PHARMACEUTICAL PHARMACEUTICAL CHEMISTRY RESEARCH CHEMISTRY RESEARCH

PROJECTS 2013PROJECTS 2013

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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)

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

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

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

ONHR

Protein modelingProtein modeling– ReceptorReceptor / Enzyme fit / Enzyme fit

‘‘Ligandfit’Ligandfit’ ‘‘Docking’Docking’

Molecular modelingMolecular modeling

Synthesis and Synthesis and CharacterisationCharacterisation NH2

R1

R2

CHH3C NH2

(1) Amantadine R1 = H, R2 = H (2) Memantine R1 = CH3, R2 = CH3

(3) Rimantadine

R

O

OO

OHO O

O O

(a)

O

(i) Dean-Strark (ii) NaBH4 /methanol-THF

(ii) HO(CH2)2OH (iv) Huang-Minlon (v) NH2OH, NaBH4

NH

OH

(vi) N2CHCO2Et (vii) F3B.OEt (viii) NaCl, DMSO, H2O, N2

OO 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% H2O2, SeO2, t-Butanol

12

R1

8

R1

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 = NO2R = NH2R = N(C2H5)2R = N(C3H7)2R = N(C4H9)2

N

OH

R

R = NO2R = NH2R = N(C2H5)2R = N(C3H7)2R = 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 = NO2R = NH2R = N(C2H5)2R = N(C3H7)2R = N(C4H9)2

N

O

R

R = NO2R = NH2R = N(C2H5)2R = N(C3H7)2R = N(C4H9)2

N

O

R

Biological evaluation - Biological evaluation - In vitro & In vivoIn vitro & In vivo

-60 -40 -20 0 20

-0.4

-0.2

0.0

Control

Compound 1

ICa

(ma

x)-I

m(n

A)

Membrane potential (mV)

[3H]-MK-801

[3H]-TCP

Tot MK M 1 8 90

20

40

60

80

100

120

% o

f C

on

tro

l

**

*

***

% o

f C

on

tro

l 4

5 Ca

2+ i

nfl

ux *

*

**

* *

**

* *

*

Background NMDA + Gly

CN A M MK 1 2 3a 3b 3c 4a 4b 4c 5a 5b 6 7 8 970

80

90

100

110

120

-8 -7 -6 -5 -4 -3 -2 -10

102030405060708090

100110

AminoguanidineCompound 1Compound 4Compound 7Compound 8Compound 97-NI

log[Compounds] (M)

En

zym

e ac

tivi

ty(%

of

con

trol

)

2. Synthesis of Novel/Hybrid Molecules 2. Synthesis of Novel/Hybrid Molecules & Biological Evaluation – Malaria and & Biological Evaluation – Malaria and

Dengue feverDengue fever

Inhibitory ActivityInhibitory Activity

Resistance reversal in MicroorganismsResistance reversal in Microorganisms

Microscopic evaluationMicroscopic evaluation

Molecular Studies Molecular Studies

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