Transcript pharmaceutical chemistry research projects 2013

PHARMACEUTICAL
CHEMISTRY RESEARCH
PROJECTS 2013
;
RESEARCH AREAS

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1. Drug Design & Discovery
(Dr. J. Joubert & Prof. S. Malan)
2. Drug Synthesis & Biological
Evaluation Against pathogenic
Microbes (Dr. J. Joubert & Prof S. Malan)
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
4. Phytochemistry (Prof P. Eagles)
1. Drug design and Discovery –
Neuroprotective Compounds
Drug design, Biological activity
and physical-chemical properties.
Dr. J. Joubert, Prof. S.F. Malan and co-workers
Targets for Neuroprotection

Calcium homeostases
– Calcium channels
– NMDA receptor channels
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
Enzyme systems involved in
neurodegeneration
Oxidative cascade,
NOS and MAO-B.
N
N
N
NADPH
O
H2N
NOH
H2N
NH2
H2N
NADPH
+
O2
O2
+
NH3
COO
27
-
-
+
OOC
NH3
-
NOS-reaction
28

N
O
+
OOC
NH3
29
30
Research within drug design
– Lead compounds
 Chemical
synthesis,
drugs in use
 New compounds from
plants
– Molecular modeling
– Synthesis and
characterization
– Biological activity
 In
vitro
 In vivo
NHR
O
Molecular modeling

Protein modeling
– Receptor / Enzyme fit
 ‘Ligandfit’
 ‘Docking’
Synthesis and
Characterisation
Synthesis and
characeterization with
NMR, MS and IR.
(1) Amantadine R1 = H, R2 = H
(2) Memantine R1 = CH3, R2 = CH3
N
(ix) 30%
H2 O2 ,
SeO2 ,
t-Butanol
(vi) N 2CHCO 2 Et
(vii) F 3B.OEt
(viii) NaCl, DMSO,
H 2O, N 2
(ii) HO(CH 2 )2 OH
(iv) Huang-Minlon
(v) NH 2 OH, NaBH 4
(3) Rimantadine
O
OH
NH
8
O
O
OH
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
O
O
N
3a; R = 4-nitrobenzylamine
3b; R = 3-nitrobenzylamine
3c; R = 2-nitrobenzylamine
N
N
OH
OH
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
R
12
11
R
R
R
1; R = benzylamine
2; R = phenyhydrazyne
2
R
O
O
O
CH
R1
R
(a)
(i) Dean-Strark
(ii) NaBH 4 /m ethanol-THF
NH2
H3C
NH2
R
N
N
O
O
R
O
4a; R = 4-methoxybenzylamine
4b; R = 3-methoxybenzylamine
4c; R = 2-methoxybenzylamine
R1
R1
5a; R = 3-methylpyridine
5b; R = 4-methylpyridine
OH
6
O
O
7
9; R = phenylethylamine
R = benzylamine
O
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
Biological evaluation - In vitro & In
*
Background
*
110
*
*
*
100
*
90
*
100
7
8
9
Aminoguanidine
Compound 1
Compound 4
Compound 7
Compound 8
Compound 9
7-NI
-6
-5
-4
-3
log[Compounds] (M)
-2
-1
*
MK
M
1
8
9
-0.2
Control
-0.4
Compound 1
-60
-7
Tot
*
0.0
ICa(m ax)-Im (nA)
2 3a 3b 3c 4a 4b 4c 5a 5b 6
110
100
90
80
70
60
50
40
30
20
10
0
-8
**
40
20
M MK 1
*
60
0
CN A
*
80
*
*
[3H]-TCP
[3H]-MK-801
120
**
80
70
NMDA + Gly
% of Control
45Ca2+
% of Control
120
Enzyme activity
(% of control)
influx
vivo
-40
-20
0
Membrane potential (mV)
20
2. Synthesis of Novel/Hybrid
Molecules & Biological Evaluation –
Malaria and Dengue fever
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Inhibitory Activity
Resistance reversal in Microorganisms

Microscopic evaluation
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Molecular Studies
3. PHYTOCHEMISTRY- Prof Eagles
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Phytochemistry is the study of phytochemicals produced
in plants, describing the isolation, purification, identification, and
structure of the large number of secondary metabolic compounds
found in plants.
Techniques commonly used in the field of phytochemistry
•Thin layer chromatography (TLC)
•Gel (column chromatography)
•High performance of liquid chromatography (HPLC)
•Gas chromatography (GC)
•Mass spectrometry