NJC H2 CHEM CM Answers

1 NJC Preliminary Examination 9812/01/17 [Turn over H3 Pharmaceutical Chemistry (9812) 2017 Preliminary Examination 1 (a) (i) Non–Narcotics Paracetamol Aspirin Diflunisal Narcotics Codeine (ii) A narcotic analgesic is a substance that depresses the activity of the central nervous system (CNS) affecting the brain’s capacity to sense pain. (Alternative answer: by binding with pain receptors in the brain and blocking transmission of pain signals between brain cells.) A non-narcotic analgesic act as inhibitor of the cyclo-oxygenase (COX) enzyme. This prevents the formation of prostaglandins that send pain messages to the brain. (iii) Prolonged consumption of aspirin inhibits cyclo -oxygenase, inhibiting the production of stomach lining (gastric mucosa). Hence, exposing the stomach wall and its associated blood supply to attack by strong acid causing ulcers and bleeding respectively. (iv) Any 2 of the following:  Paracetamol is safe for children below age of 12 (but dosage has to be different)  Less irritating sensation than aspirin  Does not cause blood thinning or prevents clot or prolonged bleeding  Used when patient has stomach ulcer  Used when anti–inflammatory action is not required.  As alternative for patients who are allergic to salicylate derivatives (v) Competitive reversible inhibition/inhibitor. With increasing [natural substrate], there is an increased competition by the natural substrate for active site of enzyme, increasing the rate of enzymatic reactions. At high [substrate], the rate of enzymatic reaction with diflunisal is the same as that without application of the drug indicating natural substrates out compete the diflunisal for the active sites of the enzyme.

2 NJC Preliminary Examination 9812/01/17 (vi) The rate of enzymatic reaction with aspirin still increases with increasing [natural substrate], however, the maximum rate is lower than the case of diflunisal. This is because aspirin is a non-competitive irreversible inhibitor of COX enzymes, where the drug is permanently bound to the enzyme blocking the access of the natural substrate reducing the maximum reaction possible. (b) (i) tertiary amine : ionic bonding/ion–dipole interaction/ionic interaction phenolic –OH : hydrogen bonding benzene ring : VDWs forces/Hydrophobic interaction (ii) 6-acetylmorphine is less polar than morphine as one of the polar –OH group is masked as ester. Diamorphine has two polar groups masked as esters making it the least polar among the 3 drugs . Hence, diamorphine is most efficient in crossing the non–polar blood–brain barrier and in greater concentration, followed by 6–acetylmorphine and least for morphine. However, 3–acetylmorphine has greater analgesic effect than diamorphine as the phenolic –OH that is needed for binding to invoke analgesic effect is free and will interact immediately with the receptors. However, the 3 -acetyl group on the phenol of diamorphine has to be first hydrolysed by esterases in the brain before interacting with the receptors, hence lesser time and lower effect.  Compare and link structure to polarity of molecule  Compare efficiency in crossing blood–brain barrier  Free phenolic –OH allows immediate interaction with receptors  Esters need to be broken down first before interaction so reduced effectiveness

3 NJC Preliminary Examination 9812/01/17 [Turn over 2 (a) (i) Nucleophilic Acyl Substitution  +  Proton Transfer  Correct intermediates (ii) Penicillin binds irreversibly to the transpeptidase enzyme in bacteria, thus inhibits the formation of structural cross -links (pentaglycine bridge) between peptide chains in (the final stage of) bacterial cell wall biosynthesis. Bacterial cell wall becomes fragile and cell lysis occurs (in low osmotic pressure solutions) and this eventually kills the bacteria. (iii) The bulky penicillin molecule poses a steric hindrance to the water molecule/ blocks access of water molecule to the active site. (iv) The β –lactam ring of penicillin G can be easily hydrolysed under the acidic condition of the stomach. This is due to high ring strain in the 4-membered ring, the highly reactive β–lactam carbonyl group and influence of the acyl side chain. (b) (i) Bulky 2-methoxy groups on the aromatic ring of methicillin act as steric shields which prevents it from binding effectively to active site of penicillase (or –lactamases), thus methicillin is not hydrolysed to the inactive form, penicilloic acid, by bacterial enzyme.

4 NJC Preliminary Examination 9812/01/17 (ii) Antibacterial activity of the analogue would be higher than methicillin. The analogue is expected to have greater resistance to enzymatic hydrolysis by –lactamases since the larger ethoxy group provides a larger steric shield. Or, Antibacterial activity of the analogue would be lower than methicillin because larger steric shield may hinder its ability to attach to the transpeptidase enzyme, thus inhibiting cell wall cross-linking to a lesser extent than methicillin itself. (c) Penicillin V has electron–withdrawing O atom while ampicillin has the basic NH2 group in the acyl side chain. Both these groups reduce the nucleophilic effect of the carbonyl O atom on the acyl side chain thus preventing acid -catalysed hydrolysis of the – lactam ring in the stomach. Penicillin G and methicillin are easily hydrolysed in the acidic stomach environment , thus cannot be taken orally (needs to be injected). (d) The –COOH group being largely deprotonated (or predominantly –COO–) under physiological pH, makes the molecule hydrophilic as it forms favorable ion-dipole interaction with water molecules. Masking the –COOH group increases lipophilicity (hydrophobicity) of the drug so that absorption through the hydrophobic gut walls is better. (e) Any two of the following sets. Appropriate examples must be given. Disruption of cell metabolism:  Sulphonamides are competitive inhibitors to the enzyme dihydropteroate synthetase, competing with natural substrate 4-aminobenzoic acid, disrupting the production of folic acid/ tetrahydrofolate/ coenzyme F needed for DNA synthesis. Disruption of protein synthesis:  Inhibits protein synthesis by binding to ribosomal RNA and inhibiting different stages of the translation process. o E.g. Tetracyclines (blocks tRNA binding), Chloramphenicol (blocks transfer of peptide), Aminoglycosides -Streptomycin (translocation), Macrolide - Erythromycin (translocation) Disruption of function of plasma membrane:  Increase permeability of the bacterial cell membrane towards cation and small hydrophilic molecules, thus upsetting the ionic balance within the cell.  Providing a hydrophilic channel through the membrane, or by masking cations with a hydrophobic coat o E.g. Hydrophilic channel: Amphotericin, Gramicidin A o E.g. Hydrophobic coat: Valinomycin, Polymyxin B Disruption of nucleic acid transcription:  Inhibiting topoisomerase enzyme in bacteria cells causing DNA double helix to not be unwound preventing replication and transcription  E.g. Quinolones, fluoroquinolones

5 NJC Preliminary Examination 9812/01/17 [Turn over 3 (a) (i) The R groups on the amino acids being alkyl groups would be expected to show signal on the 1H NMR spectrum in the 0–4 region. Chemical shift / ppm Splitting pattern Integral value Deduction 1.01