HCI H3 Chem Prelim

HWA CHONG INSTITUTION C2 PRELIMINARY EXAMINATION CHEMISTRY 9812 Higher 3: Pharmaceutical Chemistry 18 September 2008 2 h 30 min Do not open this booklet until you are told to do so. INSTRUCTIONS TO CANDIDATES 1) This paper consists of 12 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 all the work you hand in. 3) Begin each question on a FRESH sheet of writing paper. A nil return is necessary for any unattempted question. 4) 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. This question booklet consists of 12 printed pages

Antibacterials are aimed at either killing bacteria (bacteriocidal) or inhibiting them from multiplying (bacteriostatic). One type of antibacterial drugs is the penicillins, which have revolutionized the history of modern medicine by their effectiveness against several pathogenic bacterial species that cause various forms of infections. 1 Penicillin G, the parent of all these antibiotics, was first isolated from a fungal species, Penicillium notatum. Since the discovery of this antibiotic, several modifications have been introduced to the parent structure. The discovery of 6-amino penici llamic acid (6-APA) in fermentation products constituted a major breakthrough in semisynthetic penicillin synthesis. The reaction scheme for the formation of methicillin is shown below: N O H O N S H CO2H O O N O H O N S H CO2H O N S H CO2H H2N Step StepII I CH3 CH3 penicillin G 6-APA methicillin (a) (i) penicillin G 6-APA methicillin Describe the mode of action of penicillins. [2] (ii) Assign the R/S configuration for the asymmetric carbons found in penicillin G. [2] (iii) Suggest why chemical hydrolysis in step I to form 6-APA is not appropriate. [1] (iv) Give the reagent in step II and outline the mechanism for the formation of methicillin. [2] (v) Many bacteria have developed resistance to drugs by producing enzymes ( β-lactamases) capable of hydrolyzing the β-lactam ring. Describe the β-lactamase mediated β-lactam ring hydrolysis, starting with penicillin G. You may assume that the reactive species in a β- lactamase enzyme is the hydroxyl group of a serine residue in the protein. (vi) Suggest why methicillin shows improved resistance to β-lactamase mediated β-lactam ring hydrolysis. Another class of antibacterial drugs are the sulphadrugs, e.g. sulphanilamide. N-heterocyclic derivatives of sulphanilamides such as sulphadiazine have a broad-spectrum antimicrobial activity. N H2 SO2NH2 N H2 S O O N H N N sulphanilamide sulphadiazine sulphanilamide sulphadiazine [3] [1] C2 Prelim 2008 9812/01/HCI 2

The multistep synthesis of sulphadiazine, starting from phenylamine is summarized below: sulphadiazine (b) (i) Describe the mode of action of sulphadrugs. [2] sulphadiazine Step I Step II Step III (CH3CO)2O pyridine 1. HOSO2Cl H2O H+ (ii) Suggest why reaction of N-acetylaminobenzene with chlorosulphonic acid (HOSO 2Cl) results in chlorosulphonation, rather than sulphonation. [1] (iii) Outline the reaction mechanism for Step II in the conversion of phenylamine into sulphadiazine. [3] To date, over 10000 structural analogues of sulphanilamide, the parent of all sulphadrugs have been synthesized and used in structure-activity relationship (SAR) studies. From numerous studies, it has been established that the antibacterial activity of the sulphadrugs decreases in the following order: NHR SO2NH2 NH2 SO2NH2 NR2 SO2NH2 NH2 SO2NR2 NH2 SO2NH2 > > > > (c) (i) Give two deductions that could be obtained from the SAR studies. [2] (ii) The structure of Prontosil is quite similar to the structure of sulphanilamide, with the –NH 2 group modified. It does not have any in vitro antibacterial activity but displays antibacterial activity in vivo. Suggest a reason for this behaviour. SO2NH2 N N NH2 NH2 prontosil [1] prontosil [Total: 20] C2 Prelim 2008 9812/01/HCI 3

2 In the preparation of major examinations, a large number of students depend on coffee or tea to keep them awake through the long nights of self-revision. This is due to the effects of caffeine found in these beverages. Nicotine is another drug which belongs to the same class of drugs as caffeine. Both drugs have similar effects as adrenaline and may cause problems of addiction. N N N N O H3C O CH3 CH3 caffeine N N CH3 nicotine (a) Name the class of drugs that both caffeine and nicotine belong to. [1] (b) Even though the overall physiological effects of ca ffeine and nicotine are very similar, the modes of the action of these stimulants are somewhat different. Contrast the modes of action of these two drugs. (c) (i) [3] Explain, in terms of structures, why you would expect both caffeine and nicotine to absorb UV radiation. [2] (ii) Deduce which of these two drugs will absorb at a longer wavelength. [2] (d) Nicotine works as an acetylcholine agonist at nicotinic receptor, which are acetylcholine receptor on skeletal muscles and nerve synapses. The structure of acetylcholine is shown below: O N(CH3)3 O + acetylcholine (i) When there is a lack of acetylcholine acting at a certain part of the body, acetylcholine is not administered into the body even though it is easy to synthesize in the laboratory. This is due to the ease of hydrolysis of acetylcholine in the stomach. Describe the mechanism of the hydrolysis of acetylcholine in the stomach. [3] (ii) Suggest why acetylchloline is more prone to hydrolysis than other esters. [2] (iii) Suggest a possible structure of an analogue of acetylcholine that is less prone to hydrolysis. (e) With reference to the structure of nicotine, determine whether an aqueous solution of nicotine would be acidic, basic or neutral. [1] (f) Suggest the form of nicotine that is active pharmacologically and explain your answer. [1] [2] (g) Explain how nicotine may cause addiction to smokers. [3] [Total: 20] C2 Prelim 2008 9812/01/HCI 4

3 Salbutamol is used in the treatment of asthma. It can be synthesized from compound A. HO OH Cl A HO OH N salbutamol H C(CH3)3 OH (a) Propose a two step synthesis to obtain salbutamol from A, showing the intermediate formed. [2] (b) When salbutamol is synthesized from A, a mixture of compounds is formed. Column chromatography can be used to separate the stereoisomers that are present. (i) Briefly describe the principles of column chromatography [2] (ii) State the conditions required to separate the stereoisomers present using column chromatography. Apart from the benzene ring, there are many other ring systems that are aromatic, one of which is the pyridine ring. The pyridine ring can be synthesized using hydroxylamine and a 1,5-diketone. [2] R R'OO NR R' OH NR R' NH2OH heat (c) Propose the mechanism for the reaction from the 1,5-diketone to the pyridine ring. [4]