Course Outcomes :
Students will be able to understand the basic concepts of Principles of Drug Design and Drug Discovery,Discovery of a lead,Pharmacokinetics (ADME), pharmacodynamics,Nature of drug – receptor interactions and their theories,Drug discovery without lead – serendipityStudents will understand the basic concepts of Lead modification and SAR Studies,BioisosterismUnderstand the basic concepts of QSAR studies and computer aided drug designStudy the basic concepts of Combinatorial Synthesis,Automated parallel synthesis,Structure determination of active compounds,High throughput screening.OC-17: Principles of Drug design and drug discovery
OC-18: Lead modification and SAR Studies
OC 19: QSAR studies and computer aided drug design
OC 20: Combinatorial Synthesis
Introduction to drug discovery. Folklore drugs, stages involved in drug discovery- disease, drug targets, bioassay. Discovery of a lead- screening of natural products and synthetic compound libraries. Existing drugs as leads (me too drugs). Pharmacokinetics (ADME), pharmacodynamics. Nature of drug – receptor interactions and their theories – Occupancy theory, Induced – fit theory, Macromolecular purturbation theory and Two-state model of receptor activation. Natural products as lead structures in drug discovery – Pharmacophore - structure pruning technique e.g. morphine.Discovery of lead structure from natural hormones and neurotransmitters.Principles of design of agonists (e.g.Salbutamol), antagonists e.g. cimitidine) and enzyme inhibitors (e.g. captopril). Drug discovery without lead – serendipity- Penicillin and Librium as examples. Principles of prodrug design. Introduction to drug patents and Clinical trials.
SAR: Lead modification strategies, Bioisosterism, variation of alkyl substituents,chain homologation and branching, variation of aromatic substituents,extension of structure, ring expansion and ring contraction, ring variation, variation and position of hetero atoms, ring fusion, simplification of the lead, rigidification of lead.Discovery of oxaminquine, salbutamol, cimitidine and captopril Structure-Activity Relationship studies in sulfa drugs,benzodiazepines, and taxol analogs.
QSAR:Introduction, physicochemical properties - pKa, electronic effects and Hammett constants(σ), lipophilicity constant(π), steric effects and Taft’s constant, linear and nonlinear relationship between biological activityLipophilicity Substituent constants. Lipinski rule of five. Hansch analysis, Craig’s plot,Topliss scheme, Free Wilson approach, cluster significant analysis. Two case studies (QSAR study on pyranenamine and design of Crizotinib).
Computer aided drug design: Introduction, active site, allosteric binding site,use of grids in docking , rigid docking , flexible docking and induced fit docking of ligands. Basic principles and difference between structure and ligand based drug design, denovo drug design and utility to optimize the lead structure.
Introduction. Combinatorial approach. Combinatorial libraries, technologies. Solid phase synthesis, types of resins. Linkers. Reactants for solid phased synthesis. Methods of Parallel synthesis: Haughton’s tea bag procedure. Automated parallel synthesis. Methods in Mixed combinatorial synthesis: general principles. Furkas mix and split combinatorial synthesis, Structure determination of active compounds-Deconvolution, Methods in deconvolution-recursive deconvolution, tagging and use of decoded sheets. Examples of Combinatorial Chemistry. Planning and designing of combinatorial synthesis, Spider like scaffolds, drug molecules. Automation in Combinatorial chemistry. High throughput screening.
1. Burger’s medicinal chemistry and drug discovery by Manfred E. Wolf.
2. Introduction to Medicinal chemistry by Patrick.
3. Introduction to drug design by R Silverman
4. Comprehensive medicinal chemistry. Vol 1-5 by Hanzsch.
5. Principles of medicinal chemistry. by William Foye
6. Biochemical approach to medicinal chemistry. by Thomas Nogrady.
7. Pharmaceutical Chemistry and Drug synthesis by Roth and Kleeman
8. Drug design by E.J.Arienes
9. Principles of Medicinal Chemistty Vol I & II by Kadam et al
10. Medicinal chemistry An introduction by Garreth Thomas
11. Organic and Pharmaceutical chemistry By Delgrado
12. Organic Pharmaceutical chemistry By Harikishansingh
13. Medicinal Chemistry By Ashtoshkar
14. Medicinal Chemistry By Chatwal
15. Organic Drug synthesis By Ledneicer Vol 1-6
16. Strategies for organic drug synthesis and design By Daniel Ledneicer.
17. Top Drugs: Top synthetic routes By John Saunders
18. Chirotechnoiogy By Roger A. Sheldon
19. Burger’s Medicinal Chemistry and Drug Discovery: Principles and Practices. Vol. 1.
20. Medicinal Chemistry by G. Patricks.
21. Text book of Drug Design and Discovery, Edited by PovlKrogsgaard – Larsen Tommy Liljefors.
22. Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal–Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK) Martin P. Edwards, J. Med. Chem., 2011, 54 (18), pp 6342–
23. a. http://www.pfizer.com/news/featured_stories/featured_stories_martin_edwards.jsp
OC-21: Drugs acting on metabolic process, cell wall and specific enzymes
OC-22: Drugs acting on genetic material and immune system
OC-23: Drugs acting on receptors and ion channels
OC-24: Chiral drugs
Basic concepts of mechanism of drug action: Introduction to macromolecular targets,carbohydrates, proteins, lipids and nucleic acids as possible drug targets. Classification of drugs. Enzyme inhibition and its types.
a) Drugs acting on metabolic process: Antifolates –Discovery and mechanism of action of sulphonamides, Synthesis of sulfomethoxazole, sulfodoxine, sulfaguanidine and dapsone. Diaminopyrimidines -trimethoprim, bacterial resistance to sulfonamides and drug synergism
b)Drugs acting on cell wall: Structure of bacterial cell wall, β-Lactam antibiotics – mechanism of action of penicillins and cephalosporins. Synthesis of pencillin-G and cephalosporin-C, cefalexin and cycloserine. Resistance to pencillins, broad spectrum penicillins – cloxacillin, methicillin, ampicillin, amoxicillin and carbenicillin. β-Lactamase inhibitors- Structural formulae and mode of action of clavulanic acid and sulbactum c)Drugs acting on specific enzymes: H+/K+ -ATPase inhibitors- synthesis of Omeprazole and Carbonic anhydrase inhibitors-synthesis of Acetazolamide.
Drugs acting on genetic material:Introduction, classification and mechanism of action. DNA-intercalating agents-Anticancer and antimalarial agents. Structural formulae of Daunomycin, Adriamycin and Amsacrine. Synthesis of Amscarine, Nitracrine, Quinacrine and Chloroquine.DNA- Binding and nicking agents: Antiprotozoal drugs. Synthesis of Metronidazole, Dimetridazole and Tinidazole. DNA-Alkylators: Synthesis of Cyclophosphamide and Bisulphan.
DNA-Polymerase inhibitors: Antiviral agents- Synthesis of Acyclovir and AZT.
DNA-Topoisomerase inhibitors: Anti bacterial agents.Synthesis of Ciprofloxacin and Norfloxacin. Structural formulae ofloxacin and Lomefloxacin.
Inhibitors of transcribing enzymes: Anti-TB and antileprosy agents-structural formulae of Rifamycins and partial synthesis of Rifampicin.
Drugs interfering with translation process: Antibacterial drugs- Structural formulae of Erythromycin, 5-Oxytetracycline and Streptomycin. Synthesis of Chloromycetin
Drugs acting on immune system: Introduction to immune system. Immunosupressing agent-structural formula of Cyclosporin. Immunoenhancers-use of vaccines and strucrural formula of levamisol.
Introduction to nervous system: structure of neuron, nerve transmission. Definition and examples of agonist, antagonist, neurotransmitters and receptors. Drugs acting on receptors:
a)Adrenergic receptors - Introduction and classification. α-Adrenergic-receptor agonists and antagonists- Synthesis and biological activity of Nor-adrenaline, Methyl L dopa and Tetrazosin.β-Adrenergic-receptor - agonists and antagonists – Synthesis and pharmacological activity of Salbutamol, Tetrabutalin, Propranolol and Atenolol.
b)Cholinergic-receptors: Introduction and classification.Cholinergic-receptor agonists and antagonists- Structural formulae of Nicotine, Atropine and Tubocurarine. Synthesis of Acetyl choline and Succinyl choline
c)Dopamine receptors: Introduction and classification.Dopamine- receptoragonists and antagonists- Biosynthesis of Dopamine. Synthesis of L-Dopa and Chlorpromazine. d)Serotonin receptors: Introduction and classification.Serotonin receptoragonists and antagonists-synthesis and pharmacological activity of Serotonin and Metoclopramide. e)Histamine receptors:Introduction and classification.Histamine receptor agonists and antagonists-synthesis and biological action of Histamine, Chloropheneramine, and Ranitidine.Hormones and their receptors: Introduction to estrogen receptors, Structural formulae of Tamoxifen
Drugs acting on ion channels: Introduction to ion channels, drugs acting on Ca2+, Na+ and Cl-channels and their mode of action. Structural formulae of Tetracaine and synthesis and of Nifedipine, Diltiazem, Tetracine and 4-Aminopyridine.
Introduction to chiral drugs. Three-point contact model, Eutomer, Distomer and eudesmic ratio. Pfeiffer’s rule. Role of chirality on biological activity: Distomers – a) with no side effects b)with undesirable side effects c) both isomers having independent therapeutic value d)combination products having therapeutic advantages e) metabolic chirality inversion. Synthesis and pharmacological activity of S-Ibuprofen, S- Metaprolol, Ininavir sulfate, Levocetrazine, 2S-Verapamil, S,S-Ethambutol (+)Lomefloxacin, Fluvastatin, Dextropropoxyphen, (+)Ephedrine, (+)Griseofulvin, Dexormaplatin, R-Indacrinone, Nateglinide, Oxybutynin hydrochloride, S,S- Captopril and S,S,S- Enalaprilate.
1. Burger’s medicinal chemistry and drug discovery. By Manfred B. Wolf.
2. Introduction to Medicinal chemistry. By Graham Patrick.
3. Introduction to drug design. By R.B.Silverman
4. Comprehensive medicinal chemistry. Vol 1-5 by Hanzsch.
5. Principles of medicinal chemistry. By William O. Foyeetal.
6. Biochemical approach to medicinal chemistry. By Thomas Nogrady.
7. Pharmaceutical Chemistry and Drug synthesis By Roth and Kleeman
8. Drug design By E.J. Arienes
9. Principles of Medicinal Chemistry. Vols.1 & 2 By Kadam etal
10. Medicinal chemistry An introduction By Gareth Thomas
11. Wilson and Gisvold,s text book of Organic, Medicinal and Pharmaceutical chemistry By J.N.Delgado and W.A.Remers.
12. Organic Pharmaceutical chemistry By Harikishansingh.
13. Medicinal Chemistry By Ashutoshkar
14. Medicinal Chemistry By G.Chatwal
15. Organic Drug synthesis By Ledneiser Vol 1-6
16. Strategies for organic drug synthesis and design By Daniel Ledneiser
17. Top Drugs: Top synthetic routes By John Saunders
18. Chirotecchnology By Roger A. Sheldon
OC (CB1) 17: Non aromatic heterocyclics& aromaticity
OC (CB1) 18: Five and six membered heterocyclics with two hetero atoms
OC (CB1) 19: Heterocyclics with more than two hetero atoms
OC (CB1) 20: Larger ring and other heterocycles
Different types of strains, interactions and conformational aspects of nonaromatic heterocycles. Synthesis, reactivity and importance of the following ring systems. Azirines, Aziridines, Oxiranes, Thiiranes, Diazirenes, Diaziridines, Oxaziridines, Azetidines, Oxetanesandthietanes
Aromaticity: Introduction, Aromatic and anti aromatic compounds. Criteria for aromaticity.
Huckel’s 4n+2 electron rule for benzene and non benzenoid aromatic compounds. Eg. Cyclopropenium ion, cyclopentadienyl ion, cycloheptatrienium ion, azulene and annulenes.
Synthesis, reactivity, aromatic character and importance of the following heterocycles: Pyrazole, Imidazole, Oxazole, Thiazole, Isoxazole, Isothiazole, Pyridazine, Pyrimidine. Pyrazine, Oxazine, thiazine, benzimidazole, benzoxazole and benzthiazole.
Synthesis, reactivity, aromatic character and importance of the following Heterocycles: 1,2,3-triazoies,1,2,4-triazoles, Tetrazoles, 1,2,4-oxadiazole, 1 ,3,4-oxadiazole, 1,2,5- oxadiazole, 1,2,3-thiadiazoles, 1,3,4- thiadiazoles, 1,2,5- thiadiazoles, 1,2,3-triazine, 1,2,4- triazine, 1,3,5-triazine, tetrazines. Synthesis and importance of purines and pteridines. Syntheis of Caffeine, theobromine and theophylline.
Synthesis, structure, stability and reactivity ofAzepines, Oxepines and Thiepines. Synthesis of Diazepines rearrangements of 1,2 - diazepines. Synthesis of Benzoazepines, Benzodiazepines, Benzooxepines, Benzothiepines, Azocines and Azonines. Synthesis of selenophenes, Tellerophenes,Phospholesand Boroles.
1. Heterocyclic Chemistry, T.Gilchrist
2. An introduction to the Chemistry of heterocyclic compounds, R.M.Acheson
3. Heterocyclic Chemistry, J.A.Joule&K.Mills
4. Principles of Modern Heterocyclie Chemistry, A.Paquette
5. Handbook of Heterocyclic Chemistry, A.R.Katritzky
6. The aromaticity III level, units 17-19 British open university volumes
7. Aromatic character and aromaticity by G.M.Badger
8. Non-benzenoid aromatic compounds by D.Ginsberg
9. Nonbenzenoid compounds by Lloy
OC(CB3)-25: Biosynthesis of natural products
OC(CB3)-26: Structure determination of natural products-I
OC(CB3)--27: Structure determination of natural products-II
OC(CB3)--28: Total stereo selective synthesis of natural products.
Biosynthesis of secondary metabolites: Introduction,Difference between Laboratory synthesis and biosynthesis. Methods for determination of biosynthetic mechanism. Isolation and identification of Biosynthetic precursors, Feeding experiments – use of radioisotopes Measurement of incorporation – absolute incorporation, specific incorporation. Identification of the position of labels in labeled natural products by chemical degradation and spectral methods. Major biosynthetic pathways: 1) Acetate-Malonate pathway: Biosynthesis of aromatic compounds, 2) Shikimic acid pathway ; Biosynthesis of essential amino acids – phenylalanine, tyrosine and tryptophan, carboxylic acid derivatives, flavonoids and morphine alkaloids. 3) Mevalonic acid pathway : Biosynthesis of terpenes – mono,sesqui, di, tri (β-amyrin) and carotenoids, steroids – cholesterol.
Determination of structure and stereochemistry of morphine, reserpine, abietic acid, cholesterol and rotenone.
Spectroscopic techniques IR, UV, 1Hnmr, 13Cnmr, COSY, HETEROCOSY, NOESY, 2D-INADEQUATE and MS in the structure elucidations of natural products, Examples, flavones, biflavones, flavanones, isoflavones, coumarins, quinolines, isoquinolines.
Study of the following solved problems: Mass, IR, 1H, 13C NMR, HOMOCOSY, HECTOR, DEPT, 2D-INADEQUATE and NOE of Geraniol, INEPT of menthol, APT of apparicine,
Heteronuclear 2D-J resolved spectrum of stricticine,NOESY of buxaquamarine, HETEROCOSY of strictanol, 2D-INADEQUATE of α-picoline and β-methyl tetrahydran furan.
Nicalou’s synthesis of Dynemicin A , Corey’s synthesis of prostaglandins (E2, F2α) and paeoriflorin, Sharpless synthesis of L-hexoses, Nicolaous synthesis of taxol, Danishefsky synthesis of indolizomycin, Takasago synthesis of menthol, Hoffmann-LaRoche synthesis of Biotin.
1. Textbook of organic chemistry, Vol II by I L Finar
2. Chemistry of natural products, Vol 12, by Atta-Ur-Rahman
3. An introduction to the chemistry of terpenoids and steroids, by William templeton
4. Systematic identification of flavonoid compounds by Mabry &Markham
5. Steroids by Fieser arid Fieser
6. Alkaloids by Manske
7. Alkaloids by Bentley
8. The chemistry of terpenes by A Pinder
9. The terpenes by Simenson
10. Terpenoids by Mayo
11. Alkaloids by Pelletier
12. Total synthesis of Natural Products by Apsimon Vol 1-5
13. Biosynthesis by Geismann
14. Principles of organic synthesis 3rdEd.R O C Norman and J M Coxen
15. One and two dimensional nmr spectroscopy by Atta Ur Rahma
16. Classics in total synthesis K C Nicolaou and E J Sorenson
17. Spectrometric identification of organic compounds by Silverstein and Webster
Paper CH (OC) 451P: Spectroscopic identification of organic compounds & practice of chemistry software prgrammes
1. Identification of unknown organic compounds by interpretation of IR, UV, 1H -NMR, 13C NMR, and mass spectral data( two examples with 2D-NMR). A minimum of 30 representative examples should be studied.
Chemistry software programmes: Chem Draw, analysis of IR and NMR using ACD/Id NMR processor. EXCEL: Drawing graphs, Molecular docking.
Paracetamol, Phenytoin, Benzocaine, 6-Methyluracil, Chloritone,FIuorescien, 4-Aminobenzene sulfonamide, antipyrineand phenothiazine
(B) Estimation of the following drugs:
Aspirin (titrimetry), Ibuprofen (titrimetry), Analgin (titrimetry), Chloride in Ringer’s lactate (argentometry), ascorbic acid {titrimetry, Iodometry and Cerimetry), colorimetry}, Isoniazid(Iodometry), Riboflavin(colorimetry),Zn ions in Bactracin Zinc, Ca+2 ions in Calcium gluconate injection(complexometry), Riboflavin (UV-Visible Spectrophotometer).
1. Practical organic chemistry by Mann & Saunders
2. Text book of practical organic chemistry by Vogel
3. The systematic identification of organic compounds by Shriner et.al
4. Analytical chemistry by G N David Krupadanam et.al
5. Advanced practical medicinal chemistry by Ashutoshkar
6. Pharmaceutical drug analysis by Ashutoshkar
7. Quantitative analysis of drugs in pharmaceutical formulations by P D Sethi
8. Practical pharmaceutical chemistry part-1 and part-2 by A H Beekett and J B Stenlake
9. Spectroscopic identification of organic compounds by R M Silverstein and F X Webster