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Design and synthesis of isatin
analogues
By: Mateus A. da C. P��cuta
Student number: 200968513
Supervisor: Dr. Renate H. Hans
Co-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

Motivation
? Isatin and its derivatives reportedly display antiviral activity
against SARS viruses.
? Previous work reported the inhibitory activity of isatin-��-
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.

Objectives
The objectives of this study are to:
? Design analogues modelled on isatin
? Synthesize isatin analogues
? Characterize the synthesized analogues

Methodology
Design of target molecule
Triazole linker
Chalcone
R= H, Cl
X= Semicarbazide, Thiosemicarbazide
Y= H, OCH3

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
3
4
5
6
7
7a
3a

? 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).

? 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
Step1:
N-alkylation

Chemical synthesis cont��
Salicylaldehyde
4-hydroxybenzaldehyde
Vanillin
Step 2
NaN3
O-alkylation
Functional
groupinterconversion

Aldol
condensation
Step 3:

Step 4:
Click reaction

Results & DiscussionIntermediate Chemical
Formula
m.p.
(��C)
Rf value Yield
(%)
Novel
/Known
21
C11H7NO2
153
(158-161)
0.79
(EtOAc: Hex
1:1)
37
Known
20a
C9H9BrO2
125
(52-62)
0.27
(EtOAc: Hex
3:7)
27
Known
20b
C9H9BrO2
119
(61-64)
0.77
(EtOAc: Hex) 53
Known
20c
C10H11BrO3
178
(b.p. 356)
0.73
(EtOAc: Hex
3:1)
33
Known

Results & Discussion cont��
Intermediate Chemical
Formula
m.p.
(��C)
Rf value Yield
(%)
Novel
/Known
19a
C17H15BrO2
142-144
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

Results & Discussion cont��Intermediate Chemical
Formula
m.p.
(��C)
Rf value Yield
(%)
Novel
/Known
18a
C17H15N3O2
145
0.80
(EtOAc: Hex
1:1)
76
Novel
18b
C17H15N3O2 184 0.83
(EtOAc: Hex
1:1)
76 Novel
18c
C18H17N3O3 169
0.74
(EtOAc: Hex
1:1)
96 Novel

Target
Molecule
Chemical
Formula
m.p.
(��C)
Rf value Yield
(%)
Novel
/Known
17a
C28H22N4O4
116
0.62
(MeOH :
DCM 0.2 :
9.8)
51
Novel
17b
C28H22N4O4
137
0.53
(MeOH :
DCM 0.2 :
9.8)
48
Novel
17c
C29H22N4O4
136
0.67
(MeOH :
DCM 0.2 :
9.8)
35 Novel

? 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.

? 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
H-1�� a/b
H-3��
H-4, 7
H-5, 6
1
2
33a
4
5
6
7
7a
1'
2'
3'

Characterization
C-3��
C-2��
C-2
C-3
C-1��
C-5
1
2
33a
4
5
6
7
7a
1'
2'
3'

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 ��-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 ��-amino alcohol thiolactone-
chalcone and isatin-chalcone hybrids. Bioorganic & Medicinal Chemistry Letters,
20, 2234�C2237.
? 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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Mathew Pucuta - Official Research Project Presentation

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