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- 1. © Oxford University Press, 2013 Patrick: An Introduction to Medicinal Chemistry 6e Case study 4 Oxamniquine
- 2. © Oxford University Press, 2013 HN CH NH CH3 OH CH3 O2N DEVELOPMENT OF OXAMNIQUINE
- 3. © Oxford University Press, 2013 1. Schistosomiasis (bilharzia) Notes •Second most endemic parasitic disease in the world •Affects 200 million people in the developing world •500 000 deaths per year •Water-borne disease carried by flatworms •Flatworms penetrate skin as larvae •Females produce eggs that become trapped in organs and tissues •Results in symptoms of the disease •Three species (mansoni, haematobium and japonicum) •Limited number of drugs available in 1960s
- 4. © Oxford University Press, 2013 2. Early drugs Disadvantages •Stibocaptate is orally inactive •Both drugs require frequent dosing regimes •Both drugs produce toxic side effects •Not effective against all three species S O HN Me N Me Me Lucanthone Stibocaptate
- 5. © Oxford University Press, 2013 3. Desired properties for novel drugs Non toxic Oral activity Single dose regime Activity against all three species
- 6. © Oxford University Press, 2013 4. Development of oxamniquine Stage 1 - Identification of a lead compound Lucanthone S O HN Me N Me Me
- 7. © Oxford University Press, 2013 Stage 2 - Simplification 4. Development of oxamniquine Lucanthone S O HN Me N Me Me
- 8. © Oxford University Press, 2013 •Active in mice •Inactive in man •Electronegative Cl present •Beneficial at position shown Stage 3 - Vary aromatic substituents 4. Development of oxamniquine Mirasan
- 9. © Oxford University Press, 2013 4. Development of oxamniquine Stage 4 - SAR studies •Side chain and aromatic ring are both important binding groups •Both nitrogens are important •Nitrogens are present on a flexible chain - conformational flexibility •Flexibility may be bad for activity •Less chance of active conformation being present at any one time Mirasan
- 10. © Oxford University Press, 2013 One bond ‘locked’ Activity increases Inactive in man, active in monkeys Rigidification has retained active conformation Stage 5 - Rigidification Two bonds ‘locked’ Activity increases in mice Rigidification has retained active conformation Novel structure and so worth testing previous strategies again N Et2NCH2CH2 Cl Me N CH2NEt2 Cl Me 4. Development of oxamniquine
- 11. © Oxford University Press, 2013 Stage 6 - Vary substituents and substituent positions on aromatic ring •Substitution pattern on the aromatic ring is essential •Electron-withdrawing groups are best for activity - replacing Cl with nitro increases activity •Nitro group reduces basicity of the aromatic nitrogen •pKa is increased and molecule is less easily ionised •Passes through cell membranes more easily 4. Development of oxamniquine Weak base Destabilized
- 12. © Oxford University Press, 2013 Stage 7 - Vary side chain substituents •Secondary amine is better than a primary or tertiary amine at end of chain •Optimum length of the alkyl group on nitrogen = 4C •Acyl groups eliminate activity •Implies nitrogen is protonated •Implies nitrogen interacts with target by an ionic interaction 4. Development of oxamniquine 2o 3o 1o or
- 13. © Oxford University Press, 2013 TARGET TARGET TARGET No interaction Side chain interactions 4. Development of oxamniquine STERIC BLOCK Butyl residue Pentyl residue
- 14. © Oxford University Press, 2013 NH2 CH2CH2CH2CH3 + Stage 7 - Vary side chain substituents •Branched alkyl groups increase activity •Possibly implies stronger vdw interactions to a bulky pocket •Benefit in increased lipophilicity - - 4. Development of oxamniquine NH2 CH CH3 CH3 +
- 15. © Oxford University Press, 2013 •Branching on side chain eliminates activity •Prevents molecule adopting active conformation 4. Development of oxamniquine Stage 7 - Vary side chain substituents Zero Activity HN C NHR Me X Me H Zero activity
- 16. © Oxford University Press, 2013 van der Waals binding region Ionic binding region Stage 8 - Chain extension •Chain extension eliminates activity •Implies weaker interactions •Other strategies are not beneficial 4. Development of oxamniquine Strong Weak NH2R CH2 Het + CH2 CH2 NH2R Het Chain extension +
- 17. © Oxford University Press, 2013 Optimum Structure Asymmetric centre 4. Development of oxamniquine HN CH NH CH3 CH3 CH3 O2N
- 18. © Oxford University Press, 2013 Stage 9 - Drug Metabolism Studies •Oxidation of aromatic methyl group in vivo gives oxamniquine •Oxaminiquine is the active drug •Methyl analogue acts as a prodrug 4. Development of oxamniquine HN CH NH CH3 CH3 CH3 O2N HN CH NH CH3 OH CH3 O2N Metabolic oxidation
- 19. © Oxford University Press, 2013 Stage 10 - Proposed binding interactions to target binding site 4. Development of oxamniquine Binding site Binding regions Ionic Van der Waals Hydrogen bonding - CH CH3 CH3 CH2 NH2 CH2 O2N HN OH
- 20. © Oxford University Press, 2013 •Development took 11 years •Reached market in 1975 •Effective as a single dose •Orally active •Treats infections of Schistosoma mansoni •Mild side effects •Meets 3 out of original 4 aims •Highly successful and still used in some countries (e.g. Brazil) 5. Oxamniquine
- 21. © Oxford University Press, 2013 Notes •Inhibits nucleic acid synthesis in parasitic cells •Acts as a prodrug •Activated by sulphotransferase enzyme present in parasitic cells 6. Mechanism of action Oxamniquine HN H N Me Me OH O2N Sulfate ester Sulphotransferase Sulphate ester
- 22. © Oxford University Press, 2013 Notes 6. Mechanism of action -H2SO4 HN H N Me Me O2N Alkylating agent HN H N Me Me DNA O2N •Sulphate group acts as a good leaving group •Degradation takes place aided by influence of secondary amine •Produces an alkylating agent •Reacts with DNA DNA
- 23. © Oxford University Press, 2013 7. Synthesis of Oxamniquine N Me Me I N Cl Me II Cl2 Na2CO3 N H N Me Me Me III Me2CHNH2 HN H N Me Me Me IV Ni/H2 VI Desired isomer V + HNO3 H2SO4 Oxamniquine HN H N Me Me OH O2N 2) Microbial oxidation 1) Separation of isomers
- 24. © Oxford University Press, 2013 8. Other Agents Hycanthone S O HN CH2OH N Me Me Praziquantel N N O O •Metabolite of lucanthone •Same mechanism of action as oxamniquine •More active than lucanthone •Replaced by oxamniquine •Recommended treatment for schistosomiasis in UK •Active against all three pathogenic strains •Expensive •Not economically feasible in developing countries
Editor's Notes
- modified
- Stibocaptate redrawn
- Right hand structure redrawn
- Charged structrues have been redone
- Left hand structure redone
- Right hand structure redrawn
- Left hand structure redrawn
- Structures V and VI redrawn All reagents redone