Bioactive Carboxylic Compound Classes

Bioactive Carboxylic Compound Classes


Author:
Clemens Lamberth & Jürgen Dinges
Published in: Wiley-VCH
Release Year: 2016
ISBN: 978-3-527-69396-2
Pages: 529
Edition: First Edition
File Size: 13 MB
File Type: pdf
Language: English



Description of Bioactive Carboxylic Compound Classes


Three years ago, shortly after the publication of our first book “Bioactive Heterocyclic Compound Classes,” we had been contacted by several readers, but also contributors, who praised the concept of combining all important heterocyclic active ingredient classes with short, educational, similarly structured chapters within one book. This positive feedback encouraged us to apply the same concept also to the second major group of functional groups, which play an important role in pharmaceuticals and agrochemicals. These are, besides the already covered heterocycles, the derivatives of carboxylic acids, which means not only the acids themselves but also their esters, amides, ureas, carbamates, hydrazides, thioesters, and so on. According to our definition, such a carboxylic compound class is made up of three or more commercialized active ingredients that 
(i) bear the same carboxyl functionality, means acyclic C==O functions except for aldehydes and ketones; (ii) possess the same or at least a similar scaffold and a similar substitution pattern;
and 
(iii) have the same mode of action. To be able to cover the most important carboxylic active ingredient families in medicine and crop protection within one book, we had to focus. Therefore, we declared the following functional groups or compound classes to be “out of scope”: 
(i) all functional groups based on a C==S motif; 
(ii) cyclic carboxylic compounds with a C==O group (lactones, lactams,
diketopiperazines), as they have been covered already in “Bioactive Heterocyclic Compound Classes”; 
(iii) sulfonic acid derivatives with an SO2 function; and
(iv) peptides and macrocycles.
As it was already the case for “Bioactive Heterocyclic Compound Classes,” also the chapters of this book are divided into the same five sections:
(i) introduction,
(ii) history, 
(iii) synthesis,
(iv) mode of action, and 
(v) structure-activity relation-
ship. Only the agrochemical chapters possess an additional section “biological activity” to describe the target spectrum of the active ingredients. 
We are very grateful to the authors of the 36 chapters of this book, all of them expert in their field and several of them already contributing to “Bioactive Heterocyclic Compound Classes,” for spending their scarce time summarizing the historical background, typical chemical syntheses, biochemical modes of action, biological activities, and structure-activity relationships of their area of interest.

Content of Bioactive Carboxylic Compound Classes



1 Different Roles of Carboxylic Functions in Pharmaceuticals and
Agrochemicals 1
Clemens Lamberth and Jürgen Dinges
1.1 Introduction 1
1.2 Solubilizer 1
1.3 Pharmacophore 3
1.4 Prodrug 4
1.5 Bioisosteric Replacement 6
1.6 Scaffold 8
1.7 Conclusion 9
References 9
Part I Neurology 13
2 Carboxylic Ester Containing Norepinephrine–Dopamine Reuptake
Inhibitors (NDRIs) 15
David J. O’Neill
2.1 Introduction 15
2.2 History 15
2.3 Synthesis 17
2.4 Mode of Action 21
2.5 Structure-Activity Relationships 22
References 25
3 Analgesic and Anesthetic Amides 27
Thomas Erhard
3.1 Introduction 27
3.2 History 27
3.3 Synthesis 30

3.4 Mode of Action 33
3.5 Structure-Activity Relationships 34
References 37
Part II Cardiovascular Diseases 39
4 Fibrate Acids and Esters for the Treatment of Hyperlipidemia
(PPARα Activators) 41
Gavin O’Mahony
4.1 Introduction 41
4.2 History 42
4.3 Synthesis 45
4.4 Mode of Action 48
4.5 Structure-Activity Relationships 50
References 54
5 Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the
Reduction of Thrombotic Cardiovascular Events 57
Modesto de Candia, Nunzio Denora, and Cosimo D. Altomare
5.1 Introduction 57
5.2 History 57
5.3 Synthesis 60
5.4 Mode of Action 62
5.5 Structure-Activity Relationships 67
References 70
6 Carboxylic Acids and Lactones as HMG-CoA Reductase
Inhibitors 71
Xiang-Yang Ye and Pratik Devasthale
6.1 Introduction 71
6.2 History 72
6.3 Synthesis 73
6.4 Mode of Action 80
6.5 Structure-Activity Relationship 81
References 83
7 Angiotensin II Receptor Antagonists with Carboxylic Functionalities in
Cardiovascular Disease 87
Steve Swann and Simone Bigi
7.1 Introduction 87
7.2 History 89
7.3 Synthesis 90
7.4 Mode of Action 95

7.5 Structure-Activity Relationships 96
References 99
8 Carboxylic Acid Containing Direct Thrombin Inhibitors for the
Treatment of Thromboembolic Diseases 103
Harry R. Chobanian and Mathew M. Yanik
8.1 Introduction 103
8.2 History 104
8.3 Synthesis 106
8.4 Mode of Action 108
8.5 Structure-Activity Relationship 109
References 113
Part III Infectious Diseases 115
9 Tetracycline Amide Antibiotics 117
Ingo Janser
9.1 Introduction 117
9.2 History 120
9.2.1 First-Generation Tetracyclines – The Discovery 120
9.2.2 Second-Generation Semisynthetic Tetracyclines 121
9.2.3 Tetracycline Resistance 122
9.2.4 Third-Generation Tetracyclines 123
9.3 Synthesis 123
9.4 Mode of Action 127
9.5 Structure-Activity Relationships 128
References 130
10 Carboxylic-Acid-Based Neuraminidase Inhibitors 133
Stacy Van Epps
10.1 Introduction 133
10.2 History 133
10.3 Synthesis 136
10.4 Mode of Action 142
10.5 Structure-Activity Relationships 143
References 146
11 Oxazolidinone Amide Antibiotics 149
Cristiana A. Zaharia, Saverio Cellamare, and Cosimo D. Altomare
11.1 Introduction 149
11.2 History 150
11.3 Synthesis 153
11.4 Mechanism of Action 156
11.5 Structure-Activity Relationships 162
References 164

12 Sovaldi, an NS5B RNA Polymerase-Inhibiting Carboxylic Acid Ester
Used for the Treatment of Hepatitis C Infection 167
Alastair Donald
12.1 Introduction 167
12.2 History 168
12.3 Synthesis 170
12.4 Mode of Action 172
12.5 Structure-Activity Relationships 173
References 174
Part IV Metabolic Diseases 177
13 Dipeptidyl Peptidase-4 (DPP-4)-Inhibiting Amides for the Treatment of
Diabetes 179
Naomi S. Rajapaksa and Xiaodong Lin
13.1 Introduction 179
13.2 History 179
13.3 Synthesis 184
13.4 Mode of Action 187
13.5 Structure-Activity Relationships 188
References 193
Part V Oncology 197
14 Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton’s Tyrosine
Kinase 199
Timothy D. Owens
14.1 Introduction 199
14.2 History 199
14.3 Synthesis 201
14.4 Mechanism of Action 202
14.5 Structure-Activity Relationships 203
References 207
Part VI Anti-Inflammatory Drugs 209
15 Fumaric Acid Esters 211
Tony S. Gibson
15.1 Introduction 211
15.2 History 211
15.3 Synthesis 213
15.4 Mode of Action 213
15.5 Structure-Activity Relationships 215
References 218
16 Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 221
Yan Lou and Jiang Zhu
16.1 Introduction 221
16.2 History 222
16.3 Synthesis 224
16.4 Mode of Action 228
16.5 Structure-Activity Relationships 230
References 234
17 Carboxylic-Acid-Containing Antihistamines 237
Irini Akritopoulou-Zanze
17.1 Introduction 237
17.2 History 237
17.3 Synthesis 239
17.4 Mode of Action 241
17.5 Structure-Activity Relationship 241
References 243
18 Corticosteroid Carboxylic Acid Esters 245
Maurizio Franzini
18.1 Introduction 245
18.2 History 249
18.3 Synthesis 252
18.4 Mode of Action 258
18.5 Structure-Activity Relationships 261
References 264
Part VII Ophthalmology 269
19 Prostaglandins with Carboxylic Functionalities for the Treatment of
Glaucoma 271
Fabrizio Carta and Claudiu T. Supuran
19.1 Introduction 271
19.2 History 271
19.3 Synthesis 272
19.4 Mode of Action 276
19.5 Structure-Activity–Relationship (SAR) 278
References 279
Part VIII Weed Control 281
20 Herbicidal Carboxylic Acids as Synthetic Auxins 283
Paul Schmitzer, Jeffrey Epp, Roger Gast, William Lo, and Jeff Nelson
20.1 Introduction 283
20.2 History 283

20.3 Synthesis 286
20.4 Mode of Action 289
20.5 Biological Activity 289
References 291
21 Chloroacetamide Herbicides 293
Clemens Lamberth
21.1 Introduction 293
21.2 History 293
21.3 Synthesis 296
21.4 Mode of Action 297
21.5 Biological Activity 299
21.6 Structure–Activity Relationship 300
References 302
22 Carboxylic-Acid-Containing Sulfonylurea Herbicides 303
Atul Puri and Paul H. Liang
22.1 Introduction 303
22.2 History 303
22.3 Synthesis 305
22.4 Mode of Action 306
22.5 Biological Activity 308
22.6 Structure–Activity Relationship 309
References 312
23 Amino Acids as Nonselective Herbicides 315
Stephane Jeanmart
23.1 Introduction 315
23.2 History 316
23.3 Synthesis 317
23.4 Mode of Action 319
23.5 Biological Activity 320
23.6 Structure–Activity Relationships 321
References 323
24 Herbicidal Aryloxyphenoxypropionate Inhibitors of Acetyl-CoA
Carboxylase 325
William G. Whittingham
24.1 Introduction 325
24.2 History 325
24.3 Synthesis 327
24.4 Mode of Action 329
24.5 Biological Activity 330
24.6 Structure–Activity Relationships 331
References 334

25 Pyridines Substituted by an Imidazolinone and a Carboxylic Acid as
Acetohydroxyacid-Synthase-Inhibiting Herbicides 339
Dale Shaner
25.1 Introduction 339
25.2 History 339
25.3 Synthesis 341
25.4 Mode of Action 342
25.5 Biological Activity 342
25.6 Structure–Activity Relationship 344
References 345
26 Carboxylic-Acid-Containing
Protoporphyrinogen-IX-Oxidase-Inhibiting Herbicides 347
George Theodoridis
26.1 Introduction 347
26.2 History 347
26.2.1 Carboxylic Acid Functional Group Directly Attached to Aromatic
Ring of Protox Herbicide 349
26.2.2 Carboxylic Acid Functional Group Present but Not Directly Attached
to Aromatic Ring of Protox Herbicide 350
26.3 Synthesis 350
26.4 Mode of Action 351
26.5 Biological Activity 352
26.6 Structure–Activity Relationship 352
References 354
Part IX Disease Control 357
27 Phenylamide Fungicides 359
Laura Quaranta
27.1 Introduction 359
27.2 History 359
27.3 Synthesis 362
27.4 Mode of Action 364
27.5 Biological Activity 365
27.6 Structure–Activity Relationship 365
References 367
28 Complex III Inhibiting Strobilurin Esters, Amides, and Carbamates as
Broad-Spectrum Fungicides 371
Clemens Lamberth
28.1 Introduction 371
28.2 History 371
28.3 Synthesis 375
28.4 Mode of Action 379

28.5 Biological Activity 380
28.6 Structure–Activity Relationship 381
References 383
29 Scytalone-Dehydratase-Inhibiting Carboxamides for the Control of
Rice Blast 385
Andrew E. Taggi
29.1 Introduction 385
29.2 History 385
29.3 Synthesis 389
29.4 Mode of Action 390
29.5 Biological Activity 391
29.6 Structure–Activity Relationships 392
References 392
30 Carboxylic Acid Amide Fungicides for the Control of Downy Mildew
Diseases 395
Clemens Lamberth
30.1 Introduction 395
30.2 History 395
30.3 Synthesis 397
30.4 Mode of Action 399
30.5 Biological Activity 400
30.6 Structure–Activity Relationship 400
References 403
31 Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides 405
Harald Walter
31.1 Introduction 405
31.2 History 406
31.3 Synthesis 409
31.4 Mode of Action and Importance of Respiration Inhibitors 415
31.5 Biological Activity and Market Impact 416
31.5.1 The Foliar SDHI Carboxamides 416
31.5.2 The Seed Treatment SDHI Carboxamides 417
31.6 Structure–Activity Relationships 418
31.6.1 General Structure-Activity Relationship Considerations of the
Pyrazole Carboxamide Class IV 418
31.6.2 Replacement of the Pyrazole Ring by Phenyl or Pyridyl 420
31.6.3 Replacement of the Pyrazole Ring by Other Five-Membered
Heterocycles 420
31.6.4 Carboxamides not derived from Aromatic Amines 421
Acknowledgments 422
References 422

Part X Insect Control 427
32 Esters and Carbamates as Insecticidal Juvenile Hormone Mimics 429
Sebastian Rendler
32.1 Introduction 429
32.2 History 429
32.3 Synthesis 431
32.4 Mode of Action 433
32.5 Biological Activity 434
32.6 Structure–Activity Relationship 434
References 437
33 N-Benzoyl-N′

-Phenyl Ureas as Insecticides, Acaricides, and

Termiticides 439
Peter Jeschke
33.1 Introduction 439
33.2 History 439
33.3 Synthesis 442
33.4 Mode of Action 445
33.5 Biological Activity 446
33.6 Structure–Activity Relationship 448
References 451
34 Pyrethroid Esters for the Control of Insect Pests 453
Régis Mondière and Fides Benfatti
34.1 Introduction 453
34.2 History 454
34.3 Synthesis 457
34.4 Mode of Action 459
34.5 Biological Activity 461
34.6 Structure–Activity Relationship 462
References 465
35 Ecdysone Receptor Agonistic Dibenzoyl Hydrazine Insecticides 467
Ottmar F. Hüter
35.1 Introduction 467
35.2 History 467
35.3 Synthesis 468
35.4 Mode of Action 471
35.5 Biological Activity 473
35.6 Structure–Activity Relationship 473
References 476

36 Diamide Insecticides as Ryanodine Receptor Activators 479
André Jeanguenat
36.1 Introduction 479
36.2 History 479
36.3 Synthesis 481
36.4 Mode of Action 485
36.5 Biological Activity 485
36.6 Structure–Activity Relationship 486
References 489
Index 491
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