THIS PAGE IS BLANK
THIS PAGE IS BLANK
Copyright © 2007, 2005, 2000, 1993 New Age International (P) Ltd., Publishers Published by New Age International (P) Ltd., Publishers
All rights reserved. No part of this ebook may be reproduced in any form, by photostat, microfilm,
xerography, or any other means, or incorporated into any information retrieval system, electronic or mechanical, without the written permission of the publisher. All inquiries should be emailed to rights@newagepublishers.com
ISBN : 978-81-224-2305-7
P UBLISHING FOR ONE WORLD
NEW AGE INTERNATIONAL (P) LIMITED, PUBLISHERS
4835/24, Ansari Road, Daryaganj, New Delhi - 110002 Visit us at www.newagepublishers.com
DEDICATION
This Fourth Revised and Expanded Edition of Medicinal Chemistry is dedicated to :
(Late) Professor Chandrashekhar Singh Chauhan for always being there as a guiding etertnal source of inspiration to the entire academic fraternity for whom we dedidicate our professional knowledge.
LATEST TRENDS IN NEW DRUG DISCOVERY
‘‘Technogies such as lab-on-a-chip that are less than a half-inch square in size and might contain up to a million test chambers, or ‘reactors’ each capable of screening an individual drug will drive the
future drug discoveries by drastically minimizing Research and Development timelines.’’
From Reviews of the Previous Editions
“It deals exhaustively with the major clinically useful drugs of various classes and is a timely compilation as a need for such a book was felt by both students and teachers intimately associ- ated with the teaching of medicinal chemistry.”
J. Indian Chem. Soc., 1993: 70: 276-77 “The book under review has been written by a bright and enthusiastic mind having an excellent
understanding of the subject and the need of the day. It will be of enormous use for the students of Pharmacy at graduate and postgraduate levels.”
Indian J. Pharmacology : 25: 179, 1993 “For the ready reference of synthetic routes to medicinal compounds, the book is likely to be
popular with both teachers and students.” Indian J. Pharm. Educ. : 27(2), 1993 “This new volume is an attempt to equip both students and practitioners in medicinal and phar-
maceutical sciences, to approach the treatment of a patient in a more informed and confident manner.”
Tapan K. Basu. Ph.D., FACN, FICN, Prof. Univ. of Alberta, Edmonton, Alberta, Canada The author has since completed SIX fast selling textbooks: (a) Medicinal Chemistry, 4th edition, 2006 (b) Pharmacognosy and Pharmacobiotechnology, 2nd edition, 2006 (c) Advanced Practical Medicinal Chemistry, 1st edition, 2004
(d) Pharmaceutical Drug Analysis, 2nd edition, 2005 (e) Pharmaceutical Biotechnology, 1st edition, 2005 (f) Pharmaceutical Microbiology, 1st edition, 2006 All these textbooks are published under the prestigious banner of New Age International (P)
Limited, Publishers, New Delhi.
PREFACE TO THE FOURTH EDITION
The success in succession of Medicinal Chemistry has been a phenomenal achievement since the First Edition in 1993. Its general appeal is not confined to the Indian subcontinent ; it has won overwhelming popularity in other parts of the world. This lucid, handy, and exceptionally knowledge- able textbook has rightly received a well-deserved reputation as the most comprehensive and treasured companion to the teaching fraternity as well as the senior students doing B. Pharm., Degree courses ; M.Sc., Pharmaceutical Chemistry ; M.Sc., Applied Chemistry ; M.Sc., Industrial Chemistry etc.
Utmost care has been taken to maintain and sustain the fundamental philosophy of the text right from the very First Edition to the present completely revised and skilfully expanded Fourth Edition. Nevertheless, the original pattern and style of presentation of the running–text content with a specific emphasis on the synthesis of potential medicinal compounds have been anchored strongly, for the whole- some benefits of ‘the teachers and the taught’ alike.
The present edition essentially contains three new chapters entitled : (a) Molecular Modeling
and Drug Design (Chapter 3) ; (b) Adrenocortical Steroids (Chapter 24) ; and (c) Antimycobacterial
Agents (Chapter 26)—therby further strengthening and enriching the subject matter of the present textbook upto thirty chapters.
Numerous genuine and authentic feedbacks/comments received from a wide-spectrum of august teachers from reputed Universities, Academic Institutions across the country overwhelmingly opine their views as under :
• Highly recommended textbook to the Pharmacy Degree Institutions all over the country. • Ideal textbook for undergraduate students who can have an easy grasp of Medicinal Chem-
istry. • Absolutely superb and lucid in language and style. • Informations provided in best presentable form. • Most handy ready-reference textbook. • Works like-a-guide for teachers. • Good companion for GATE-Examination.
Medicinal Chemistry has virtually widened the scope to tackle all vital aspects related to such super specialities as : Bulk Drug Industry ; Small Scale Drug Manufacturing Units ; R & D Laboratories in Pharmaceutical Industries ; PG/Ph.D., Research Scholars ; and above all the highly spirited, enthusi- astic, and research-oriented young teachers specialized in medicinal chemistry.
The Fourth Revised and Expanded Edition of Medicinal Chemistry has been designed artisti- cally and presented in a beautiful two-colour-scheme so as to facilitate a more effective use of the book.
It is earnestly hoped that the present edition of Medicinal Chemistry will surely win a place for itself.
The author extends his deep sense of gratitude from the core of his heart to Shri Saumya Gupta MD, New Age International (Pvt.) Ltd., and his exceptionally dedicated editorial and production wings who have brought out this edition in a record time-frame.
Ashutosh Kar Gurgaon
THIS PAGE IS BLANK
PREFACE TO THE FIRST EDITION
This book, ‘Medicinal Chemistry’ has two objectives in view. The first objective is to attract the interest of the undergraduate students in developing countries, so that they feel a spontaneous urge to explore and understand the basic theories of medicinal chemistry. These students often encounter enor- mous difficulties in grasping the fundamentals of synthesis of simple as well as complex compounds including those belonging to the therapeutic group, and they often get confused when they are supplied with inadequate information of vitally important medicinal compounds, their chemical formulae and chemical names. So this book aims at removing this inadequacy by furnishing copious information about medicinal compounds and pointing out their inter-relations wherever they exist. This method, it is believed, will add new incentive to the study of the subject, and will boost the spirit of research and provide a new dimension to the study of medicinal chemistry. Thus, in this book an attempt has been made to include and correlate detailed accounts of most of the important categories of drugs usually taught in the various Universities of developing countries offering diploma, degree and honours courses in Pharmacy. The second objective that has been kept in view is to make this a handy reference book for the professional class. With a view to fulfilling this second objective the author has adopted a specific style.
Each chapter has been sub-divided into three sections in the following manner. First, a brief introduction. Second, it follows classification based on either chemical or pharmacological basis. Each category of compound also includes the important representative members of the respective groups together with their International Non-proprietory Names (INN), British Approved Names (BAN) and United States Approved Names (USAN) wherever applicable. Then comes the statement of its chemical name(s), official status in B.P., U.S.P., Eur. P., Int. P., Ind. P., and their proprietory name(s).
The third part, perhaps the most significant, contains the synthesis of various important members treated individually, brief description of the synthesis, therapeutic applications of each compound, to- gether with its dosage in various diseases, and routes of administration. The dosage for adults and children have been separately mentioned. The usual and maintenance doses, wherever applicable, have also been specified. The mode of action of various classes of medicinal compounds in addition to the structure-activity relationship (SAR) have also been elaborated wherever relevant. Greater emphasis has been laid on the chemistry of various compounds treated in this book, so that an undergraduate student may acquire a comprehensive knowledge on the basic concepts of the medicinal chemistry.
For the reasons mentioned above, it is believed that this book will enjoy equal favour and confi- dence with pharmacy students, practising pharmacists and also with medical service representatives. Manufacturing pharmacists engaged in basic drug manufacture may also find it a useful reference book, and will appreciate its originality of approach and its significant departure from similar books available on the subject.
The author is particularly grateful to his colleague Professor P.I. Akubue, Professor of Pharma- cology, University of Nigeria, Nsukka, (Nigeria) for making valuable suggestions to update the pharmacologic aspect dealt with in this book and other constructive criticisms.
A. KAR New Delhi
THIS PAGE IS BLANK
CONTENTS
Preface to the Fourth Edition (vii) Preface to the First Edition
(ix)
CHAPTER 1: Drug Design—A Rational Approach
1. Introduction
2. Analogues and Prodrugs
3. Concept of Lead
3.1. Examples
4. Factors Governing Drug-Design
5. Rational Approach to Drug-Design
5.1. Quantum Mechanical Approach
5.2. Molecular Orbital Approach
5.3. Molecular Connectivity Approach
5.4. Linear Free Energy Approaches
6. Drug-Design : The Method of Variation
6.1. Drug Design Through Disjunction
6.2. Drug Design Through Conjunction
7. Drug Design and Development: An Overview
7.2. Revolutions in Drug Discovery
7.3. Research and Development Strategies
8. Molecular Hybridization
9. Rigidity and Flexibility Vs Drug Design
9.1. Increased Rigidity
9.2. Increased Flexibility
10. Tailoring of Drugs
11. General Considerations
CHAPTER 2: Physical-Chemical Factors and Biological Activities
2. Physical Properties
2.1. Features Governing Drug Action in Active Site
2.2. Structurally Specific Drugs
2.3. Structurally Non-Specific Drugs
(xi)
(xii)
2.4. Thermodynamic Activity
2.5. Meyer-Overton and Meyer-Hemmi Theory
2.6. Ferguson’s Theory
2.7. Van der Waal’s Constants
2.8. The Cut-off Point
2.9. Steric Factors
2.9.1. Taft’s Steric Factor (Es)
2.9.2. Molar Refractivity (MR)
2.9.3. Verloop Steric Parameter
2.10. Hansch Equation
2.11. The Craig Plot
2.12. The Topliss Scheme
3. Factors Governing Ability of Drugs to Reach Active Site
3.3. Metabolism (Biotransformation)
3.5. Intramolecular Distances and Biological Activity
4. Dissociation Constants
4.1 Drug Exerting Action as Undissociated Molecules
4.2. Drugs Exerting Action as Ionized Molecules
5. Isosterism and Bio-Isosterism
5.1. Classical Bioisosteres
5.2. Nonclassical Bioisosteres
6. Stereochemistry and Drug Action
6.3. Stereochemistry and Biologic Activity
6.3.1. Positional Isomers (or Constitutional Isomers)
6.3.2. Geometrical Isomers
6.3.3. Absolute Configuration
6.3.4. Easson-Stedman Theory
6.3.5. Conformationally Flexible to Conformationally Rigid Molecule
7. Chemical Properties
7.1. Molecule Negentropy
7.2. Cammarata Correlation
(xiii)
CHAPTER 3: Molecular Modeling and Drug Design
2. Methodologies : Molecular Modeling
2.1. Molecular Mechanics
2.2. Quantum Mechanics (or Quantum Mechanical Methods)
2.2.1. Charge and Electrostatics
2.2.2. Parameterization of Force Fields
2.2.3. Chemical Reaction(s) Modeling and Design of Transition State Inhibitors 65
3. Known Receptor Sites
3.1. 3D Structure of Macromolecular Targets
3.2. Structure-Based Drug-Design
3.3. Major Steps in Structure-Based Drug Design
3.4. Ligand Receptor Recognition
3.5. Active Site for a Target Molecule
3.6. Meaning of Site
3.7. Characterization of Site
3.7.1. Hydrogen Bonding and Other Group Binding Sites
3.7.2. Electrostatic and Hydrophobic Fields
3.8. Design of Ligands
3.8.1. Visually Assisted Design
3.8.2. 3D Databases
3.8.3. ‘Divide and Rule’ Concept in Design of Ligands
3.8.4. De Novo Design
3.9. Calculation of Affinity
3.9.1. Components of Bonding Affinity
3.9.2. Binding Energetics and Comparisons
3.9.3. Simulations and the Thermodynamic Cycle
3.9.4. Multiple Binding Modes
4. Unknown Receptor Sites
4.1. Pharmacophore Vs Binding-site Models
4.1.1. Pharmacophore Models
4.1.2. Binding-Site Models
4.1.3. Molecular Extensions
4.1.4. Activity Vs Affinity
4.2. Searching for Similarity
4.2.1. Simple Comparisons
4.2.2. Visualization of Molecular Properties
4.3. Molecular Comparisons
(xiv)
5. Predictive ADME
6. Reverse Designing
6.1. High Throughput Screening
6.2. Combinatorial Chemistry
7. CADD-Methods : Comparison for Determining Relative Binding Affinities of COX-2 Inhibitors
CHAPTER 4: General Anaesthetics 105
1. Introduction 106
2. Classification 106
2.1. Inhalation Anaesthetics 106
2.2. Intravenous Anaesthetics 111
2.3. Basal Anaesthetics 116
3. Mode of Action of General Anaesthetics 118
3.1. Lipid Theory 118
3.2. Physical Theory 119
3.3. Biochemical Theory 119
3.4. Miscellaneous Theory 119
3.5. Meyer-Overton Theory 119
3.6. Minimum Alveolar Concentration (MAC) 119
3.7. Stereochemical Effects 120
3.8. Ion Channel and Protein Receptor Hypotheses 121
4. Mechanism of Action General Anaesthetics 121
CHAPTER 5: Local Anaesthetics 127
1. Introduc tion 128
2. Classification 131
2.1. The Esters 131
2.2. Piperidine or Tropane Derivatives 140
2.3. The Amides 143
2.4. The Quinoline and Iso-Quinoline Analogues 149
2.5. Miscellaneous Type 152
3. Chemical Considerations of Local Anaesthetic Drug Substances 155
3.1. Löfgren’s Classification 155
3.1.1. Lipophilic Entity 156
3.1.2. Intermediate Chain 160
3.1.3. Hydrophilic Entity 160
(xv)
4. Benzoic Acid and Aniline Analogues with Potential Local Anaesthetic Profile
5. Mode of Action of Some Selected Local Anaesthetics 164
CHAPTER 6: Sedatives and Hypnotics 169
2.2. Non barbiturates 190
3. Mode of Action of Barbiturates 194
4. Mechanism of Action 194
5. Barbiturates Vs Benzodiazepines 195
6. Structure-Activity Relationship 195
7. Barbiturates Vs Dissociation Constant (pKa) 196
8. Substitutions on Hetero Atoms in Barbiturates 197
9. OH – Catalyzed Degradation of Barbiturates 197
10. Specific Mechanism of Action of Some Sedatives and Hypnotics 198
CHAPTER 7: Anticonvulsants 203
2.2. Hydantoin Derivatives 206
3. Chemotherapy of Epilepsy 216
4. Mechanisms of Action for the Anticonvulsants 218
5. Specific Mechanisms of Selected Anticonvulsants 220
CHAPTER 8: Muscle Relaxants 225
1. Introduction 226
2. Classification 226
2.1. Neuromuscular Blocking Drugs 226
2.2. Centrally Acting Muscle Relaxants 235
3. General Mechanism of Action of Muscle Relaxants 244
4. Mode of Action of Some Specific Muscle Relaxants 247
(xvi)
CHAPTER 9: Central Nervous System Stimulants 253
1. Introduction 254
2. Classification 255
2.1. Xanthine Derivatives 256
2.2. Analeptics 260
2.3. Miscellaneous Central Nervous System Stimulants 264
3. CNS-Peptides, S-Glutamate and Blockade of NMDA Induced Responses 267
3.1. CNS-Peptides 267
3.2. S-Glutamate and Blockade of NMDA-Induced Responses 268
4. Mechanism of Action of Selected CNS-Stimulants 269
CHAPTER 10: Antipyretic Analgesics 273
1. Introduction 274
2. Classification 275
2.1. Aniline and p-Aminophenol Analogues 275
2.2. Salicylic Acid Analogues 279
2.3. Quinoline Derivatives 285
2.4. Pyrazolones and Pyrazolodiones 287
2.5. The N-Arylanthranilic Acids 294
3. Mechanism of Action 296
4. Mechanism of Action of Selected Antipyretic-Analgesics 297
CHAPTER 11: Narcotic Analgesics (Opiate Analgesics) 303
1. Introduction 304
2. Limitations of Opiate Analgesics 305
3. Characteristics Features of Opioids 306
3.1. Opioid Peptides 306
3.2. Opioid Receptors 307
3.3. Orphan Opioid Receptors 307
3.4. Mu Opioid Receptors 307
3.5. Kappa Opioid Receptors 308
3.6. Delta Opioid Receptors 310
3.7. Opioid Receptors: Identification and Activation 311
4. Classification 312
4.1. Morphine Analogues 312
4.2. Morphinan Analogues 317
4.3. Morphan Analogues 320
(xvii)
4.4. 4-Phenylpiperidine Analogues 322
4.5. Phenylpropylamine Analogues 327
4.6. Miscellaneous Analogues 330
5. Narcotic Antagonists 332
6. Morphine: Structural Representations 334
7. Mechanism of Action of Certain Narcotic Analgesics 336
CHAPTER 12: Cardiovascular Drugs 343
1. Introduction 344
2. Classification 345
3. Cardiac Glycosides 345
3.1. Designing the Cardiac Glycoside Receptor 345
3.2. Mechanism of Action 348
4. Antihypertensive and Hypotensive Drugs 348
4.1. Renin-Angiotensin Pathway 349
4.2. Angiotensin II Receptor Antagonists 349
4.3. Potential Dependent Calcium Channels 350
4.4. Mechanism of Action of Selected Antihypertensive and Hypotensive Drugs
5. Antiarrythmic Agents 355
5.1. Membrane-Stabilizing Agents 358
5.1.1. Mechanism of Action of Membrane Stabilizing Agents
5.2. Antisympathetic Drugs 363
5.2.1. Mechanism of Action 364
5.3. Prolonging Cardiac Action 364
5.3.1. Mechanism of Action 366
5.4. Interference with Calcium Conductance 366
5.4.1. Mechanism of Action 367
6. Vasopressor Drugs 367
6.1. Mechanism of Action 370
CHAPTER 13: Autonomic Drugs 373
1. Introduction 374
2. Classification 375
3. Sympathomimetic Drugs 375
3.1. Mechanism of Action 384
3.2. Structure Activity Relationships (SARs) 385
(xviii)
4. Beta Adrenergic Receptor Stimulants 386
4.1. Mechanism of Action 387
5. Adrenergic Receptor Blocking Agents 388
5.1. α-Adrenergic Blocking Agents 388
5.1.1. Mechanism of Action 391
5.2. β-Adrenoreceptor Blocking Agents 391
5.2.1. First Generation β-Blockers 392
5.2.2. Second Generation β-Blockers (Selective β 1 -Blockers)
5.2.3. Third Generation β-Blockers 397
5.3. Alpha- and Beta-Adrenergic Recepter Blocking Agent 399
6. Cholinomimetic (Parasympathomimetic) Drugs 399
6.1. Directly Acting 399
6.2. Indirectly Acting (Anticholinesterase) Drugs 403
6.2.1. Mechanism of Action 407
7. Antimuscarinic (Anticholinergic) Agents 408
7.1. Aminoalcohol Esters 409
7.2. Aminoalcohol Ethers 416
7.3. Aminoalcohol Carbamates 416
7.7. Miscellaneous Amines 420
7.8. Mechanism of Action 423
8. Ganglionic Blocking Agents 426
8.1. Mechanism of Action 430
9. Adrenergic Neurone Blocking Agents 431
9.1. Mechanism of Action 433
CHAPTER 14: Diuretics 437
1. Introduction 438
2. Classification 438
2.1. Mercurial Diuretics 439
2.2. Non-Mercurial Diuretics 444
2.2.1. Thiazides (Benzothiazines)
2.2.2. Carbonic Anhydrase Inhibitors
2.2.3. Miscellaneous Sulphonamide Diuretics
(xix)
2.2.4. ‘Loop’ and ‘High-Ceiling’ Diuretics
2.2.5. Aldosterone Inhibitors
2.2.6. Purine or Xanthine Diuretics
2.2.7. Pyrimidine Diuretics
2.2.8. Osmotic Diuretics
2.2.9. Acidotic Diuretics
2.2.10. Miscellanous Diuretics
CHAPTER 15: Antihistamincs 483
1. Introduction 484
2. Classification 485
2.1. Histamine H 1 -Receptor Antagonists
2.1.3. Thiophene Derivatives 494
2.1.4. Cyclic Basic Chain Analogues 497
2.1.5. Phenothiazine Derivatives 501
2.1.6. Second Generation Nonsedating Antihistamines 505
2.1.7. Miscellaneous Agents 510
2.2. Prevention of Histamine Release 515
2.2.1. Mechanism of Action 516
2.3. Histamine (H 2 ) Receptor Blockers
2.3.1. Mechanism of Action 517
CHAPTER 16: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 521
1. Introduction 522
2. Classification 523
2.1. Heteroarylacetic Acid Analogues 523
2.1.1. Mechanism of Action 526
2.2. Arylpropionic Acid Analogues 527
2.2.1. Mechanism of Action 529
2.3. Arylpropionic Acid Analogues 530
2.3.1. Mechanism of Action 532
2.4. Naphthalene Acetic Acid Analogues 533
2.4.1. Mechanism of Action 534
2.5. Gold Compounds 534
2.5.1. Mechanism of Action 537
(xx)
2.6. Miscellaneous Anti-Inflammatory Drugs 538
2.6.1. Antimalarial Agents 538
2.6.2. Uricosuric Agents 538
2.7. Salicylic Acid Analogues 542
2.8. Pyrazolones and Pyrazolodiones 542
CHAPTER 17: Antiparkinsonism Agents 545
1. Introduction 546
1.1. Etiology 546
1.2. Parkinsonism Produced by MPTP 548
2. Classification 549
2.1. Piperidine Analogues 549
2.1.1. Mechanism of Action 552
2.2. Pyrrolidine Analogue 553
2.2.1. Mechanism of Action 554
2.3. Phenothiazine Analogue 554
2.3.1. Mechanism of Action 555
2.4. Miscellaneous Drugs 556
2.4.1. Mechanism of Action 560
CHAPTER 18: Expectorants and Antitussives 565
1. Introduction 566
2. Classification 568
2.1. Sedative Expectorants 568
2.2. Stimulant (Irritant) Expectorants 571
2.3. Centrally Acting Antitussive Agents 573
CHAPTER 19: Sulphonamides 581
1. Introduction 582
2. Classification 584
2.1. Sulphonamides for General Infections 584
2.1.1. Mechanism of Action 592
2.2. Sulphonamides for Urinary Infections 595
2.2.1. Mechanism of Action 598
2.3. Sulphonamides for Intestinal Infections 598
2.3.1. Mechanism of Action 602
2.4. Sulphonamide for Local Infection 603
2.4.1. Mechanism of Action 604
(xxi)
2.5. Sulphonamide Related Compounds 604
2.5.1. Mechanism of Action 606
3. Ionizaton of Sulphonamides 607
4. Sulphonamide Inhibition and Probable Mechanisms of Bacterial Resistance to Sulphonamides
5. Chemotherapeutic Consideration 608
CHAPTER 20: Antimalarials 611
1. Introduction 612
2. Classification 614
2.1. 4-Aminoquinoline Analogues 614
2.1.1. Mechanism of Action 621
2.2. 8-Aminoquinoline Analogues 623
2.2.1. Mechanism of Action 631
2.3. 9-Aminoacridines 632
2.3.1. Mechanism of Action 636
2.4. Guanidine Analogues (Biguanides) 637
2.4.1. Mechanism of Action 640
2.5. Pyrimidine Analogues (Diaminopyrimidines) 640
2.5.1. Mechanism of Action 644
2.6. Sulfones 644
2.6.1. Mechanism of Action 645
2.7. Quinine Analogues 646
2.7.1. Mechanism of Action 646
2.8. New Antimalarial Drugs 646
CHAPTER 21: Anthelmintics 651
2.5. Natural Products 661
CHAPTER 22: Insulin and Oral Hypoglycemic Agents 667
1. Introduction 668
2. Insulin-Primary Structure 669
2.1. Variants of Insulin Products 670
(xxii)
3. Oral Hypoglycemic Agents 672
3.1. Sulfonylureas 672
3.1.1. First-Generation Sulfonylureas 673
3.1.2. Second-Generation Sulfonylureas 676
3.5. α-Glucosidase Inhibitors 682
CHAPTER 23: Steroids 685
1. Introduction 686
2. Steroid Nomenclature, Numbering, Double Bonds and Stereochemistry 686
3. Classification 690
3.1. Sterols 690
3.2. Sex Hormones 691
3.3. Cardiac Glycosides 709
3.3.1. Mechanism of Action 712
3.4. Bile Acids 712
3.5. Sapogenins 713
CHAPTER 24: Adrenocortical Steroids 717
1. Introduction 718
2. Classification 720
2.1. Short to Medium Acting Glucocorticoids 720
2.2. Intermediate Acting Glucocorticoids 727
2.3. Long Acting Glucocorticoids 728
2.4. Mineralocorticoids 731
CHAPTER 25: Antibiotics 735
1. Introduction 736
2. Classification 737
3. β-Lactam Antibiotics 737
3.1. Penicillins 737
3.2. Cephalosporins 754
(xxiii)
4. Aminoglycoside Antibiotics 763
5. Chloramphenicol 767
5.1. Structure of Chloramphenicol 767
5.2. Synthesis of Chloramphenicol 769
5.3. Structure Activity Relationship 771
6. Tetracyclines 772
6.1. Salient Features of Tetracyclines 772
6.2. Nomenclature 772
6.3. General Characteristics of the Tetracyclines 773
6.4. Structure Activity Relationship (SAR) 776
6.5. Newer Tetracyclines 777
CHAPTER 26: Antimycobacterial Drugs 781
1. Introduction 782
2. Classification 784
2.1. First-Line Drugs 784
2.2. Second-Line Drugs 785
CHAPTER 27: Antineoplastic Agents 793
1. Introduction 794
1.1. Chemotherapeutic Intervention 796
1.1.1. Phase Specificity 796
1.1.2. Tumour Selectivity and Response 797
1.1.3. Determinants of Sensitivity and Selectivity 798
1.1.4. Requirements for Kill 799
1.1.5. Combination Chemotherapy 799
1.1.6. Log Cell-Kill Principle 799
1.1.7. Drug Resistance 800
2. Classification 801
2.1. Alkylating Agents 801
2.2.1. Antifolic Acid Compounds 811
2.2.2. Analogues of Purines 813
2.2.3. Analogues of Pyrimidines 815
2.2.4. Amino Acid Antagonists 817
(xxiv)
2.3. Antibiotics 817
2.3.1. Mechanism of Action 819
2.4. Plant Products 819
2.4.1. Imides and Amides 820
2.4.2. Tertiary Amines 821
2.4.3. Heterocyclic Amines 824
2.4.4. Lactones 824
2.4.5. Glycosides 825
2.5. Miscellancous Compounds 826
2.5.1. Mechanism of Action 828
2.6. Hormones 830
2.6.1. Mechanism of Action 831
2.7. Immunotherapy 831
2.7.1. Mechanism of Action 832
CHAPTER 28: Antipsychotics (Tranquilizers) 835
1. Introduction 836
2. Classification 837
2.1. Reserpine and Related Alkaloids 837
2.1.1. Mechanism of Action 839
2.2. Alkylene Diols 839
2.3. Diphenylmethane Compounds 840
2.3.1. Mechanism of Action 843
2.4. Phenothiazine Compounds 843
2.4.1. Mechanism of Action 846
2.5. Dibenzazepines 847
2.5.1. Mechanism of Action 848
2.6. Butyrophenones 859
2.6.1. Mechanism of Action 850
2.7. Azaspirodecanediones 850
2.7.1. Mechanism of Action 851
CHAPTER 29: Antiviral Drugs 853
1. Introduction 853
1.1. Replication and Transformation 855
2. Classification 855
2.1. Substances that Inhibit Early Stages of Viral Replication 855
2.1.1. Mechanism of Action 856
(xxv)
2.2. Substances that Interfere with Viral Nucleic Acid Replication 857
2.2.1 Mechanism of Action 859
2.3. Substances that Affect Translation on Cell Ribosomes 860
2.3.1. Mechanism of Action
CHAPTER 30: Newer Drugs for Newer Diseases 863
1. Introduction 864
2. Newer Drugs 864
2.1. Prostaglandins and Other Eicosanoids 865
2.1.1. Nomenclature
2.2. Antilipemic Drugs 869
2.2.1. Mechanism of Action
2.3. Hormone Antagonists 870
2.3.3. Aldosterone Antagonists
2.3.4. Antiprogestational Steroids
2.4. Antithyroid Drugs 875
2.4.1. Mechanism of Action
2.5. Antimycobacterial Drugs 877
2.5.1. Antitubercular Drugs
2.6. Cardiac Steroids and Related Inotropic Drugs 882
2.6.1. Cardiac Steroids
2.6.2. Phosphodiesterase Inhibitors
2.6.3. Adenylate Cyclase Stimulants
2.6.4. Drugs that Enhance the Ca 2+ Sensitivity of
Myocardial Contractile Proteins
2.8.1. Therapeutic Radioisotopes
2.8.2. Imaging Radioisotopes
2.9. Cromakalim 889
2.10. Drugs to Combat AIDS 890
Index 897
THIS PAGE IS BLANK
Drug Design—A Rational Approach
+D=FJAH
Drug DesignaA Rational
Approach
1. INTRODUCTION
In the past few decades there has been a hiatus in the momentum of research and discovery of ‘novel medicinal compounds’. This particular trend in drug development perhaps is augmented due to two vital factors, namely : first, strict empirical and rational approach to drug design ; and secondly, high
standards of safety and therapeutic efficacy together with tremendous increased costs of research and development and finally the clinical trials.
‘Drug design’ or ‘tailor-made compound’ aims at developing a drug with high degree of chemotherapeutic index and specific action. It is a logical effort to design a drug on as much a rational basis as possible thus reducing to the minimum the trial and error approach. It essentially involves the study of biodynamics of a drug besides the interaction between drug molecules and molecules compos- ing the biological objects.
Drug design seeks to explain : (a) Effects of biological compounds on the basis of molecular interaction in terms of molecu- lar structures or precisely the physico-chemical properties of the molecules involved. (b) Various processes by which the drugs usually produce their pharmacological effects. (c) How the drugs specifically react with the protoplasm to elicit a particular pharmacological
response. (d) How the drugs usually get modified or detoxicated, metabolized or eliminated by the or- ganism. (e) Probable relationship between biological activity with chemical structure. In short, drug design may be considered as an integrated whole approach which essentially involves various steps, namely : chemical synthesis, evaluation for activity-spectrum, toxicological studies, metabolism of the drug, i.e., biotransformation and the study of the various metabolites formed, assay procedures, and lastly galenical formulation and biopharmaceutics.
The ‘drug design’ in a broader sense implies random evaluation of synthetic as well as natural products in bioassay systems, creation of newer drug molecules based on biologically-active-prototypes derived from either plant or animal kingdom, synthesis of congeners displaying interesting biological actions, the basic concept of isosterism and bioisosterism, and finally precise design of a drug to enable it to interact with a receptor site efficaciously.
DRUG DESIGN—A RATIONAL APPROACH
3 HAPTER In the recent past, another terminology ‘prodrugs’ has been introduced to make a clear distinc-
tion from the widely used term ‘analogues’. Prodrugs are frequently used to improve pharmacological
or biological properties. Analogues are primarily employed to increase potency and to achieve specificity of action.
2. ANALOGUES AND PRODRUGS
In the course of drug design the two major types of chemical modifications are achieved through the formation of analogues and prodrugs.
An analogue is normally accepted as being that modification which brings about a carbon-skel- etal transformation or substituent synthesis. Examples : oxytetracycline, demclocycline,
chlortetracycline, trans-diethylstilbesterol with regard to oestradiol.
The term prodrug is applied to either an appropriate derivative of a drug that undergoes in vivo hydrolysis to the parent drug, e.g., testosterone propionate, chloramphenicol palmitate and the like ; or an analogue which is metabolically transformed to a biologically active drug, for instance : phenyl-
butazone undergoes in vivo hydroxylation to oxyphenbutazone.
3. CONCEPT OF ‘LEAD’
Another school of thought views ‘drug design’ as the vital process of envisioning and preparing specific new molecules that can lead more efficiently to useful drug discovery. This may be considered broadly in terms of two types of investigational activities. These include :
(a) Exploration of Leads, which involves the search for a new lead ; and (b) Exploitation of Leads, that requires the assessment, improvement and extension of the lead. From the practical view-point it is the latter area wherein rational approaches to drug design have
been mostly productive with fruitful results.
3.1 Examples
It is worthwhile to look into the right perspective of a few typical and classical examples of drug design as detailed below :
(i) Narcotic Analgesics
In the year 1939, Schaumann first identified and recognized the presence of a quaternary-carbon- atom in the morphine molecule, which eventually formed an altogether new basis and opened up a new horizon in the field of drug design of narcotic analgesics. Intensive research further led to the evolution of pethidine (meperidine) which incidentally combines both the properties of morphine and atropine. It possesses a quaternary carbon-atom and quite astonishingly a much simpler chemical structure to that of morphine.
MEDICINAL CHEMISTRY
Ehrhardt suggested a general formula relevant to the analgesic activity in 1949 as stated below :
O ||
where, Ar is the aromatic ring, X the basic side chain and (—C—) carbonyl function in the form of an ester, ketone or an amide.
Later on, the above general formula was modified slightly as follows :
which successfully led to the development of the following three narcotic analgesics, namely : metha-
done, dextromoramid and dextropropoxyphen.
(ii) Antipyretic Analgesics Another fruitful approach in drug design is the meticulous screening of the metabolite for prob-
able pharmacological activity. The most interesting example is the bio-oxidation of acetanilide into para -aminophenol which subsequently on chemical manipulation has yielded better tolerated antipy- retic-analgesics like paracetamol and phenacetine.
DRUG DESIGN—A RATIONAL APPROACH
5 HAPTER
Quite recently phenacetine has been withdrawn completely because of its toxic after effects, though it dominated the therapeutic field for over 30 years as a potent antipyretic analgesics.
(iii) Antirheumatic Drugs
The study of the metabolite conversion of the antirheumatic drug phenylbutazone resulted in the introduction of a better tolerated drug oxyphenylbutazone as an antirheumatic drug and
phenylbutazone alcohol as an uricosuric agent.
MEDICINAL CHEMISTRY
4. FACTORS GOVERNING DRUG-DESIGN
A few cardinal factors governing the efficacy towards the evaluation of drug design include : (a) The smaller the expenditure of human and material resources involved to evolve a new
drug of a particular value, the more viable is the design of the programme. (b) Experimental animal and clinical screening operations of the new drugs. (c) Relationships between chemical features and biolgoical properties need to be established
retrospectively. (d) Quantitative structure-activity relationships (QSARs) vary to an appreciable extent in
depth and sophistication based on the nature of evaluation of structure or activity. A pur- poseful relation of structural variables must include steric factors, electronic features of component functional groups and, in general, the molecule as a whole.
(e) The trend to synthesize a huge number of newer medicinal compounds indiscriminately for exploratory evaluation still prevails which exclusively reflects the creative genuineness and conceptual functions of a highly individualized expression of novelty by a medicinal chemist.
(f) Introduction of functional groups in a molecule that need not essentially resemble metabolites, but are capable of undergoing bonding interactions with important functional groups of biochemical components of living organisms affords an important basis for exploration.
(g) Disease etiologies and various biochemical processes involved prove useful.
5. RATIONAL APPROACH TO DRUG DESIGN
A rational approach to drug design may be viewed from different angles, namely :
DRUG DESIGN—A RATIONAL APPROACH
7 HAPTER
5.1. Quantum Mechanical Approach
Quantum mechanics (or wave mechanics) is composed of certain vital principles derived from
fundamental assumptions describing the natural phenomena effectively. The properties of protons, neu- trons and electrons are adequately explained under quantum mechanics. The electronic features of the
molecules responsible for chemical alterations form the basis of drug molecule phenomena.
5.2. Molecular Orbital Approach
Based on the assumption that electrons present in molecules seem to be directly linked with orbitals engulfing the entire molecule which set forth the molecular orbital theory. The molecular or- bital approach shows a dependence on electronic charge as evidenced by the study of three volatile inhalation anaesthetics, and also on molecular conformation as studied with respect to acetylcholine by such parameters as bond lengths and angles including torsional angles.
Molecular orbital calculations are achievable by sophisticated computers, and after meticulous interpretations of results the molecular structure in respect of structure-activity analysis is established.
5.3. Molecular Connectivity Approach
This approach establishes the presence of structural features like cyclization, unsaturation, skel- etal branching, and the position and presence of heteroatom in molecules with the aid of a series of numerical indices. For example : an index was determined to possess a correlative factor in the SAR study of amphetamine-type hallucinogenic drugs.
Molecular connectivity approach has some definite limitations, such as : electronegativity variance between atoms, non-distinguishable entity of cis-trans isomerism.
5.4. Linear Free-Energy Approaches
This method establishes the vital link between the proper selection of physicochemical parameters with a specific biological phenomenon. However, such a correlation may not guarantee and allow a direct interpretation with regard to molecular structure, but may positively offer a possible clue towards the selection of candidate molecules for synthesis.
6. DRUG-DESIGN : THE METHOD OF VARIATION
Under this method a new drug molecule is developed from a biologically active prototype. The various advantages are as follows :
(a) At least one new compound of known activity is found. (b) The new structural analogues even if not superior may be more economical.
(c) Identical chemical procedure is adopted and hence, considerable economy of time, library and laboratory facilities.
(d) Screening of a series of congener (i.e., member of the same gene) gives basic information with regard to pharmacological activity.
(e) Similar pharmacological technique for specific screening may be used effectively. The cardinal objectives of the method of variation are : • To improve potency
MEDICINAL CHEMISTRY
• To modify specificity of action • To improve duration of action • To reduce toxicity • To effect ease of application or administration or handling • To improve stability • To reduce cost of production
In order to obtain a therapeutically potent and better-tolerated drug there exists invariably an apparent conflict of pure scientific objectives and practical objectives. This may be expatiated by
citing the instance of an exceedingly toxic congener (say an anti-neoplastic agent) that possesses a very high degree of specificity and the researcher may have in mind to prepare still more toxic
compounds so as to develop the highest possible specificity of action. On the contrary, absolutely from the practical aspect, the proposed clue may not be pursued solely depending on the policy of the organization and not the individual or group of researchers.
In fact, there are a few generalized approaches utilizing the method of variation. In this particular context, the familiarity with the molecular structure is of the prime importance. The various possible approaches in designing newer drugs by applying variation of a prototype are quite numerous. Once the molecular structure of the compound in question is drawn on the drawing board, one takes into consid- eration such information as the following :
(a) study of the core nucleus of the hydro-carbon skeleton ; (b) variation of functional groups and their proximity to one another ; (c) various probable rotational and spatial configurations ; (d) possibility of steric hindrance between various portions of the molecule in different configu-
rations in space ; and (e) probability of electronic interactions between various portions of the molecule including such
matters as inductive and mesomeric effects, hyper-conjugation, ionizability, polarity, possibility of chelation, asymmetric centres and zwitterion formation.
The application of the method of variation, depending on the considerations enumerated above, is exploited in two different manners to evolve a better drug. The two main approaches for this goal can
be indicated as : (a) drug design through disjunction ; and (b) drug design through conjunction.
6.1. Drug Design through Disjunction
Disjunction comes in where there is the systematic formulation of analogues of a prototype agent, in general, toward structurally simpler products, which may be viewed as partial or quasi-replicas of the prototype agent.
The method of disjunction is usually employed in three different manners, namely : (i) unjoining of certain bonds ;
(ii) substitution of aromatic cyclic system for saturated bonds ; and (iii) diminution of the size of the hydrocarbon portion of the parent molecule.
DRUG DESIGN—A RATIONAL APPROACH
9 HAPTER
Example :
The extensive study on the estrogenic activity of oestradiol via drug design through disjunction
ultimately rewarded in the crowning success of the synthesis and evaluation of trans-diethylstilbesterol. The flow-sheet of estrogen design is stated below :
Flow-sheet of Estrogen Design
MEDICINAL CHEMISTRY
From the above the following three observations may be made. They include : (i) Various steps in design of II to III to IV designate nothing but successive simplification through
total elimination of the rings B and C in oestradiol (I). (ii) The above manner of drug design finally led to successively less active products (i.e., II, III,
IV). (iii) Upon plotting oestrogenic activity against various structures (I to VII) it was quite evident
that the maximal activity in this series was attributed to trans-diethylstilbesterol. It is, however, pertinent to mention here that in the following three different possible structures
of diethylstilbesterol analogues, the oestrogenic potency decreases substantially as the distance ‘D’ between the two hydroxyl groups decreases.
D 1 >D 2 >D 3 > [D 1 = 14.5°A]
6.2. Drug Design through Conjunction
This is known as the systematic formulation of analogues of a prototype agent, in general, toward structurally more complex products, which may be viewed as structures embodying, in a general or specific way, certain or all of the features of the prototype.
In this type of drug-design, the main principle involved is the ‘principle of mixed moieties’. A drug molecule is essentially made up with two or more pharmacophoric moieties embedded into a single molecule.
Example : Ganglionic blocking agent—its development based on the principle of mixed moieties.
The principle of mixed moieties actually involve the conjunction of two or more different types of pharmacophoric moieties within a single molecule.
Acetylcholine is an effective postganglionic parasympathetic stimulant in doses that afford no appreciable changes in the ganglionic function ; whereas hexamethonium possesses only a slight action at postganglionic parasympathetic endings in doses that produce a high degree of ganglionic blockade.
DRUG DESIGN—A RATIONAL APPROACH
11 HAPTER
(where Sv 1 = steric factor 1 ; Sv 2 = steric factor 2 ; Sv 3 = steric factor 3 ; Sd = steric distance factor ; P 1
= polarity factor 1 and P 2 = polarity factor 2). The moiety requirements for postganglionic parasympathetic stimulant action (muscarinic moi-
ety) have been duly summarized for convenience to the above structure of acetylcholine wherein the various operating factors have been highlighted.
The foregoing generalization of the muscarinic moiety on being studied in relation to the particu- lar bisquaternary type of structure, e.g. hexamethonium, promptly suggests the following proposed de- sign, thus embodying the ganglionic moiety and the muscarinic moiety into a single molecule.
It is, however, pertinent to mention here that the ‘internitrogen distance’ essentially constitute an important factor in many series of bisquaternary salts that possess ganglionic blocking activity. It is worthwhile to note that this distance is almost similar to that present in hexamethonium in its most extended configuration.
However, the actual synthesis and pharmacological evaluation of the above hexamethyl ana- logue reveal the presence of both muscarinic stimulant and ganglionic blocking actions. Interestingly, the corresponding hexaethyl analogue possesses a ganglionic blocking effect and a weak muscarinic stimulant action.
7. DRUG DESIGN AND DEVELOPMENT : AN OVERVIEW
7.1. Preamble
The overwhelming qualified success in the evolution of ‘ethical pharmaceutical industry’ in the twentieth century have not only registered an unquestionable growth in improving the fabric of society to combat dreadful diseases across the globe but also made a significant legitimate cognizance
MEDICINAL CHEMISTRY
The twentyfirst century may obviously record and witness an apparent positive tilt in population demographics ultimately leading to a much healthier, stronger and happier elderly population.
However, in the 21st century, the ‘ethical pharmaceutical industry’ has been fully geared to- wards the production of relatively safer, less toxic, more effective, higher therapeutic index, novel, innovative medicaments that will evidently help the mankind to afford a disease-free society ; besides, the elder ones with a glaring hope to live a still longer life span.
Following is the brief description in a chromological order for the development of ‘ethical phar- maceutical industry’ in the world :
Year
Country
Historical Development
1600s
Japan
—Takeda in 1637*.
1800s
—Fine chemical industries**. 1880s
Europe and USA
Germany and UK
—Hoechst (Germany) and Wellcome (UK) for
immunological drugs.
UK
—Aspirin (as NSAID)
France
—Rhone Poulenc
—Engaged in US-operations 1929
Europe
—Aureomycin (Lederle) ; Chloromycetin (Parke-Davis) ; Teramycin (Pfizer) ; 1950
USA
France and Belgian
—Chlorpromazine [Rhone-Poulenc (France)] ; Haloperidol [Janssen (Belgium)]—both psychotropic drugs
1950s
—Pharmaceutical Industry showed a steady to
—Greater advancement on molecular focus in the regimen of ‘drug discovery’ picked up substantial momentum with the strategic induction of noted scientists in the US National Academy of Sciences, namely : Needleman P (Monsanto) ; Cuatrecasas P (Burroughs Wellcome) ; and Vagelos PR (Merck).
*Sneader WJ, ‘Drug Discovery : The Evolution of Modern Medicines,’ John Wiley, Chichester, UK, 1997.
** Di Masi, d J et al. Research and Development costs for new drugs for therapeutic category, Pharmaco.Econ., 7 : 52, 169, 1995. ***Drayer JI and Burns JP. From discovery to market : the development of pharmaceuticals. In : Wolff ME, ed, Burgers Medicinal Chemistry and Drug Discovery, 5th edn, Vol I, Wiley, New York, 1995, pp 251-300.
DRUG DESIGN—A RATIONAL APPROACH
13 HAPTER The various phases of transformations in ‘ethical pharmaceutical industry’ between 1600 to
1970s brought about a sea-change with a significant shift from the core techniques of molecular phar-
macology and biochemistry to those of molecular biology and genomics (biotechnology). Based upon these fundamental newer concepts amalgamated with various paradigm shifts resulted into the evolution of an exclusive progressive change in the scenario of both culture and the environment of the ‘ethical pharmaceutical industry’ in developed as well as developing countries in the world.
7.2. Revolutions in Drug Discovery
A tremendous noticeable change in the ‘process of drug discovery’ in the past three decades has been focused solely on the ‘biotechnology revolution’. In short, the techniques employed invariably in ‘molecular biology’ and ‘biotechnology’ opened up an altogether ‘new trend in biomedical research’.
In 1997, a staggering 1150 companies were established based on ‘biotechnology’, engaging three lacs research scientists working round-the-clock, and generated USD 12 billion. The six major biotech companies in USA, established in mid 1980s, now proudly enjoys the number one status not only in US but also in rest of the world, namely :
(a) Genentech—Presently subsidiaries of Roche Biosciences ; (b) Genetics Institute—Presently subsidiaries of American Home Products, (c) Amgen ; Genzyme ; Chiron and Biogen—Presently emerged as major pharmaceutical
companies.
In the light of the huge accelerated costs for drug development, touching USD 359 million in 1991, to almost USD 627 million in 1995 and a projected USD 1.36 billion in 2000, have virtually pumped in lots of force geared towards superb efficacies and efficiencies in the pharmaceutical indus- try.* And this could only be accomplished through appreciable consolidation amalgamated with contin- ued efforts of outsourcing of higher risk, early drug discovery to venture capital-aided-biotech units ; besides, clinical trials to the clinical-research organizations exclusively.
In order to significantly cut down the overhead expenses, and encash on sizable profitability various giants in the pharmaceutical industry have more or less adopted the following stringent meas- ures to face the cut-throat competition in the global market and also survive gainfully, such as :
(a) To enhance the required productivity in the R and D activities of major pharmaceutical companies to sustain and maintain profitability,
(b) Increased productivity without enhancing R and D resources, (c) Focusing on new research activities/strategies thereby creating a possible balance between
internal research and external alliances, (d) Merger and alliances in Pharmaceutical Industries dates back to 1970s with the formation
of Ciba-Geigy** ; and till 2000 more than 20 such acquisitions/mergers have already been materialized across the globe.
*Carr G : The Alchemists : A survey of the Pharmaceutical Industry, Economist, February 21, 1998, pp 3-18.
** de Stevens G., Conflicts and Resolutions., Med. Res Rev., 1995, 15, pp 261-275.
MEDICINAL CHEMISTRY
7.3. Research and Development Strategies
It has been proved beyond any reasonable doubt that the ‘rate of success’ in drug discovery is exclusively dependent on the ability to identify, characterize novel, patentable newer ‘target-drug- molecules’ usually termed as New Chemical Entities (NCEs), which essentially possess the inherent