C)

Rf value

Yield(%)

Novel /Known

17a

C28H22N4O4

116

0.62

(MeOH : DCM 0.2 :

9.8)

51Novel

17b

C28H22N4O4

137

0.53

(MeOH : DCM 0.2 :

9.8)

48Novel

17c

C29H22N4O4

1360.67

(MeOH : DCM 0.2 :

9.8)

35 Novel

N

NN

N

O

O

O

O

O

O

N NN

N

O

O

OCH3

N

NN

N

O

O

O

O

Results & Discussion cont… The yields of acetylenic isatin and the O-alkylated benzaldehydes might have been affected by the nitrogen gas that was not 100 % dry.

To obtain dry N2 gas, a drying tube filled with anhydrous CaCl2

should have been connected to the nitrogen cylinder. The presence of moisture in the reaction mixture might have affected the yields as well.

Results & Discussion cont… For the O-alkylated benzaldehyde

derivatives, the melting points in the literature have a very strong difference in their magnitudes and this may be due to the impurities present in the synthesized intermediate.

The azido chalcone and the triazoles are all novel compounds and thus comparisons with literature melting point values could not be done.

Characterization

1.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000MP1_1H

0.90

2.47

-0.0

11.

001.

07

2.04

1.18

1.22

2.25

3.41

4.47

7.06

7.07

7.09

7.11

7.12

7.52

7.56

7.56

7.57

7.59

H-1’ a/b

H-3’H-4, 7

H-5, 6

1

2

33a

4

5

6

77a

1'2'

3'

N

O

O

Characterization

30405060708090100110120130140150160170180190f1 (ppm)

-200

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300MP1_13C

32.0

7

75.9

678

.31

79.4

579

.67

79.8

8

113.

71

120.

30

126.

8112

8.06

141.

05

152.

22

159.

76

175.

32

182.

08

185.

13

C-3’C-2’

C-2C-3C-1’

C-5

1

2

33a

4

5

6

77a

1'2'

3'

N

O

O

Way Forward After all structure confirmation of the analogues, intermediates and target molecules, will be submitted for testing of inhibitory activity against HIV protease and reverse transcriptase at the Chemistry and Biochemistry Department (UNAM)).

Conclusion Analogues modelled on isatin have successfully been designed, synthesized and characterized.

The Schiff bases were not synthesized due to time constraint.

The objectives stated for this study were partially fulfilled and therefore it can be said that the research was successful.

References • Banerjee, D., Yogeeswari, P., Bhat, P., Thomas, A., Srividya, M., & Sriram, D. (2011). Novel isatinyl thisemicarbazones derivatives as potential molecule to combat HIV-TB co-infection. European Journal of Medicinal Chemistry, 46, 106-121.

• Buttler, M. S. (2004). The Role of Natural Product Chemistry in Drug Discovery. Journal of Natural Products, 12, 2141-2153.

• Chegyuan, L., Juan, X., Dong, L., Xiang, L., Qizheng, Y., & Jin , G. (2014). Synthesis, in vitro and in vivo antitumor activity of symmetrical bis-Schiff base derivative of isatin. European Journal of Medicinal Chemistry, 74, 742-750.

• Chin, Y. W., Balunas, M. J., Chai, H. B., & Kinghorn, A. D. (2006). Drug discovery from natural sources. Aaps Journal, 8, 239-253.

• Dias, A. D., Urban, S., & Roessener, U. (2012). An historical overview of natural products in drug discovery. Metabolites Journal, 2, 303-336.

References cont… • Esron, D. (2002). (T. o. surveillance, Ed.) OASIS Open Journal.

• Farnsworth, N. R., Akerele, O., Bingel, A. S., Soejarto, D. D., & Guo, Z. (1985). Medicinal plants in therapy. Bullentin of the World Health Organization, 63(6), 965-981.

• Haefner, B. (2006). Drug from the deep: marine natural products as drug candidates. Drug Discovery Today, 8, 536-544.

• Han, K., Zhou, Y., Liu, F., Guo, Q., Wang, P., Yang, Y., . . . Teng, Y. (2014). Design, synthesis and in vitro cytotoxicity evaluation of 5-(2-carboxyethenyl) isatin derivatives as anti-cancer agents. Bioorganic & Medicinal Chemistry Letters, 24, 756-759.

• Hans, R. H. (2009). Novel Antimalarial and Antitubercular Agents Based on Natural Products. PhD thesis, University of Cape Town. Republic of South Africa.

References cont… • Hans, R. H., Gut, J., Rosenthal, P., & Chibale, K. (2010). Comparison of anti-plasmodial and falcipain-2 inhibitory activity of β-amino alcohol thiolactone-chalcone and isatin hybrids. Bioorganic & Medicinal Chemistry Letters, 20, 2234-2237.

• Hans, R. H., Jiri, G., Rosenthal, P. J., & Chibale, K. (2010). Comparison of the antiplasmodial and falcipain-2 inhibitory activity of β-amino alcohol thiolactone-chalcone and isatin-chalcone hybrids. Bioorganic & Medicinal Chemistry Letters, 20, 2234–2237.

• Hans, R. H., Wiid, I. J., Van Helden, P. D., Wan, B., Franzblau, S. G., Gut, J., . . . Chibale, K. (2011). Novel thiolactone-isatin hybrids as potential anti-malarial and anti-tubercular agents. Bioorganic & Medicinal Chemistry Letters, 21, 2055-2058.

• Huang, G. S., Lopez-Barcons, L., Freeze, B. S., Smith, A. B., Golberg, G. L., Horwitz, S. B., & McDavid, H. M. (2006). potentiation of taxol efficacy and by discodermolide in ovarian carcinoma xenograft-bearing mice. Clinical cancer Research, 12, 298-304.

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