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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