Drug_d;::::mlesign_and_development-2013.ppt

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1. PHARMACEUTICAL PHARMACEUTICAL
CHEMISTRY RESEARCH CHEMISTRY RESEARCH
PROJECTS 2013PROJECTS 2013
;;

2. RESEARCH AREASRESEARCH AREAS

1. Drug Design & Discovery1. Drug Design & Discovery

(Dr. J. Joubert & Prof. S. Malan)(Dr. J. Joubert & Prof. S. Malan)

2. Drug Synthesis & Biological 2. Drug Synthesis & Biological
Evaluation Against pathogenic Evaluation Against pathogenic
Microbes (Dr. J. Joubert & Prof S. Malan)Microbes (Dr. J. Joubert & Prof S. Malan)

4. Phytochemistry (Prof P. Eagles)4. Phytochemistry (Prof P. Eagles)

3. 1. Drug design and Discovery – 1. Drug design and Discovery –
Neuroprotective CompoundsNeuroprotective Compounds
Drug design, Drug design, Biological activity Biological activity
and physical-chemical properties.and physical-chemical properties.
Dr. J. Joubert, Prof. S.F. Malan and co-workers

4. Targets for NeuroprotectionTargets for Neuroprotection

Calcium homeostasesCalcium homeostases
–Calcium channelsCalcium channels
–NMDA receptor channelsNMDA receptor channels

Enzyme systems involved Enzyme systems involved
in neurodegenerationin neurodegeneration

Oxidative cascade,Oxidative cascade,
NOS and MAO-B.NOS and MAO-B.
NOS-reaction

5. Research within drug designResearch within drug design
–Lead compoundsLead compounds

Chemical synthesis, Chemical synthesis,
drugs in usedrugs in use

New compounds from New compounds from
plantsplants
–Molecular modeling Molecular modeling
–Synthesis and Synthesis and
characterizationcharacterization
–Biological activityBiological activity

In vitroIn vitro

In vivoIn vivo
O
NHR

6. 
Protein modelingProtein modeling
–ReceptorReceptor / Enzyme fit / Enzyme fit

‘‘Ligandfit’Ligandfit’

‘‘Docking’Docking’
Molecular modelingMolecular modeling

7. Synthesis and Synthesis and
CharacterisationCharacterisation NH
2
R
1
R
2
CH
H
3C
NH
2
(1) Amantadine R
1 = H, R
2 = H
(2) Memantine R
1 = CH
3, R
2 = CH
3
(3) Rimantadine
R
O
O
O
OH
O
O
O O
(a)
O
(i) Dean-Strark
(ii) NaBH
4 /methanol-THF
(ii) HO(CH
2)
2OH
(iv) Huang-Minlon
(v) NH
2OH, NaBH
4
NH
OH
(vi) N
2CHCO
2Et
(vii) F
3B.OEt
(viii) NaCl, DMSO,
H
2O, N
2
O
O O
1; R = benzylamine
2; R = phenyhydrazyne
3a; R = 4-nitrobenzylamine
3b; R = 3-nitrobenzylamine
3c; R = 2-nitrobenzylamine
4a; R = 4-methoxybenzylamine
4b; R = 3-methoxybenzylamine
4c; R = 2-methoxybenzylamine
5a; R = 3-methylpyridine
5b; R = 4-methylpyridine

9; R = phenylethylamine
(ix) 30%
H
2O
2,
SeO
2,
t-Butanol
12
R
1
8
R
1
11
6 7
R = benzylamine
Synthesis and
characeterization with
NMR, MS and IR.
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
N
OH
R
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
N
OH
R
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
N
OH
R
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
N
O
R
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
N
O
R
R = NO2
R = NH2
R = N(C2H5)2
R = N(C3H7)2
R = N(C4H9)2
N
O
R

8. Biological evaluation - Biological evaluation - In vitro & In In vitro & In
vivovivo
-60 -40 -20 0 20
-0.4
-0.2
0.0
Control
Compound 1
I
C
a
(
m
a
x
)
-
I
m
(
n
A
)
Membrane potential (mV)
[
3H]-MK-801
[
3H]-TCP
TotMK M 1 8 9
0
20
40
60
80
100
120
%

o
f

C
o
n
t
r
o
l
*
*
*
*
*
*
%
o
f

C
o
n
t
r
o
l

4
5
C
a
2
+

in
f
l
u
x
*
*
**
* *
*
*
**
*
Background NMDA + Gly
CNAMMK123a3b3c4a4b4c5a5b6789
70
80
90
100
110
120
-8-7-6-5-4-3-2-1
0
10
20
30
40
50
60
70
80
90
100
110
Aminoguanidine
Compound 1
Compound 4
Compound 7
Compound 8
Compound 9
7-NI
log[Compounds] (M)
E
n
z
y
m
e

a
c
t
i
v
i
t
y
(
%

o
f

c
o
n
t
r
o
l
)

9. 2. Synthesis of Novel/Hybrid 2. Synthesis of Novel/Hybrid
Molecules & Biological Evaluation – Molecules & Biological Evaluation –
Malaria and Dengue feverMalaria and Dengue fever

Inhibitory ActivityInhibitory Activity

Resistance reversal in MicroorganismsResistance reversal in Microorganisms

Microscopic evaluationMicroscopic evaluation

Molecular Studies Molecular Studies

10. 3. PHYTOCHEMISTRY- Prof Eagles3. PHYTOCHEMISTRY- Prof Eagles

Phytochemistry is the study of phytochemicals produced Phytochemistry is the study of phytochemicals produced

in plants, describing the isolation, purification, identification, and in plants, describing the isolation, purification, identification, and

structure of the large number of secondary metabolic compounds structure of the large number of secondary metabolic compounds

found in plants. found in plants.

Techniques commonly used in the field of phytochemistryTechniques commonly used in the field of phytochemistry

••Thin layer chromatography (TLC)Thin layer chromatography (TLC)

••Gel (column chromatography)Gel (column chromatography)

••High performance of liquid chromatography (HPLC)High performance of liquid chromatography (HPLC)

••Gas chromatography (GC)Gas chromatography (GC)

••Mass spectrometryMass spectrometry