DESIGN AND SYNTHESIS OF ISATIN ANALOGUES

MADC Pucuta1, P Shanika1, RH Hans1*

1Department of Chemistry and Biochemistry, faculty of Science, University of Namibia, Windhoek, Namibia;

*Corresponding author: rhans@unam.na

2. Objectives

1. Introduction

6. The way forward

Approximately 60 % of the world’s population relies almost entirely on plants for

medication.

Natural products have been recognized as an important sources of therapeutically

effective medicines (Farnsworth, Akerele, Bingel, Soejarto, & Guo, 1994). They are

a consistent, valuable source of drug leads and provide greater structural diversity

than compounds obtained through standard combinatorial synthesis.

Natural product research also offers major opportunities for finding novel low

molecular weight lead structures that are potentially active against a wide range of

assay targets (Dias, Urban, & Roessener, 2012).

Isatin (fig. 1) from Isatis tictoria (fig. 1) is the natural product scaffold selected for

this study. It is an indole derivative (1H-indole-2,3-dione) which is a synthetically

versatile substrate and was selected because of its use as starting material for the

synthesis of a large variety of heterocyclic compounds - indoles and quinolines

(Abele, E. & Abele, R., 2003).

Isatin derivatives reportedly display wide range of biological activities which

include antimalarial (Hans, et al, 2010), anticancer (Han, et al, 2014), antiHIV

(Banerjee at al, 2011), antiTB (Sriram at al, 2005).

Isatis tictoria Calanthe Isatin

Figure 1: Sources of isatin and its structure

The objectives of this study are:

Design analogues modelled on isatin

Synthesize isatin analogues

Characterize the advanced intermediates and analogues

3. Methodology

The research project involves the designing and synthesis of triazole-linked isatin

derivatives. The isatin scaffold will be derivatized at:

The nitrogen atom through N-alkylation

The ketonic oxygen by a condensation reaction (Schiff base)

The synthesis of analogues was done in the following order (Scheme 1):

N-alkylation of isatin with propargyl bromide to form an acetylenic isatin

O-alkylation of aldehydes

Aldol condensation reaction of the O-alkylated aldehydes with

acetophenone derivatives to form O-alkylated chalcones

Synthesis of azido chalcone

Click reaction (formation of triazole-linked isatin analogues by clicking the

acetylenic isatin with the azido chalcone).

Characterization of the analogues will be done using physical data (melting

point and retardation factor) and spectroscopy data (Infrared, 1H NMR and 13C NMR).

4. Results and Discussion

7. Acknowledgements

Scheme 1: Synthesis of intermediates and the target molecule

Intermediate/Target

molecule

Chemical Formula

Melting Point (°C)

Rf value

Yield (%)

Novel or

Known

C11H7NO2

153

(158-161) 1

0.79 (EtOAc: Hex 1:1)

37

Known

C9H9BrO2

125

0.27 (EtOAc: Hex 3:7)

27

Known

C9H9BrO2

119

0.77 (EtOAc: Hex)

53

Known

C10H11BrO3

178

0.73 (EtOAc: Hex 3:1)

33

Known

C17H15BrO2

142-144

0.77 (EtOAc: Hex 1:1)

95

Novel

C17H15BrO2

176

0.81 (EtOAc: Hex 1:1)

89

Novel

C18H17BrO3

168

0.73 (EtOAc: Hex 3:1)

61

Novel

C17H15N3O2

145

0.80 (EtOAc: Hex 1:1)

76

Novel

C17H15N3O2

184

0.83 (EtOAc: Hex 1:1)

76

Novel

C18H17N3O3

169

0.74 (EtOAc: Hex 1:1)

96

Novel

Intermediates and analogues have been submitted for NMR analysis (University of

Stellenbosch). After confirmation of the structure analogues (target molecules) will

be submitted for biological testing at UNAM and UCT. Structure Activity

Relationship data delineated from biological results will be used to further improve

the structure of analogues.

University of Namibia, Department of Chemistry and Biochemistry

Prof. Koch, University of Stellenbosch, Faculty of Science, Chemistry Department

Prof Chibale, University of Cape Town, Drug Discovery and Development Centre

(H3-D).

1. Literature value ( http://www.chemspider.com/Chemical-Structure.1468549.html retrieved Oct 23,

2014)

7. References

1. Sriram, D., Yogeeswari, P., & Gopal, G. (2005). Synthesis, anti-HIV and anti-tubercular

activities of lamivudine prodrugs. European Journal of Medicinal Chemistry, 40, 1373-1376.

2. Hans, R. H., Gut, J., Rosenthal, P., & Chibale, K. (2014). 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.

3. 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.

4. 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.

5. Dias, A. D., Urban, S., & Roessener, U. (2012). An historical overview of natural products

in drug discovery. Metabolites Journal, 2, 303-336.

6. Farnsworth, N. R., Akerele, O., Bingel, A. S., Soejarto, D. D., & Guo, Z. (1994). Medicinal

plants in therapy. Bull World Organ, 63(6), 965-981.

Table 1: Physical data and yields of intermediates

Isatin

Propargyl bromide

Acetylenic isatin

R1

R1= Azido Chalcone

N-alkylation Triazole linker

Chalcone

R= H, ClX= SemicarbazideY= H, OCH3

Thirteen (13) molecules were synthesized and subjected to partial characterization.

Of the 13 compounds 6 compounds are novel and are reported here for the first

time.

Yields obtained for the acetylenic isatin and the O-alkylated aldehydes were lower

than that reported in the literature. This could be due to the presence of moisture in

the reaction mixtures.

5. Discussion