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SAM821S - SYNTHETIC ASPECTS OF MEDICINAL CHEMISTRY - 2ND OPP - JANUARY 2025 |
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nAm I BIA UnlVERSITY
OF SCIEnCE Ano TECHnDLOGY
Facultyof Health,Natural
ResourceasndApplied
Sciences
Schoolof Natural andApplied
Sciences
Department of Biology,
Chemistryand Physics
13JacksonKaujeuaStreet T: +264612072012
Private Bag13388
F: •264 612079012
Windhoek
E: dbcp@nust.na
NAMIBIA
W: www.nust.na
QUALIFICATION: BACHELOR OF SCIENCE HONOURS
QUALIFICATION CODE: 08BOSCH
LEVEL: 8
COURSE: SYNTHETIC ASPECTS OF MEDICINAL CHEMISTRY COURSECODE: SAM821S
DATE: JANUARY 2025
SESSION: 1
DURATION: 3 HOURS
MARKS: 100
SECOND OPPORTUNITY/ SUPPLEMENTARY: QUESTION PAPER
EXAMINER:
MODERATOR:
DR MARIUS MUTORWA
DR RENATE HANS
INSTRUCTIONS:
1. Answer ALL the questions.
2. Write clearly and neatly.
3. Number the answers clearly
4. All written work must be done in blue or black ink and sketches can be done in
pencil.
5. No books, notes and other additional aids are allowed.
PERMISSIBLE MATERIALS
Non-programmable calculators
ATTACHMENTS
1. List of Amino Acids
This paper consists of thirteen (13) pages including this front page.
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SECTION A:
[SO MARKS]
QUESTION 1: MULTIPLE CHOICE QUESTIONS
Evaluate the statements in each numbered section and select the most appropriate answer
or phrase from the given possibilities. Fill in the appropriate letter next to the number of the
correct statement/phrase on your ANSWERSHEET.
1.1 Which of the following descriptions best describes a coenzyme?
A. A non-protein substance that is required by an enzyme if it is to catalyse a reaction
B. A non-protein organic molecule that is required by some enzymes in order to
catalyse a reaction on a substrate
C. A non-protein organic molecule that is bound covalently to the active site of an
enzyme, and which is required if the enzyme is to catalyse a reaction on a substrate
D. A compound which is bound to the active site and undergoes a reaction
1.2 What term is used for enzymes such as COX-1 and COX-2 which vary in structure and
location but which catalyse the same reaction?
A. lsosteres
B. lsozymes
C. Isotopes
D. Isomers
1.3 Which of the following statements is true with respect to the Michaelis constant?
A. It is equal to the concentration of inhibitor at which the reaction rate is half of its
maximum value
B. It is equal to the concentration of substrate at which the reaction rate is at its
maximum value
C. It is equal to the concentration of inhibitor at which the reaction rate is zero.
D. It is equal to the concentration of substrate at which the reaction rate is half of its
maximum value
1.4 Which of the following statements is true about a G-protein coupled receptor?
A. It contains five transmembrane hydrophobic sections
B. There are more extracellular loops than intracellular loops
C. The binding region for the G-protein involves two extracellular loops
D. The N-terminal chain is extracellular and the C-terminal chain is intracellular
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1.5 Which of the following descriptions best fits an inverse agonist?
A. A compound that has the same effect on a receptor as the endogenous chemical
messenger
B. A compound that binds to a receptor, and activates it, but to a lesser extent than
the endogenous chemical messenger
C. A compound that binds to a receptor fails to activate it and prevents the
endogenous chemical messenger from binding
D. A compound that binds to a receptor fails to activate it and leads to a drop in
inherent biological activity
1.6 Which of the following statements best describes the potency of a drug?
A. The maximum biological effect resulting from a drug binding to its target
B. The measure of how strongly a drug binds to a receptor
C. The amount of drug required to produce a defined biological effect
D. The lifetime of the drug in the body
1.7 What is the pharmacokinetic advantage of drugs having amine functional groups?
A. They are strong bases and are fully ionised
B. They are very weak bases and are not ionised at all
C. They are weak bases and are in equilibrium between the ionised and free base
forms
D. They are able to form hydrogen bonds
1.8 How can advantage be taken of the blood brain barrier in drug design?
A. Drugs can be made more hydrophobic such that they act in the brain and not
peripherally
B. Drugs can be made more hydrophilic such that they act in the brain and not
peripherally
C. Drugs can be made more hydrophobic such that they act peripherally and not
in the brain
D. Drugs can be made more hydrophilic such that they act peripherally and not in
the brain
1.9 Which of the following reflects the order in which various stages of the drug discovery and
development take place?
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A. Determining a target, establishing a bioassay, finding a lead compound, structure
activity relationships
B. Establishing a bioassay, determining a target, finding a lead compound, structure
activity relationships
C. Determining a target, establishing a bioassay, structure activity relationships,
finding a lead compound
D. Determining a target, finding a lead compound, structure activity relationships,
establishing a bioassay
1.10 In the development of the antifungal agent, nevirapine, structure (II} was found to bind
more strongly to the target enzyme than the lead compound (I}. Which of the following
statements is correct?
6N z-:b-
CO/Bu
(I) Lead compound
(II)
Nevirapine
A. The strategy used was one of ring expansion
B. The extra nitrogen allows an extra binding interaction to take place through van
der Waals interactions
C. The extra nitrogen in blue can act as a hydrogen bond donor
D. The strategy used could be described as extension since a further binding
interaction has occurred
1.11 Structure (Ill} is a serotonin antagonist. A methyl group has been introduced into
analogue (IV) resulting in increased activity. What could be the reason for the observed
increase in activity?
ill
N
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A. The methyl group interacts with an extra hydrophilic binding region through van
der Waals interactions
B. The methyl group increases the basicity of the ring nitrogen, making it a better
hydrogen bond donor
C. The methyl group increases the basicity of the ring nitrogen, making it a better
hydrogen bond donor
D. The methyl group prevents the pyridine rings from being coplanar and forces the
molecule into the active conformation
1.12 Examine the Lineweaver-Burk Plot below, whereby the arrow indicates the trend of
increasing inhibitor concentration. What type of inhibitor is being used in this series of
plots?
i
1/jS)
A. Reversible competitive
B. Reversible uncompetitive
C. Reversible non-competitive
D. Irreversible
1.13 An enzyme has a Kmvalue of 750nM for its natural substrate. Three research groups
investigate potential inhibitors for the same enzyme. The three groups report their data of
the best inhibitor as ICsovalues as shown in the table below. Based on the equation and
values reported, which lab group developed the most potent inhibitor?
IC;o
Ki=
(
1+-
[S])
Km
lab number /C50 (nM) tested [S] (nM)
40
3,000
2
25
2,000
3
10
200
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A. Lab 1
B. Lab 2
C. Lab 3
D. Cannot be determined from the results provided
1.14 Which of the following agents act as irreversible inhibitors?
A. Sulphonamides
B. Penicillins
C. Statins
D. Protease inhibitors
1.15 Which of the following situations is feasible as an explanation for tolerance and
dependence?
A. An increased production of receptors to counteract the presence of an
antagonist.
B. An increased production of receptors to counteract the presence of an agonist.
C. A decreased production of receptors to counteract the presence of an
antagonist.
D. A decreased synthesis of chemical messenger to counteract the presence of an
antagonist.
1.16 An agonist contains an alcohol, amine and aromatic ring, all of which act as binding
groups. Which of the following modifications is most likely to result in an antagonist?
A. Converting the alcohol to a methyl ether
B. Adding an extra aromatic ring to the structure
C. Synthesizing an analogue which lacks the aromatic ring
D. Converting the amine to an amide
1.17 It is common practice to vary the length and size of alkyl groups when making analogues
of a lead compound. Which of the following statements is not true?
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A. Replacing a straight chain alkyl group with a branched alkyl group may increase
activity by filling up a hydrophobic pocket and increasing van der Waals
interactions.
B. Increasing the chain length or size of an alkyl group may increase target selectivity
if one target binding site is more spacious than another.
C. Increasing the chain length or size of an alkyl group increases activity and
selectivity by stabilising the analogue.
D. Increasing the chain length of an alkyl group may increase activity by leading to
better van der Waals interactions with a hydrophobic region of the binding site.
1.18 Which of the following is not an enzyme involved in catalysing Phase II metabolic
reactions?
A. Adenosyl methionine.
B. Peptidase.
C. Glutathione transferase.
D. Sulfotransferase.
1.19 A secondary amide group in a lead compound was reduced to an amine functional group.
In vitro tests showed that the lead compound was active and that the product was inactive.
However, in vivo tests showed that both the amide and amine were inactive. Which of the
following statements is not plausible?
A. The amide is an important binding group but the amine is not.
B. Both the amide and the amine are important binding groups.
C. The carboxyl group of the amide may be an important hydrogen bond acceptor
group.
D. In the in vivo bioassay, the amide is converted to the amine by metabolic or
digestive enzymes.
1.20 Which of the following statements best describes a bio-isostere?
A. A group having the same valency as another group.
B. A group that is the same as a non-classical isostere.
C. A group that can be used in place of another group whilst retaining the important
biological activity of the drug.
D. A group having the same size as another group.
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1.21 The following structures are various non-steroidal anti-inflammatory agents developed
by a ring variation strategy. Which of the following terms has been used for drugs of this
sort?
F
F
F
Br
A. Family drugs.
B. Analogue drugs.
C. Me-too drugs.
D. lsosteric drugs.
1.22 Which of the following descriptions refers to the absorption process known as
pinocytosis?
A. The process by which a drug is 'wrapped up' by a protein in the cell membrane
such that it can be carried across the cell membrane.
B. The process by which small molecules can squeeze through the small pores that
exist between different cells in the gut wall.
C. The process by which drugs of large molecular weight are enveloped by the cell
membrane of a cell lining the gut wall, leading to the pinching off of a membane
bound vesicle which carries the drug into the cell.
D. The process by which ion channels open to allow the crossing of ions across the
cell membrane.
1.23 There are several sources and methods of discovering new compounds. Which of the
following is an in silica method?
A. Combinatorial chemistry.
B. Database mining.
C. Screening plant extracts.
D. Me too drugs.
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1.24 Many drugs containing ester functional groups have a limited duration of action. There
are several strategies which can be used to avoid this problem. Which of the following is not
a suitable strategy?
A. Replacing the ester group with an amide.
B. Adding a steric shield close to the ester.
C. Adding an electron withdrawing group to the alkoxy moiety of the ester.
D. Replacing the ester group with a urethane.
1.25 Why should the addition of an alcohol or phenol group to a drug decrease the drug's
duration of action?
A. It acts as a 'polar handle' for conjugation reactions. The conjugates are excreted
more quickly.
B. It increases the polarity of the drug and reduces the amount of drug absorbed.
C. It reacts with proteins in the body such that the drug is irreversibly linked to the
proteins by a covalent bond.
D. It acts as an electron-withdrawing group and affects the binding strength of
important binding groups.
END OF SECTION A
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SECTION B:
[SO MARKS]
QUESTION 2
[101
2.1 Candesartan cilexetil is an anti-hypersensitive prodrug that antagonizes the AT1
angiotensin receptor. Within the structure are four lead modification approaches with which
you should be familiar. Working backwards, draw a lead molecule from which this drug may
have been derived and point out where and which lead modifications occurred.
(5)
2.2 Explain the change in log D vs pH for omeprazole shown below. Refer to the structure
when discussing the logD changes to pH.
(5)
LogD
1.00
0.97
O.IJ
G
B
10 \\ 12
It pH
\\
\\
H-C'tx:'.1-l, OCH:,
·'
I
--..;:
,,--
.
D·::<J1N-.I__OOC'f-11
:'\\i
"\\ N...--- /,
11
Omeprazole
QUESTION 3
[101
3.1 A lead compound containing a methyl ester was hydrolysed to give a carboxylic acid. An
in vivo bioassay suggested that the ester was active and the acid was inactive. However, an in
vitro bioassay suggested that the ester was inactive and the acid was active. Explain these
contradictory results.
(6)
3.2 CGP52411 is a useful inhibitor of a protein kinase enzyme. Studies on structure-activity
relationships demonstrate that substituents on the aromatic ring such as chlorine, methyl or
hydroxyl group are bad for activity. Drug metabolism studies show that para-hydroxylation
occurs to produce inactive metabolites. How would you modify the structure to protect it
from metabolism?
(4)
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H
H
CGP52411
QUESTION 4:
[10]
4.1 You are employed as a medicinal chemist and have been asked to initiate a research
programme aimed at finding a drug which will prevent a novel tyrosine kinase receptor from
functioning. There are no known lead compounds that have this property. What approaches
will you consider or take to establish a lead compound?
(5)
4.2
a. Explain the principles of rigidification and show how you would apply it to structure IV
below in order to improve its pharmacological properties.
(3)
H
XV-I:N'CH
3
h'
IV
b. Give two specific examples of rigidified structures with respect to structure IV.
(2)
QUESTION 5:
[10]
5.1 Compound DU 122290 was developed from sultopride (a dopamine antagonist). DU
122290 shows increased activity towards the dopamine receptor class D3-receptor, rather
than the dopamine receptor class D2-receptor. Additionally, DU 122290 shows improved
selectivity towards the D3-receptor over the D2-receptor. Suggest possible reasons for these
observations.
(5)
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Py1rnle
nng:
OMe
Et02S
Sultopride
DU 1.22290
5.2 The oral bioavailability of the antiviral drug aciclovir is only 15-30%. Suggest why this may
be the case and suggest two possible methods how one might increase the bioavailability of
this drug. Explain which of the two methods you suggested is more plausible or preferred. (5)
Acidovir
QUESTION 6:
[10]
Cytidine deaminase is an enzyme that converts cytidine to uridine, as shown below.
0~)Cyti<linc
dcamina~c
>
I
Ribose
Cytidine
0
OHANN:J
I
Ribose
Uricline
Draw a mechanism by which this reaction occurs, involving a highly conserved water molecule
and a nucleophilic amino acid residue which are present in the active site. Hint: a histidine
amino acid residue provides the proton (W) required in the mechanism.
(10)
END OF QUESTION PAPER
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NON POLAR
(hydrophobic)
0 Hr
0
H3Nl••C-C02
I
CH3
Alanine
(Ala or A)
LIST OF AMINO ACIDS
H
0f
0
H3N1 • ·C-C02
I
'CH
H3C/ CH3
Valine
(Val or V)
Leucine
(Leu or L)
0 Hr
0
H3N1 • ·CI -CO, •
H-C-CI H, ,
CH,
I-
CH3
lsoleucine
(lie or I)
Phenylalanine
(Phe or F)
0 Hr
<')
H3N' ' ·(I - co,.
ccf
N
H
Tryptophan
(Trp orW)
H
0
T8
H2N1,, .. , .. (-C0 2
V
Proline
(Pro or P)
POLAR
H
0I
0
H3N-C-C02
I
H
Glycine
(Gly or Gl
H
Gl
(;.)
H3N" ·C-C02
I
CH20H
Serine
(Ser or 5)
H
H3(iN) 1 •·C' -C02 0
I
H-C-OH
CH3
Threonine
(Thr or T)
H
0'
0
H3N" ·C-C02
I
CH2
I
SH
Cysteine
(Cys or C)
Asparagine
(Asn or N)
H
0l
0
H3N1 '·C-C02
I
CH2
I
CH2
I
O:r 'NH2
Glutamine
(Gin or Q)
IONIZED
H
0f
9
H3N1 • ·(-CO2
I
CH2
I
CI H-,
CH2
I
CH2
I
NH3
8
Lysine
(Lys or K)
H
(i) '
8
H3N1 •·C-C02
I
CI H-,
CI H-,
CIH.,
N-H
I
-:,:::.C,
H2N
0
NH2
Arginine
(Arg or R)
Histidine
(His or H)
Aspartate
(Asp or D)
H
0T
0
H3N1 •·CI-CO, .
CI H•"
CI H.,
5
I
CH3
Methionine
(Met or M)
H
(,) '
0
H3N1 •·C-C02
I
9
OH
Tyrosine
(Tyr or Y)
H
0l
0
H3N1 • ·C-C02
I
1H2
CH,
I-
o~c.....o. 0
Glutamate
(Glu or E)
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