Privileged Structures in Drug Discovery E-Book

Larry Yet

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1218

Veröffentlichungsjahr: 2018

Beschreibung

A comprehensive guide to privileged structures and their application in the discovery of new drugs 

The use of privileged structures is a viable strategy in the discovery of new medicines at the lead optimization stages of the drug discovery process.  Privileged Structures in Drug Discovery offers a comprehensive text that reviews privileged structures from the point of view of medicinal chemistry and contains the synthetic routes to these structures. In this text, the author—a noted expert in the field—includes an historical perspective on the topic, presents a practical compendium to privileged structures, and offers an informed perspective on the future direction for the field.

The book describes the up-to-date and state-of-the-art methods of organic synthesis that describe the use of privileged structures that are of most interest. Chapters included information on benzodiazepines, 1,4-dihydropyridines, biaryls, 4-(hetero)arylpiperidines, spiropiperidines, 2-aminopyrimidines, 2-aminothiazoles, 2-(hetero)arylindoles, tetrahydroisoquinolines,  2,2-dimethylbenzopyrans, hydroxamates, and bicyclic pyridines containing ring-junction nitrogen as privileged scaffolds in medicinal chemistry. Numerous, illustrative case studies document the current use of the privileged structures in the discovery of drugs. This important volume:

• Describes the drug compounds that have successfully made it to the marketplace and the chemistry associated with them
• Offers the experience from an author who has worked in many therapeutic areas of medicinal chemistry
• Details many of the recent developments in organic chemistry that prepare target molecules
• Includes a wealth of medicinal chemistry case studies that clearly illustrate the use of privileged structures

Designed for use by industrial medicinal chemists and process chemists, academic organic and medicinal chemists, as well as chemistry students and faculty, Privileged Structures in Drug Discovery offers a current guide to organic synthesis methods to access the privileged structures of interest, and contains medicinal chemistry case studies that document their application.

Leseprobe

Privileged Structures in Drug Discovery

Medicinal Chemistry and Synthesis

Larry Yet

Department of Chemistry,University of South AlabamaMobile, AL, USA

This edition first published 2018© 2018 John Wiley & Sons, Inc.

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Library of Congress Cataloging‐in‐Publication Data

Names: Yet, Larry, author.Title: Privileged structures in drug discovery : medicinal chemistry and synthesis / Dr. Larry Yet, University of South Alabama, USA.Description: Edition 1. | Hoboken, NJ : Wiley, 2018. | Includes bibliographical references and index. |Identifiers: LCCN 2017047741 (print) | LCCN 2017058921 (ebook) | ISBN 9781118686355 (pdf) | ISBN 9781118686331 (epub) | ISBN 9781118145661 (cloth)Subjects: LCSH: Pharmaceutical chemistry. | Drug development–Methodology.Classification: LCC RS403 (ebook) | LCC RS403 .Y48 2018 (print) | DDC 615.1/9–dc23LC record available at https://lccn.loc.gov/2017047741

Cover Design: WileyCover Image: © MirageC/Gettyimages

1Introduction

1.1 The Original Definition of Privileged Structures

In 1988, Ben Evans and his research team at Merck in their quest for potent, selective, orally effective cholecystokinin (CCK) antagonists studied the prototype 3‐(acylamino)‐5‐phenyl‐2H‐1,4‐benzodiazepines as therapeutic agents derived from the natural product lead asperlicin [1]. Evans recognized the core structure exhibited affinity toward central and peripheral benzodiazepine, opiate, CCK‐A, α‐adrenergic, serotonin, muscarinic, and angiotensin I receptors. To quote verbatim from the words of Ben Evans in this seminal publication, which set in force the term “privileged structures” for the next three decades in two different paragraphs:

Thus, this single ring system, the 5‐phenyl‐1,4‐benzodiazepine ring, provided ligands for a surprisingly diverse collection of receptors, the natural ligands for which appear to bear little resemblance to one another or to the benzodiazepines in question. The only obvious similarity is among the benzodiazepine structures themselves. These structures appear to contain common features which facilitate binding to various proteinaceous receptor surfaces, perhaps through binding elements different from those employed for binding of the natural ligands.

Arguments have been constructed to suggest that structures with high affinity for a given receptor may be more numerous, but at the same time more difficult to pinpoint than has heretofore been appreciated. The development of the compounds described here has illustrated an approach to that end having potentially wider utility, selective modification of “privileged structures” known to have provided ligands for diverse receptors in the past.

IUPAC has provided a structural definition of privileged structures—“Substructural feature which confers desirable (often drug‐like) properties on compounds containing that feature. Often consists of a semi‐rigid scaffold which is able to present multiple hydrophobic residues without undergoing hydrophobic collapse” [2].

1.2 The Role of Privileged Structures in the Drug Discovery Process

There are many steps in the drug discovery process to deliver a drug from initial chemical hits, lead optimization, chemical development and scale‐ups, clinical trials, and FDA approvals to the market. Nowadays, it takes an average of 12–15 years and almost 800 million to 1 billion dollars of investment to deliver a single therapeutic drug to the market [3]. The lead optimization strategies are key steps for the medicinal chemists, and for this to occur, chemical hits for specific targets need to be validated. There are many strategies that have been employed in the search for chemical hits such as high‐throughput screening of corporate compound libraries [4–6], virtual screening [7–10], and natural products as sources of new drugs [11–13]. Once the chemical hits are discovered, “medicinal chemistry” tools such as fragment‐based drug design [14, 15], analogue‐based drug design [16–18], Lipinski’s Rule of Five [19], bioisosteric replacements [20–22], “repurposing” old drugs [23–25], computer‐aided drug design (CADD) [7, 26–29], scaffold hopping [30, 31], selective optimization of side activities (SOSA approach) [32], and early ADME pharmacokinetic analyses [33, 34] are employed in the lead optimization stages of the drug discovery process.

The use of privileged structures is a viable strategy in the discovery of new medicines at the lead optimization stages of the drug discovery process. There are several published reviews which find that “privileged structures” are useful concepts for the rational design of new lead drug candidates [35–40]. These “privileged structures” tend to provide highly favorable characteristics in which alterations to the core structures lead to different levels of potency and specificity. Using these privileged structures as starting points for drug discovery, thousands of molecules can be synthesized for a range of therapeutic biological targets of interest. Furthermore, privileged structures typically exhibit drug‐like properties, which could lead to viable leads for further development. One must be careful and thoughtful in the drug discovery process that sometimes there are no true explanations why certain structures are privileged or why they are active against a particular group of targets. Though numerous repeated frameworks appear in biologically active molecules, no clear explanations exist for their privileged nature.

1.3 The Loose Definitions of “Privileged Structures”

Since the original definition of “privileged structures” coined by Evans in 1988, the definition has gone through several reiterations [39]. Privileged structures are liberally referred nowadays in many different terms such as privileged scaffolds, chemotypes, molecular fragments, privileged structural motifs, and molecular scaffolds. There are no rigorous rules that define a structure as “privileged,” but typically they contain two or three ring systems that are connected by single bonds or by ring‐fusion. The structures that results from such arrangements are usually rigid frameworks that can show the appended functionality in a well‐defined fashion that is desirable for molecular recognition of the biological target, and it is usually the variable nature of these functionalities that define the selectivity on a privileged core for a particular target.

1.4 Synthesis and Biological Activities of Carbocyclic and Heterocyclic Privileged Structures

Stockwell assembled one of the most comprehensive listings of privileged scaffolds in tabular forms [38]. We also provide a detailed tabular presentation of the privileged scaffolds based on ring size and fused‐ring classifications. The series of tables are based on structures, the titles of the review article, and the reference numbers in each table under the appropriate listings. We hope it will be a useful source of inspiration for the drug discovery community of organic and medicinal chemists.

1.4.1 Synthesis and Biological Activities of Three‐ and Four‐Membered Ring Privileged Structures

There are only a few reviews published on the three‐ and four‐membered ring privileged structures and they are listed in Table 1.1.

Table 1.1 List of three‐ and four‐membered ring privileged structures reviews.

Structure

Number

Review title

Reference

Phenylcyclopropylamines

1

An overview of phenylcyclopropylamine derivatives: Biochemical and biological significance and recent developments

[41]

Aziridines

2

Synthetic aziridines in medicinal chemistry: A mini‐review

[42]

Oxetanes

3

Oxetanes: Recent advances in synthesis, reactivity, and medicinal chemistry

[43]

Oxetanes

3

Oxetanes as versatile elements in drug discovery and synthesis

[44]

1.4.2 Synthesis and Biological Activities of Five‐Membered Ring Privileged Structures

Numerous reviews on the synthesis and biological activities of five‐membered ring privileged structures are outlined in Table 1.2.

Table 1.2 List of five‐membered ring privileged structures reviews.

Structure

Number

Review title

Reference

Pyrroles

4

Pyrrole: An emerging scaffold for construction of valuable therapeutic agents

[45]

Pyrazolines

5

Synthesis and biological activity of chiral dihydropyrazole: Potential lead for drug design

[46]

Pyrazolines

5

Pyrazolines: A biological review

[47]

Pyrazoles

6

Recent advances in bioactive pyrazoles

[48]

Pyrazoles

6

The therapeutic voyage of pyrazole and its analogs: A review

[49]

Pyrazoles

6

Pyrazoles as promising scaffold for the synthesis of anti‐inflammatory and/or antimicrobial agents: A review

[50]

Pyrazoles

6

Pyrazole derivatives as antitumor, anti‐inflammatory and antibacterial agents

[51]

Pyrazoles

6

Recent progress on pyrazole scaffold‐based antimycobacterial agents

[52]

2‐Imidazolines

7

Biologically active compounds based on the privileged 2‐imidazoline scaffold: The world beyond adrenergic/imidazoline receptor modulators

[53]

Imidazoles

8

Imidazoles as promising scaffolds for antibacterial activity: A review

[54]

Imidazoles

8

Imidazoles as potential antifungal agents: A review

[55]

Imidazoles

8

Comprehensive review in current developments of imidazole‐based medicinal chemistry

[56]

2‐Aminoimidazoles

9

2‐Aminoimidazoles in medicinal chemistry

[57]

1,2,3‐Triazoles

10

Click chemistry for drug development and diverse chemical‐biology applications

[58]

1,2,3‐Triazoles

10

1,2,3‐Triazole in heterocyclic chemistry, endowed with biological activity, through 1,3‐dipolar cycloadditions

[59]

1,2,3‐Triazoles

10

In situ

click chemistry: probing the binding landscapes of biological molecules

[60]

Tetrazoles

11

Potential pharmacological activities of tetrazoles in the new millennium

[61]

Tetrazoles

11

5‐Substituted‐1

H

‐tetrazoles as carboxylic acid isosteres: Medicinal chemistry and synthetic methods

[62]

Tetrazoles

11

Tetrazole as a core unit biological evaluation agent

[63]

Isoxazolidines

12

Isozazolidine: A privileged scaffold for organic and medicinal chemistry

[64]

Isoxazole

13

The isoxazole ring and its

N

‐oxide: A privileged core structure in neuropsychiatric therapeutics

[65]

Thiazoles

14

Recent applications of 1,3‐thiazole core structures in the identification of new lead compounds and drug discovery

[66]

Thiazoles

14

Bioactive thiazole and benzothiazole derivatives

[67]

Oxadiazoles

15, 16

Recent updates on biological activities of oxadiazoles

[68]

Oxadiazoles

15, 16

Synthesis and biological activities of oxadiazole derivatives: A review

[69]

1,2,4‐Oxadiazoles

15

[1,2,4]‐Oxadiazoles: Synthesis and biological applications

[70]

1,3,4‐Oxadiazoles

16

1,3,4‐Oxiadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents

[71]

1,3,4‐Oxadiazoles

16

1,3,4‐Oxadiazole: A privileged structure in antiviral agents

[72]

1,3,4‐Oxadiazoles

16

1,3,4‐Oxadiazole: A biologically active scaffold

[73]

1,3,4‐Oxadiazoles

16

1,3,4‐Oxadiazole derivatives as potential biological agents

[74]

1,3,4‐Oxadiazoles

16

Oxadiazoles as privileged motifs for promising anticancer leads: Recent advances and future prospects

[75]

1,3,4‐Thiadiazoles

17

Biological and pharmacological activities of 1,3,4‐thiadiazole based compounds

[76]

1,3,4‐Thiadiazoles

17

Thiadiazole–a promising structure in medicinal chemistry

[77]

2,4‐Thiazolidinediones

18

Therapeutic journey of 2,4‐thiazolidinediones as a versatile scaffold: An insight into structure–activity relationship

[78]

Cyclopentenediones

19

Chemical properties and biological activities of cyclopentenediones

[79]

1.4.3 Synthesis and Biological Activities of Six‐Membered Ring Privileged Structures

Plenty of reviews are available for the synthesis and biological activities of six‐membered ring privileged structures listed in Table 1.3.

Table 1.3 List of six‐membered ring privileged structures reviews.

Structure

Number

Review title

Reference

Chalcones

20

Anti‐cancer chalcones: Structural and molecular target perspectives

[80]

Chalcones

20

Exploring pharmacological significance of chalcone scaffold: A review

[81]

Chalcones

20

Chalcone: A privileged structure in medicinal chemistry

[82]

Benzoquinones

21

Perspectives on medicinal properties of benzoquinone compounds

[83]

1,4‐Dihydropyridines

22

1,4‐Dihydropyridines: A class of pharmacologically important molecules

[84]

1,4‐Dihydropyridines

22

1,4‐Dihydropyridines as calcium channel ligands and privileged structures

[85]

1,4‐Dihydropyridines

22

Dihydropyridines: Evaluation of their current and future pharmacological applications

[86]

Piperidin‐4‐ones

23

Piperidin‐4‐one: The potential pharmacophore

[87]

Piperazines

24

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

[88]

Piperazines

24

An evolving role of piperazine moieties in drug design and discovery

[89]

Dihydropyrimidinones

25

Recent advances in the pharmacology of dihydropyrimidinones

[90]

Dihydropyrimidinones

25

Recent synthetic and medicinal perspectives of dihydropyrimidinones: A review

[91]

2,5‐Diketopiperazines

26

2,5‐Diketopiperazines as neuroprotective agents

[92]

Pyridazinones

27

The therapeutic journey of pyridazinone

[93]

Uracils

28

In search of uracil derivatives as bioactive agents. Uracils and fused uracils: Synthesis, biological activity and applications

[94]

Pyrazines

29

Unequivocal role of pyrazine ring in medicinally important compounds: A review

[95]

1,2,3‐Triazines

30

1,2,3‐Triazine scaffold as a potent biologically active moiety: A mini‐review

[96]

1,2,3‐Triazines

30

Triazine as a promising scaffold for its versatile biological behavior

[97]

1,2,4‐Triazines

31

1,2,4‐Triazine analogs as novel class of therapeutic agents

[98]

1,3,5‐Triazines

32

Medicinal chemistry discoveries among 1,3,5‐triazines: recent advances (2000–2013) as antimicrobial, anti‐TB and antimalarials

[99]

1,3,5‐Triazines

32

1,3,5‐Triazine‐based analogues of purines: From isosteres to privileged scaffolds in medicinal chemistry

[100]

1.4.4 Synthesis and Biological Activities of Bicyclic 5/5 and 6/5 Ring Privileged Structures

There is no shortage of synthesis and biological activities of bicyclic 5/5 and 6/5 ring privileged structures reviews listed in Table 1.4.

Table 1.4 List of bicyclic 5/5 and 6/5 ring privileged structures reviews.

Structure

Number

Review title

Reference

Pyrrolizines

33

An integrated overview on pyrrolizines as potential anti‐inflammatory, analgesic and antipyretic agents

[101]

Pyrroloisoxazoles

34

Pyrroloisoxazole: A key molecule with diverse biological actions

[102]

Indoles

35

From nature to drug discovery: The indole scaffold as a “privileged structure”

[103]

Indoles

35

Indoles as therapeutics of interest in medicinal chemistry: Bird’s eye view

[104]

Indoles/indazoles

35/40

Chemistry and biology of indoles and indazoles

[105]

3‐Acetylindoles

36

3‐Acetylindoles: Synthesis, reactions and biological activities

[106]

Oxindoles

37

Oxindole: A chemical prism carrying plethora of therapeutic benefits

[107]

Oxindoles

37

Indolinones as promising scaffold as kinase inhibitors

[108]

Spirooxindoles

38

Spiroxoindoles: Promising scaffolds for anticancer agents

[109]

Phthalimides

39

Recent advances in the chemistry of phthalimide analogues and their therapeutic potential

[110]

Benzimidazoles

41

Comprehensive review in current developments of benzimidazole‐based medicinal chemistry

[111]

Benzimidazoles

41

Functionalized benzimidazole scaffolds: Privileged heterocycle for drug design in therapeutic medicine

[112]

Benzimidazoles

41

Benzimidazoles: An ideal privileged drug scaffold for the design of multitargeted anti‐inflammatory ligands

[113]

Imidazo[1,2‐

a

]pyridines

42

Recent progress in the pharmacology of imidazo[1,2‐

a

]pyridines

[114]

Imidazo[1,2‐

a

]pyridines

42

Imidazo[1,2‐

a

]pyridine scaffold as prospective therapeutic agents

[115]

Benzotriazoles

43

Benzotriazole: An overview on its versatile biological behavior

[116]

Benzofurans

44

Bioactive benzofuran derivatives: An insight on lead developments, radioligands and advances of the last decade

[117]

Benzofurans

44

Bioactive benzofuran derivates: A review

[118]

Benzofurans

44

Biological and medicinal significance of benzofuran

[119]

Benzoxazoles

45

Recent advances in the development of pharmacologically active compounds that contain a benzoxazole scaffold

[120]

Benzoxazoles

45

Benzoxazoles and oxazolopyridines in medicinal chemistry studies

[121]

2(3

H

)‐Benzoxazolones

46

2(3

H

)‐Benzoxazolone and bioisosteres as “privileged scaffold” in the design of pharmacological probes

[122]

Benzothiazoles

47

Recent advances in the chemistry and biology of benzothiazoles

[123]

2‐Arylbenzothiazoles

48

2‐Arylbenzothiazole as a privileged scaffold in drug discovery

[124]

Pyrazolo[1,5‐

a

]pyrimidines

49

An insight on synthetic and medicinal aspects of pyrazolo[1,5‐

a

]pyrimidine scaffold

[125]

Pyrazolo[3,4‐

d

]pyrimidines

50

4‐Amino‐substituted pyrazolo[4,3‐

d

]pyrimidines: Synthesis and biological properties

[126]

Pyrazolo[3,4‐

d

]pyrimidines

50

Biologically driven synthesis of pyrazolo[3,4‐

d

]pyrimidines as protein kinase inhibitors: An old scaffold as a new tool for medicinal chemistry and chemical biology studies

[127]

8‐Azapurines

51

8‐Azapurine nucleus: A versatile scaffold for different targets

[128]

Thalidomides

52

Thialidomide as a multi‐template for development of biologically active compounds

[129]

Thiazolo[4,5‐

d

]pyrimidines

53

Thiazolo[4,5‐

d

]pyrimidines as a privileged scaffold in drug discovery

[130]

Thieno[2,3‐

d

]pyrimidin‐4‐ones

54

Recent developments regarding the use of thieno[2,3‐

d

]pyrimidin‐4‐one derivatives in medicinal chemistry, with a focus on their synthesis and anticancer properties

[131]

Tetrahydrothieno‐pyridines

55

Synthesis and biological activity of substituted‐4,5,6,7‐tetrahydrothienopyridines: A review

[132]

1.4.5 Synthesis and Biological Activities of Bicyclic 6/6 and 6/7 Ring Privileged Structures

Again, there is no shortage of synthesis and biological activities of the popular bicyclic 6/6 ring privileged structures reviews listed in Table 1.5.

Table 1.5 List of bicyclic 6/6 and 6/7 ring privileged structures reviews.

Structure

Number

Review title

Reference

Coumarins

56

Biological importance of structurally diversified chromenes

[133]

Coumarins

56

Current developments of coumarin‐based anti‐cancer agents in medicinal chemistry

[134]

Coumarins

56

Coumarin: A privileged scaffold for the design and development of antineurodegenerative agents

[135]

Coumarins

56

Benzocoumarins: Isolation, synthesis, and biological activities

[136]

Isocoumarins

57

Isocoumarins, miraculous natural products blessed with diverse pharmacological activities

[137]

Chromones

58

Chromone: A valid scaffold in medicinal chemistry

[138]

Chroman‐4‐ones

59

Recent advances of chroman‐4‐one derivatives: Synthetic approaches and bioactivities

[139]

2‐Styrylchromones

60

Biological activities of 2‐styrylchromones

[140]

2‐Styrylchromones

60

An overview of 2‐styrylchromones: Natural occurrence, synthesis, reactivity and biological properties

[141]

Quinolines

61

The concept of privileged structures in rational drug design: Focus on acridine and quinoline scaffolds in neurodegenerative and protozoan diseases

[142]

Quinolines

61

Biological activities of quinoline derivatives

[143]

Quinolines

61

Quinoline as a privileged scaffold in cancer drug discovery

[144]

Quinolines

61

A review on anticancer potential of bioactive heterocycle quinolone

[145]

8‐Hydroxyquinolines

62

8‐Hydroxyquinolines in medicinal chemistry: A structural perspective

[146]

8‐Hydroxyquinolines

62

8‐Hydroxyquinoline: A privileged structure with a broad‐ranging pharmacological potential

[147]

Quinoxalines

63

Quinoxaline, its derivatives and applications: A state of the art review

[148]

Quinoxalines

63

Quinoxaline‐based scaffolds targeting tyrosine kinases and their potential anticancer activity

[149]

Quinazolines

64

Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification

[150]

4‐Aminoquinazolines

65

4‐Aminoquinazoline analogs: A novel class of anticancer agents

[151]

1,8‐Naphthyridines

66

1,8‐Naphthyridine derivatives: A review of multiple biological activities

[152]

4‐Quinolone‐3‐carboxylic acids

67

The 4‐quinolone‐3‐carboxylic acid motif as a multivalent scaffold in medicinal chemistry

[153]

Dihydroquinazolinones

68

Synthetic strategy with representation on mechanistic pathway for the therapeutic applications of dihydroquinazolinones

[154]

Phthalazinones

69

Phthalazin‐1(2

H

)‐one as a remarkable scaffold in drug discovery

[155]

Dihydrobenzo[1,4]‐oxathiines

70

Dihydrobenzo[1,4]oxathiine: A multi‐potent pharmacophoric heterocyclic nucleus

[156]

1,4‐Benzothiazines

71

Functionalized 1,4‐benzothiazine: A versatile scaffold with diverse biological properties

[157]

Pyridopyrimidines

72

Recent advances in the chemistry and biology of pyridopyrimidines

[158]

1,4‐Benzodiazepine

73

Recent development in [1,4]benzodiazepines as potent anticancer agents: A review

[159]

1,4‐Benzodiazepine

73

Benzo‐ and thienobenzodiazepines: Multi‐target drugs for CNS disorders

[160]

1,5‐Benzothiazepine

74

1,5‐Benzothiazepine, a versatile pharmacophore: A review

[161]

1.4.6 Synthesis and Biological Activities of Tricyclic and Tetracyclic Ring Privileged Structures

A general review on the use of tricyclic structures in medicinal chemistry appeared a decade ago [162]. Table 1.6 outlines recent reviews on the use of specific tricyclic and tetracyclic structures employed in medicinal chemistry programs.

Table 1.6 List of tricyclic and tetracyclic ring privileged structures reviews.

Structure

Number

Review title

Reference

Acridines

75

The concept of privileged structures in rational drug design: Focus on acridine and quinolone scaffolds in neurodegenerative and protozoan diseases

[142]

Xanthones

76

Recent insight into the biological activities of synthetic xanthone derivatives

[163]

Carbazoles

77

Biological potential of carbazole derivatives

[164]

Pyrrolo[1,2‐

a

]indoles

78

Synthesis and some biological properties of pyrrolo[1,2‐

a

]indoles

[165]

Pyrazoloquinolines

79

An overview on synthetic methodologies and biological activities of pyrazoloquinolines

[166]

Pyrazoloquinazolines

80

Pyrazoloquinazolines: Synthetic strategies and bioactivities

[167]

Pyrroloquinazolines

81

The chemistry and pharmacology of privileged pyrroloquinazolines

[168]

Pyrroloquinoxalines

81

Recent progress in biological activities and synthetic methodologies of pyrroloquinoxalines

[169]

Imidazoquinolines

82

Imidazoquinolines: Recent developments in anticancer activity

[170]

Pyrrolobenzodiazepines

83

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

[171]

Anthraquinones

84

Anthraquinones as pharmacological tools and drugs

[172]

6

H

‐indolo[2,3‐

b

]quinoxalines

85

6

H

‐indolo[2,3‐

b

]quinoxalines: DNA and protein interacting scaffold for pharmacological studies

[173]

1.5 Combinatorial Libraries of “Privileged Structures”

If we entertained the idea of “privileged structures” as core structures for low molecular weight compounds, analogous to the fragment‐based method of drug discovery, combinatorial chemistry protocols can be established for privileged structures, with their inherent affinity for diverse biological receptors, represent an ideal source of core scaffolds and capping fragments for the design and synthesis of combinatorial libraries to enable numerous targets to be processed simultaneously across different therapeutic areas [174]. The majority of privileged structures contain multiple sites for diversification by chemical modifications to achieve a huge number of possible pharmacological profiles.

Dolle published very comprehensive surveys of combinatorial libraries annually for over a decade [175–187]. Many of the information in the annual surveys show original library syntheses based on privileged structures. Table 1.7 shows combinatorial synthetic reviews on privileged structures.

Table 1.7 Combinatorial synthesis of privileged structures reviews.

Review title

Reference

Recent advances in the solid‐phase combinatorial synthetic strategies for the quinoxaline, quinazoline and benzimidazole based privileged structures

[188]

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

[189]

Privileged scaffolds for library design and drug discovery

[38]

Recent advances in the solid‐phase combinatorial synthetic strategies for the benzodiazepine based privileged structures

[190]

Exploring privileged structures: the combinatorial synthesis of cyclic peptides

[191]

Libraries from natural product‐like scaffolds

[192]

Privileged structure‐based combinatorial libraries targeting G protein‐coupled receptors

[193]

Nitrogen containing privileged structures and their solid phase combinatorial synthesis

[194]

Design, synthesis, and evaluation of small‐molecule libraries

[195]

Advances in solution‐ and solid‐phase synthesis toward the generation of natural product‐like libraries

[196]

1.6 Scope of this Monograph

The author’s inspiration for this monograph occurred years ago when three pivotal reviews in the literature appeared on the topic of privileged structures in drug discovery. Stockwell’s [38] monumental and comprehensive tables of privileged scaffolds for library design and Fraga’s [37], DeSimone’s [39], and Costantino’s [40] reviews on selected privileged structures case studies spurred the author’s motivation to pursue a monograph on this topic of “privileged structures.” During the preparation of this monograph, Bräse edited a book titled Privileged Scaffolds in Medicinal Chemistry – Design, Synthesis, Evaluation in 2016 from different viewpoints [197]. Chapters included β‐lactams, (benz)imidazoles, pyrazoles, quinolones, isoquinolines, rhodanines, coumarins, xanthones, spirocycles, and cyclic peptides as privileged scaffolds in medicinal chemistry. Other key chapters included heterocycles containing nitrogen and sulfur as potent biologically active scaffolds, thiirane class of gelatinase inhibitors as a privileged template that crosses the blood–brain barrier, natural product scaffolds of value in medicinal chemistry, and ergot alkaloids. We will keep the nomenclature of “privileged structures” for the rest of the book !!!

The author has selected a dozen privileged structures such as the benzodiazepines, 1,4‐dihydropyridines, biphenyls, 4‐arylpiperidines, spiropiperidines, 2‐aminopyrimidines, 2‐aminothiazoles, 2‐arylindoles, tetrahydroisoquinolines, 2,2‐dimethylbenzopyrans, hydroxamates, and imidazopyridines to showcase the use of these structures in drug discovery programs. Each chapter will have a listing of the FDA‐approved marketed drug with that “privileged structure,” followed by detailed sections of medicinal chemistry case studies across multiple therapeutic areas and finally comprehensive sections on the syntheses of the structures employing classical and state‐of‐the‐art organic chemistry reactions.

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