HCI H3 CHEM P1

This document consists of 15 printed pages and 1 blank page. HWA CHONG INSTITUTION JC2 Preliminary Examinations Higher 3 CANDIDATE NAME CT GROUP 10S CENTRE NUMBER INDEX NUMBER PHARMACEUTICAL CHEMISTRY Paper 1 9812/01 21 September 2011 2 hours 30 minutes INSTRUCTIONS TO CANDIDATES 1) This paper consists of 15 printed pages (including this page). You should have a Data Booklet, a cover page and a set of writing papers. 2) Answer any five questions. 3) Write your name and CT clearly on the cover page and on all the work you hand in. 4) Begin each question on a FRESH sheet of writing paper. A nil return is necessary for any unattempted question. 5) At the end of the examination, fasten your cover page securely together with your answer scripts. INFORMATION FOR CANDIDATES The number of marks is given in brackets [ ] at the end of each question or part question. A Data Booklet is provided. You may use a calculator. You are reminded of the need for good English and clear presentation in your answers.

2 © Hwa Chong Institution 2011 9812 / 01 / JC2 Prelim 2011 1 (a) Penicillin belongs to a big family of -lactam antibiotics which inhibits bacterial cell wall biosynthesis by inhibiting glycopeptides transpe ptidase. The latter is an important enzyme in the synthesis of peptidoglycan. (i) Describe two modes of actions of antibacterial drugs other than inhibitions of cell wall biosynthesis. [2] (ii) Bacterial resistance to antibiotics is a problem in the pharmaceutical industry and one possible mode of action by -lactamase can be represented as follow. N SR O OH O -lactamase HN SR O OH O OH penicillin penicilloic acid By representing -lactamase as R-OH, suggest a mechanism to the above reaction. [3] (iii) Penicillin works as an inhibitor because of the conformational similarity between the amide bond of the -lactam ring and the D-Ala-D-Ala termini in glycopeptides transpeptidase. Suggest why penicilloic acid is inactive in killing bacteria. [1] (iv) One approach that was taken to fight -lactamase was to develop potent inhibitors for -lactamase. The -lactamase inhibitor can be used in conjunction with penicillins to allow the antibiotic to destroy bacterial cell without being affected by the -lactamase. An example of a -lactamase inhibitor is sulbactam and its reaction with -lactamase is shown below. N S O OH O O O R-OH + R O O HN CO2H SO2H sulbactam Is sulbactam a reversible or an irreversible inhibitor? Explain briefly. [2]

3 © Hwa Chong Institution 2011 9812 / 01 / JC2 Prelim 2011 (b) Novobiocin is a coumarmycin-family antibiotics and it inhibits the function of DNA gyrase. O OR OHH3CO OCONH2 novobiocin O OH O N H O where R = Draw two possible chair conformations of novobi ocin, indicating the more stable conformation. Justify your answers. [4] (c) Amoxicillin is a wide spectrum antibiotics. Although it is more acid resistant and shows more activity against certain Gram-negative bacteria t han Penicillin G, it tends to cause diarrhoea due to its poor absorption through the gut wall. This is due to the presence of a free amino and a free carboxylic acid group. A way to go around this problem is to use a prodrug where one of the polar groups is chemically modified which can then be removed metabolically once the prodrug has been absorbed. One such drug developed was pivampicillin. N S O H N O NH2 OH O N S O H N O NH2 O O O O ampicillin pivampicillin (i) Suggest why pivampicillin is less likely to cause diarrhoea in the patient. [1] (ii) In the first stage of the metabolism of pivampicillin, the ester group further away from the penicillin nucleus was hydrolysed by esterase first. Suggest why this is so. [1] (iii) In the metabolism of pivampicillin to ampicillin, the following two side products are obtained. esterase O O H H Suggest the side products from the metabolism of talampicillin, another prodrug of ampicillin. [1] N S O H N O NH2 O O O talampicillin O

4 © Hwa Chong Institution 2011 9812 / 01 / JC2 Prelim 2011 (d) Isoniazid is an antibacterial drug, commonly used against tuberculosis bacteria. N O H N NH2 isoniazid N O H N NH2 isoniazid-A N O H N NH2 isoniazid-B Cl BrBr Br (i) A researcher synthesises isoniazid-A and isoniazid-B to see if they have improved activity against tuberculosis bacteria. Sketch the mass spectra about the molecular ion peak for both compounds and state the ratio of the peaks. [2] (ii) The synthesis of isoniazid is shown below. N Cl N CN N NH2O N O H N NH2 Stage 1 Stage 2 Stage 3 (I) Suggest the reagent for stage 1 and give the name of the mechanism. (II) Given that stage 3 occurs via nucleophilic acyl substitution, suggest what reagent could be used. [3] [Total : 20]

5 © Hwa Chong Institution 2011 9812 / 01 / JC2 Prelim 2011 2 (a) A migraine headache can cause intense throbbing or pulsing in one area of the head and is commonly accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Excedrin is a drug that helps to ease migraine pain and contains aspirin as one of the active ingredients. CO2H O CH3 O aspirin (i) Explain how aspirin can reduce pain. [2] Apart from aspirin, acetaminophen and caffeine are also found in Excedrin. HO N CH3 O H N N N N O O CH3 CH3 CH3 acetaminophen caffeine An analysis was carried on a sample of Excedrin using reversed-phase HPLC to which a known amount of benzoic acid has been added as an internal standard. The following spectrum was obtained. (ii) Identify the peak due to aspirin, giving your reasoning. [1] (iii) Determine the relative concentration of the three drugs in the given sample of Excedrin. [2] [Note: Identification of peak due to acetaminophen and caffeine is not required] 2 1 3 benzoic acid

6 © Hwa Chong Institution 2011 9812 / 01 / JC2 Prelim 2011 (b) Compound A is used primarily as an anesthetic but studies have shown that it can help to relieve pain for certain headaches. It contains carbon, hydrogen, nitrogen and oxygen only. A has the following NMR spectrum. The resonance at  8.92 disappears in the presence of D2O.  1.13 (t 6H) 2.23 (s 6H) 2.29 (q 4H) 3.22 (s 2H) 7.09 (m 3H) 8.92 (s 1H) (s is singlet, t is triplet, q is quadruplet and m is multiplet) The mass spectrum of A shows a molecular ion at m/e 234. The (M+1) + peak has an intensity 15.4 % of that of the molecular ion and the base peak occurs at m/e 86. The IR spectrum of A is shown below. Deduce the molecular formula of A and suggest a possible structural formula of compound. Show your reasoning. [10]

7 © Hwa Chong Institution 2011 9812 / 01 / JC2 Prelim 2011 (c) Indomethacin is another analgesic that is used to treat inflammatory diseases such as rheumatoid arthritis. The following scheme shows the synthesis of indomethacin. CH3O NH NH2 1 HCl / ethanol HO NH NH2 2 N H CH3 CH3O CO2H indomethacin CH3O NH N CH3 CO2H N CH3 CH3O CO2H O Cl B Cl O Cl F 3 (i) Suggest reagents and conditions for reactions 1 and 2. [2] (ii) Reaction 3 involves tautomerisation of compound B to give C which undergoes a rearrangement to form D. D undergoes further reaction to form E which on losing an ammonia gives F. B CH3O H N N CH3 CO2H CH3O H N N CH3 CO2H H NH CH3O CO2H NH CH3 C H N CH3 CH3O CO2H NH2H DE Propose a mechanism for the formation of E from C. [3] [Total : 20]

8 © Hwa Chong Institution 2011 9812 / 01 / JC2 Prelim 2011