Medicinal Chemistry Chapter 25 Key

Type: multiple choice Title: Chapter 25 - Question 01 01) What sort of heterocyclic ring is present in histamine? Feedback: The ring systems given are as follows incorrect a.# Imidazolidine. incorrect b.# Pyridine. incorrect c.# Pyrrole. Correct d.# Imidazole. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 02 02) Which ailment is not treated by conventional histamine antagonists acting on the H1 receptor? Feedback: Anti-ulcer agents acting as histamine antagonists target H2-receptors on parietal cells. incorrect a.# Hay fever. incorrect b.# Insect bites. Correct c.# Ulcers. incorrect d.# Asthma. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 03 03) There are two possible tautomers for histamine. Tautomer A is more stable than tautomer B. Why? Feedback: The side chain is electron withdrawing due to the positively charged ammonium group at the end of the chain. Since this is an inductive effect, it is felt more at the  nitrogen than the  nitrogen since the former is nearer the side chain. Inductive effects decrease with the number of bonds involved. This means that the  nitrogen is going to be less basic and less likely to use its lone pair of electrons to form a bond to hydrogen. Correct a.# The side chain has an inductive electron-withdrawing effect on the ring making the  nitrogen less basic than the  nitrogen. incorrect b.# The side chain has an inductive electron-donating effect on the ring making the  nitrogen less basic than the  nitrogen. incorrect c.# incorrect d.# The side chain has an inductive electron-withdrawing effect on the ring making the  nitrogen less basic than the  nitrogen. The side chain has an inductive electron-donating effect on the ring making the  nitrogen less basic than the  nitrogen. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 04 04) There are two possible tautomers for histamine. 4 4 NH3 HN NH3 N N NH A B What would be the effect on the tautomer population if a methyl group were to be placed at position 4 of the ring? Feedback: The methyl group has an inductive effect which is electron donating. The  nitrogen is closer to this substituent than the  nitrogen and so the  nitrogen experiences this inductive effect to a greater extent. This makes the  nitrogen more basic and more likely to use its lone pair of electrons to bond to hydrogen. incorrect a.# The relative population of B would increase. incorrect b.# There would be no difference. Correct c.# The relative population of A would increase. incorrect d.# It is not possible to predict the effect. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 05 05) There are two possible tautomers for histamine. A methyl group at position 4 plays an important role in favouring tautomer A through an inductive effect. 4 4 NH3 HN NH3 N N NH A B What other important effect arises from the presence of a methyl group at position 4? Feedback: It introduces selectivity for the H 2 receptor and is present in anti-ulcer drugs such as cimetidine. incorrect a.# It introduces selectivity for the H1 receptor. Correct b.# It introduces selectivity for the H2 receptor. incorrect c.# It protects the molecule from metabolism. incorrect d.# It increases the ability of the compound to cross cell membranes. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 06 06) N-Guanylhistamine was the first lead compound for the development of H2-antagonists. What strategy was used in developing the guanidine structure (A)? Feedback: Extension indicates the addition of a new functional group to find an extra binding region. Here, the functional group is already present and has been moved further away from the imidazole ring by chain extension. Substituent variation and isosteric replacement indicate the replacement of a group with another group which has not occurred here. incorrect a.# Extension. Correct b.# Chain extension. incorrect c.# Substituent variation. incorrect d.# Isosteric replacement. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 07 07) N-Guanylhistamine was the first lead compound for the development of H2-antagonists. What was the rationale for the strategy used in developing the guanidine structure (A)? Feedback: The antagonist binding region is further away from the imidazole binding region than the agonist binding region. Therefore, extending the distance between the guanyl group and the imidazole ring increases the chances that the molecule will bind as an antagonist rather than as an agonist. incorrect a.# To reduce the inductive effect of the guanidine unit on the imidazole ring. incorrect b.# To increase the flexibility of the chain by allowing more single bond rotations. incorrect c.# To move the binding group closer to the agonist binding region and away from the antagonist binding region. Correct d.# To move the binding group closer to the antagonist binding region and away from the agonist binding region. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 08 08) During the search for H2 antagonists, the following binding theory was proposed between a guanidine unit and a carboxylate unit in the binding site. What was it called? Feedback: The binding theory was called the chelation binding theory and involves the guanidine and carboxylate ion interacting through ionic and hydrogen bonding interactions. incorrect a.# Ionic binding theory. incorrect b.# Hydrogen bonding theory. Correct c.# Chelation binding theory. incorrect d.# Complexation binding theory. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 09 09) The following structures show some of the important molecules leading to the discovery of structure B. What sort of functional group has been introduced in SK&F 91581? Feedback: The functional groups described in the options are as shown below: incorrect a.# Guanidine. incorrect b.# Urea. Correct c.# Thiourea. incorrect d.# Thioamide. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 10 10) The following structures show some of the important molecules leading to the discovery of structure B. A functional group has been introduced in SK&F 91581. What was the rationale for introducing this functional group? Feedback: Structure B is burimamide. The rationale was to replace the basic guanyl group with a neutral group such that it would interact by hydrogen bonding rather than ionic bonding. A neutral group was chosen that was as similar as possible to the guanyl group in terms of size and shape. incorrect a.# To reduce the number of possible hydrogen bond donors present. Correct b.# To replace an ionic group with a neutral group. incorrect c.# To change the shape of the terminal functional group. incorrect d.# To change the size of the terminal functional group. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 11 11) The following structures show some of the important molecules leading to the discovery of structure B. What was the rationale for the strategy used in developing structure B from SK&F 91581? Feedback: Structure B is burimamide. The antagonist binding region is further away from the imidazole binding region than the agonist binding region. Therefore, extending the distance between the thiourea group and the imidazole ring increases the chances that the molecule will bind as an antagonist rather than an agonist. incorrect a.# To reduce the inductive effect of the terminal functional group on the imidazole ring. incorrect b.# To increase the flexibility of the chain by allowing more single bond rotations. incorrect c.# Correct d.# To move the terminal functional group closer to the agonist binding region and away from the antagonist binding region. To move the terminal functional group closer to the antagonist binding region and away from the agonist binding region. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 12 12) The following diagram shows the various tautomers of the terminal functional group in structure cimetidine Which is considered to be the most stable tautomer? Feedback: Since the electron-withdrawing effect of the cyanide group is inductive, it is experienced most by the nitrogen directly attached to cyanide. As a result, this nitrogen will be the least basic of the three nitrogens present in the guanidine moiety and the least likely to bond to hydrogen. incorrect a.# Tautomer I. Correct b.# Tautomer II. incorrect c.# Tautomer III. incorrect d.# They are all equal in stability. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 13 13) The following graph measures log(activity) versus log P. What does the graph show about activity? Feedback: As log P increases, activity increases. Log P is a measure of hydrophobicity and so increased activity is associated with increasing hydrophobicity. Correct a. Activity increases with hydrophobic character. # incorrect b. Activity decreases with hydrophobic character. # incorrect c. Activity increases with basicity. # incorrect d. Activity increases with the size of the group. # END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 14 14) The following graph measures log(activity) versus log P. The nitroketeneaminal group does not fit the straight line. Which of the following statements is true? Feedback: The log P value for this group is relatively low and the compound should have a lower activity than it actually has. Correct a.# The activity is too great for the hydrophobicity of the group. incorrect b.# The activity is too great for the size of the group. incorrect c.# The activity is too great for the basicity of the group. incorrect d.# The activity is too small for the hydrophobicity of the group. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 15 15) The following graph measures log(activity) versus log P. What physical feature other than log P is important to the activity of cimetidine analogues? Feedback: To be precise, the orientation of the dipole moment is important to the activity rather than the size of the dipole moment. incorrect a.# Hydrophobicity. incorrect b.# Basicity. incorrect c.# Molecular weight. Correct d.# Dipole moment. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 16 16) A QSAR study of cimetidine analogues with different planar groups produced the following equation; log (Activity) = 9.12 cos + 0.6logP -2.71. What is the relevance of the cos entry? Feedback: The cos entry quantifies the orientation of a dipole moment.  is the deviation in angle of the dipole moment from the ideal orientation of 30°. Correct a.# It quantifies the orientation of a dipole moment . incorrect b.# It quantifies the magnitude of a dipole moment. incorrect c.# It quantifies the orientation of hydrogen bonds. incorrect d.# It quantifies the strength of hydrogen bonding. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 17 17) A QSAR study of cimetidine analogues with different planar groups produced the following equation; log (Activity) = 9.12 cos + 0.6logP -2.71. What is the ideal value of ? Feedback: At 0°, cos is equal to a maximum value of 1. At any other value, the cos value will be a fraction. This means that the calculated activity will be smaller. Correct a.# 0° incorrect b.# 45° incorrect c.# 60° incorrect d.# 90° END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 18 18) What enzyme catalyses the following reaction? Feedback: Carbonic anhydrase catalyses the formation of carbonic acid from water and carbon dioxide. The acid dissociates to give a proton and a hydrogen carbonate ion. incorrect a.# Carbonic synthase. incorrect b.# Carbonic ligase. Correct c.# Carbonic anhydrase. incorrect d.# Carbonic hydrolase. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 19 19) What reaction is catalysed to power the proton pump? Feedback: Hydrolysis of ATP to ADP involves the splitting of the terminal phosphate group from the triphosphate chain of ATP, generating energy which can be used to power the proton pump. Correct a.# ATP to ADP. incorrect b.# ATP to AMP. incorrect c.# ATP to cyclic AMP. incorrect d.# ATP to adenosine. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 20 20) The proton pump inhibitors are prodrugs. Where do they get activated? Feedback: The proton pump inhibitors are activated by strong acidic conditions found only in the canaliculae of parietal cells. incorrect a.# In the liver. incorrect b.# In the blood supply. incorrect c.# In parietal cells. Correct d.# In the canaliculae of parietal cells. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 21 21) What is the typical pKa for proton pump inhibitors? Feedback: The proton pump inhibitors are weak bases and require strong acidic conditions before they protonate and become activated. Correct a.# 4 incorrect b.# 6 incorrect c.# 7.4 incorrect d.# 9 END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 22 22) What conditions are required to activate proton pump inhibitors? Feedback: The proton pump inhibitors are weak bases and require strong acidic conditions before they protonate and become activated. Correct a.# Strongly acidic conditions. incorrect b.# Weakly acidic conditions. incorrect c.# Neutral conditions. incorrect d.# Slightly basic conditions. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 23 23) The following diagram shows the development of the first commercially available proton pump inhibitor omeprazole (A). During this study, timoprazole was found to be a promising looking candidate. Addition of methyl and methoxy substituents to the pyridine ring increases the activity of timoprazole. What effect do these groups have? Feedback: The activation of the drug under acidic conditions requires the pyridine nitrogen to act as a base. The addition of electron-donating substituents increases the basicity of the pyridine nitrogen. incorrect a.# Correct b.# incorrect c.# incorrect d.# They fit into hydrophobic binding pockets in the active site and increase binding strength. They are electron-donating groups and increase the basicity of the pyridine ring. They act as steric shields to prevent metabolism at exposed regions of the pyridine ring. They block the drug binding to alternative targets. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 24 24) The following diagram shows the development of the first commercially available proton pump inhibitor omeprazole (A). During this study, it was found that the methyl and methoxy substituents on the pyridine ring had an important role in increasing activity. What effect would you predict if the coloured substituents on the pyridine ring of omeprazole (A) were swapped such that the methoxy group was at the meta position relative to the nitrogen of the ring ? Feedback: The methoxy substituent can interact with the pyridine ring by resonance. When the substituent is located at the para position, a resonance structure can be drawn where a negative charge is placed on the pyridine nitrogen, thus increasing its basic character and the activity of the compound. If the substituent is at the meta position, this resonance structure is no longer possible. This means that the pyridine ring will be less basic and the structure will be less active. incorrect a.# Activity would be unaffected. incorrect b.# Activity would increase. Correct c.# Activity would decrease. incorrect d.# It is impossible to predict what would happen. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 25 25) The following structure (esomeprazole) has been marketed as the more active enantiomer of omeprazole. What is the name of the strategy where a clinically important racemic drug is replaced with the active enantiomer of the drug? Feedback: Chiral switching has been used on several drugs which were previously marketed as racemates. incorrect a.# Patent switching. incorrect b.# Enantiomeric switching. incorrect c.# Asymmetric switching. Correct d.# Chiral switching. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 26 26) What type of triple therapy is most commonly used to treat ulcers caused by Helicobacter pylori? Feedback: The proton pump inhibitor serves to reduce the quantity of hydrochloric acid released into the stomach by parietal cells. The antibacterial agents are used to combat the bacterium Helicobacter pylori which is known to cause inflammation and cell damage in the stomach. incorrect a.# An H2 antagonist, proton pump inhibitor and an antibacterial agent. incorrect b.# An H2 antagonist, and two antibacterial agents. Correct c.# A proton pump inhibitor and two antibacterial agents. incorrect d.# Two proton pump inhibitors and an antibacterial agent. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 27 27) Which of the following structures represents histamine at physiological pH? Feedback: The side chain nitrogen is fully ionised and the heterocyclic nitrogens are not ionised. Correct a.# Structure A. incorrect b.# Structure B. incorrect c.# Structure C. incorrect d.# Structure D. END OF QUESTION Type: multiple choice Title: Chapter 25 – Question 28 28) Several binding regions were proposed to be present in the binding site of the H2 receptor. Which of the following statements is incorrect? Feedback: The imidazole binding region is the same for agonists and antagonists. Correct a.# incorrect b.# incorrect c.# incorrect d.# There are two binding regions for the imidazole ring of histamine analogues, one which is occupied by agonists and one which is occupied by antagonists. There is a binding region which interacts ionically with the -nitrogen of histamine and results in agonist activity. There is a binding region further away from the imidazole ring that produces an antagonist effect if occupied. The -nitrogen of histamine can only bind to the agonist binding region while the guanyl group of N-guanylhistamine can bind either to the antagonist binding region or the agonist binding region. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 29 29) The following structures show some of the important molecules leading to the discovery of structure B. Which of the following statements concerning structure B is untrue? Feedback: It established that binding to the antagonist binding region involved hydrogen bonding and not ionic bonding. incorrect a.# It established the existence of H2-receptors. incorrect b.# It was a good antagonist at H2 receptors with no agonist activity. incorrect c.# It inhibited gastric acid release from parietal cells. Correct d.# It indicated that binding to the antagonist binding region involved ionic bonding and not hydrogen bonding. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 30 30) The following structure is cimetidine. Which electron-donating group is present to favour the active tautomeric form of the imidazole ring shown? Feedback: The methyl group has an inductive electron-donating effect on the imidazole ring. This inductive effect is more pronounced at the -nitrogen than the -nitrogen since the former is closer to the substituent. The inductive effect makes the -nitrogen more basic and favours the tautomer where this nitrogen is bonded to a hydrogen. Correct a.# Group a. incorrect b.# Group b. incorrect c.# Group c. incorrect d.# Group d. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 31 31) The following structure is cimetidine. Which electron-withdrawing group is present to favour the active tautomeric form of the imidazole ring shown? [ Feedback: The sulfur has an inductive electron-withdrawing effect on the imidazole ring. This inductive effect is more pronounced at the -nitrogen than the -nitrogen since the former is closer to the substituent. The inductive effect makes the -nitrogen more basic and favours the tautomer where this nitrogen is bonded to a hydrogen. incorrect a.# Group a. Correct b.# Group b. incorrect c.# Group c. incorrect d.# Group d. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 32 32) The following structure is cimetidine. Which group is present to interact with a hydrogen bonding region not used by histamine? Feedback: Group d is a naturally occurring moiety which is neutral and interacts with a binding region through hydrogen bonding. It was used to replace a thiourea group in previous structures since the latter was responsible for toxic side effects. incorrect a.# Group a. incorrect b.# Group b. incorrect c.# Group c. Correct d.# Group d. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 33 33) The following structure is cimetidine. The guanidine moiety at the end of the side chain is neutral which is unusual since guanidine moieties are usually basic. Which one of the coloured groups shown is responsible for this? Feedback: The cyanide group has a strong inductive effect which is electron withdrawing. As a result the basicity of the guanidine group is reduced and it is less likely to ionise. Correct a.# Group a. incorrect b.# Group b. incorrect c.# Group c. incorrect d.# Group d. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 34 34) Which of the following structures is a metabolite of cimetidine? Feedback: The metabolites of cimetidine are shown below. Correct a.# Structure A. incorrect b.# Structure B. incorrect c.# Structure C. incorrect d.# Structure D. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 35 35) The following conformation for the cyanoguanidine group of cimetidine is not favoured due to a bad steric interaction. Which of the following diagrams illustrates this? Feedback: In diagram A, the methyl group is too close to the side chain. In the other diagrams, there is very little steric interaction since one of the groups involved is a small hydrogen atom. Correct a.# Diagram A. incorrect b.# Diagram B. incorrect c.# Diagram C. incorrect d.# Diagram D. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 36 36) The following diagram shows various conformations for the cyanoguanidine group of cimetidine. A study was carried out to find out the most stable conformations. Which of the following statements is true? Feedback: The study showed that the E,Z and Z,E tautomers were favoured and that the Z,Z and E,E tautomers were not. This demonstrated that two hydrogen bonding interactions were taking place to two different hydrogen bonding groups in the binding site, thus disproving the chelation bonding theory. incorrect a.# The study showed that only the Z,E tautomer is favoured. incorrect b.# incorrect c.# The study established that there is only one hydrogen bonding interaction between the guanidine unit and the binding region. The study showed that only the E,Z tautomer is favoured. Correct d.# The study disproved the chelation theory of hydrogen bonding. END OF QUESTION Type: matching Title: Chapter 25 – Question 37 37) The following diagram shows a parietal cell releasing HCl into the stomach. Identify A-D. Feedback: The proton pump is responsible for pumping protons out of the parietal cell and potassium ions into the parietal cell. Acetylcholine is a neurotransmitter that interacts with cholinergic receptors on parietal cells to increase the release of hydrochloric acid into the stomach. The hormone gastrin and the local hormone histamine have the same effect when they interact with their corresponding receptors. a.# Gastrin = D. b.# Histamine = B. c.# Proton pump = A. d.# Acetylcholine = C. END OF QUESTION Type: matching Title: Chapter 25 - Question 38 38) The following diagram illustrates a parietal cell where feature F is the proton pump. What are the species labelled A-D? Feedback: Feature F is the proton pump responsible for pumping protons into the lumen of the stomach. Potassium ions are brought into the parietal cell in exchange and the process is powered by the hydrolysis of ATP. Chloride and potassium ions depart the parietal cells through ion channels which are separate from the proton pump. a.# Hydrochloric acid = D. b.# Chloride ions = C. c.# Potassium ions = B. d.# Protons = A. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 39 39) The following structure is the proton pump inhibitor omeprazole Omeprazole undergoes a series of arrangements in the acid conditions of the canaliculus before reacting with cysteine residues of the proton pump. Which of the following structures is the structure responsible for that alkyation? Feedback: The thiol group of cysteine acts as a nucleophile and reacts with structure A to produce a disulfide covalent bond between the amino acid and the drug. The other structures shown are formed in the mechanism by which omeprazole is converted to structure A. Correct a.# Structure A. incorrect b.# Structure B. incorrect c.# Structure C. incorrect d.# Structure D. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 40 40) The following mechanism shows how proton pump inhibitors are activated. Which arrow is incorrect? Feedback: Arrow B is pointing the wrong way. Curly arrows represent the movement of electrons. A proton has no electrons and so it never makes sense to draw an arrow from a proton. incorrect a.# A. Correct b.# B. incorrect c.# C. incorrect d.# D. END OF QUESTION Type: multiple choice Title: Chapter 25 - Question 41 41) The following molecule is omeprazole, an important proton pump inhibitor. Which of the following structures is a metabolite? Feedback: The two major metabolites of omeprazole are shown below. Correct a.# Structure A. incorrect b.# Structure B. incorrect c.# Structure C. incorrect d.# Structure D. END OF QUESTION