Chapter-I

1

INTRODUCTION

Heterocyclic chemistry is one of the most complex and intriguing branch; many

broader aspects of heterocyclic chemistry are recognized as disciplines of general

significance that impinge on almost all aspects of modern organic chemistry, medicinal

chemistry and biochemistry. Heterocyclic compounds offer a high degree of structural

diversity and have proven to be broadly and economically useful as therapeutic agents.

Heterocyclic compounds played a vital role in biological processes and are wide spread

as natural products. They are widely found in nature as well as synthetically produced

heterocycles designed by organic chemists are used for instance as agrochemicals and

pharmaceuticals and play an important role in human life. In most cases the chemist

has specific reasons for synthesizing a particular compound, usually based on

theoretical considerations, medicinal chemistry, biological mechanisms or a

combination of all three. Aromatic heterocycles are of significant interest due to their

presence in advanced pharmaceutical agents, for example, Lipitor, which lowers

cholesterol levels and Plavix, a blockbuster drug used in the treatment of vascular

diseases1, etc...

Heterocyclic compounds offer a high degree of structural diversity and have

proven to be broadly and economically useful as therapeutic agents. Almost unlimited

combinations of carbon, hydrogen and heteroatoms can be designed, making available

compounds with the most diverse physical, chemical and biological properties. Since

diverse organic molecules of animal and plant origins have predominance of nitrogen

and oxygen heterocycles proved their utility in different fields.

In the recent years much attention has been focused on the synthesis of

heterocycles containing oxygen atom because of their biological and medicinal

importance including ontological research. They are widely distributed in nature and

are essential for life.

Amongst all the oxygen heterocyclic’s, coumarins and its analogues occupy an

important position, the coumarins (2H-chromen-2-ones, 2H-1-benzopyran-2-ones)

Chapter-I

2

(Fig-1.1) are among the best-known oxygen heterocycles, well represented as a

structural motif in numerous natural products2.

O O1

2

3

45

6

7

8

Fig-1.1

The isolation of coumarin was first reported by Vogel3 in Munich in 1820. The

name coumarin originates4 from a Caribbean word ‘coumarou’ for the tonka tree,

which was known botanically at one time as ‘coumarouna odoratea Aubl’ and it acts as

a structural subunit of more complex natural products5. These molecules generally have

a broad range of technological6,7 and biological activities which includes

1. Anticancer8-18

2. Anticoagulant and Cardiovascular19-22

3. Antiviral23-27

4. As Enzyme Inhibition28-32

5. Antimicrobial and Molluscicidal33-46

6. Antioxidant47-50

7. Effect on Central Nervous System151-53

8. Anti-inflammatory54-58

9. Anti-HIV59-63

10. For Alzheimer’s disease64

11. Used as dyes65

Chapter-I

3

Naturally, there has been a continuous effort to develop new, convenient and

versatile syntheses of coumarins with defined structural features. Classical routes to

coumarins incorporate Pechmann66-68, Knoevenagel69-71, Perkin72-73, Reformatsky74 and

Wittig75-77 condensation reactions. Among these reactions, Pechmann reaction is the

most widely used method for the preparation of substituted coumarins since it proceeds

from very simple starting materials and gives good yields of various substituted

coumarins. And also substituted coumarins can be prepared by using various reagents

such as H2SO4, POCl378, AlCl3

79, Cation exchange resins, trifluoro acetic acid80,

Montmorillonite Clay81, solid acid catalysts82, W/ZrO2 solid acid catalyst83,

Chloroaluminate ionic liquid84 and Nafion-H catalyst85.

Coumarin nucleus possesses diversified biological Activities; few are briefly

summarized as under:

Name Structure Activity

Aminocoumarin

O O O

O

NH2

O

OH

OH

O

NH

O

OH

Antibiotic

Brodifacoum

O O

OH

Br

Anticoagulant

Warfarin

O

OH

O

O

Anticoagulant

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4

Tioclomarol

O

OH

O

OH

Cl

S

Cl

Anticoagulant

Cloricromen O O

N

Cl

OO

O

Platelet aggregation

inhibitor

Seselin OO O

Anti cancer

Neo Tanshinlactone

O O

O

Anti cancer

Calanolide-A OO O

O R

OH

Anti HIV

Bergapten

O O

O

OCH3

Alzheimer’s

disease agent

Batoprazine O

O

N

NH

Anti aggressive

agent

Chapter-I

5

Since last two decades a rapid progress in synthetic organic chemistry is

associated with a search for new compounds with desired properties. Such compounds

are widely used in pharmaceutical industries. Among these, the heterocycles form the

largest of the classical division of organic chemistry and are of immense biological and

industrial importance. Analysis of scientific papers in the last two decades revealed that

there is a general trend in research for new drugs involving modification of existing

biologically active matrices and molecular design of the structures of compounds.

Both naturally occurring and synthetic coumarins have attracted intensive

attention from chemists due to their broad spectral properties and potential for

biological activities. The never-ending thrust in this area is made me to synthesis of

coumarin derivatives and physiological interest of those compounds.

Burger86 stated that “the great advances of medicinal chemistry have been

achieved by two types of investigators: those with the genius of prophetic logic, who

have opened a new field by interpreting correctly a few well-placed experiments,

whether they pertained to the design or the mechanism of action of drugs and those

who have varied patiently the chemical structures of physiologically active compounds

until a useful drug could be evolved as a tool in medicine.”

In the present thesis, we explore the methods for synthesis and biological

activities of new Triazole, Tetrazole, Oxadiazole and Pyrazole derivatives of

coumarins.

Triazole Introduction:

A survey on the triazole derivatives reveals that these compounds possess

biological activities, and the synthetic utility of substituted groups depends on their

stereochemistry. Generally triazols are 1,2,3-triazol, 1,2,4-triazol and 1,3,5-triazol

systems are present almost all, all types of triazols are having a wide range of

applications. Members of 1,2,3-triazol family have been widely used as antifungal and

antimicrobial agents87, antihypertensive agents88, anti-AIDS agents89, and potassium

channel activators90.

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6

Compounds of 1,2,4-triazole derivatives are found to be associated with diverse

pharmacological activity. Recently, some new triazole derivatives have been

synthesized as possible anticonvulsants, antidepressants, tranquilizers, and plant-

growth regulators91-93. Some of the iron (II) complexes containing substituted 1,2,4-

triazole ligands are spin-crossover materials, which could be used as molecular-based

memory devices, displays, and optical switches94-95. The 1,2,4-triazole nucleus has

recently been incorporated into a wide variety of therapeutically interesting drugs96,

including H1/H2 histamine receptor blocker, cholinesterase active agents, CNS

stimulants, antianxiety agents, and sedatives. Substituted 1,2,4-triazoles have been

actively studied as bridging ligands coordinating through their vicinal N atoms. The

complexes containing 1,2,4-triazole ligands possess specific magnetic properties97-99.

On the other hand, some of the 1,2,4-triazole derivatives have anti-inflammatory

activities100 and some are antifungal agents101.

Scheme-1: Potential pharmaceuticals based on triazoles

N

R1

R2

R3

R4 O

NN

N

H

OH

N

N

N NN R

RR

F

HIV Protease Inhibitors Antituberculosis

OH

N

NN

N

N

N

F

F

NN

N

O

Antifungal Anticancer

Chapter-I

7

Cl

Cl

O

O

N

NN

O N N N N

N

O

Antifungal

Scheme-2: Potential pharmaceuticals based on 1,2,3-triazoles with lactam rings

SN

NN

OO

O

H

COOH

HO

NH2 HN

O N

S

COOHN

NN

O

H

Tazobactam Cefatrizine

Tetrazole Introduction:

Tetrazole and its derivatives have important applications in major areas, such as

medicine, agriculture and imaging technology, and are very stimulating heterocycles

from an academic viewpoint.

Despite the high nitrogen content, tetrazole and most of its derivatives are

relatively stable, on heating or under microwave irradiation and also in the presence of

various chemical reagents (oxidants, acids, bases, alkylating agents, dienophiles, etc.).

In naturally occurring molecules, the tetrazole fragment is virtually lacking. Yet, its

presence in metabolic products of some protozoa was reported102. It is postulated that

tetrazole, alongside other unusual polynitrogen heterocycles, may be formed under the

natural conditions of other planets of the Solar system or their satellites, provided that

they contain hydrocarbons and nitrogen in the composition of the atmosphere or on the

surface102.

The tetrazolyl system is to the same extent unusual in structure and unique in

acid-base characteristics. For instance, compared with other thermally and chemically

stable azoles, tetrazoles possess abnormally high acidity and very weak basicity102–113.

Chapter-I

8

In the tetrazole ring, the four nitrogen atoms connected in succession may be involved

in protolytic processes, and many physical, chemical, physicochemical, and biological

properties of tetrazoles are closely related to their ability to behave as acids and bases.

In fact, most medical applications of tetrazoles stem from the acidic properties of the

tetrazolyl ring. The tetrazolic acid fragment, –CN4H, has similar acidity to the

carboxylic acid group, – CO2H, and is almost allosteric with it, but is metabolically

more stable at physiologic pH. Hence, synthetic methodologies leading to the

replacement of –CO2H groups by –CN4H groups in pharmacologically active

molecules are of major relevance114. The tetrazole ring is found in drugs or drug

candidates with antihypertensive, antiallergic and antibiotic activity115–117, or of use as

anticonvulsants118, in cancer or in AIDS treatments119,120. Tetrazoles are also used in

agriculture as plant growth regulators, herbicides and fungicides121. Due to the high

enthalpy of formation, tetrazole decomposition results in the liberation of two nitrogen

molecules and a significant amount of energy. Therefore, several tetrazole derivatives

have been explored as explosives, propellant components for missiles and as gas

generators for airbags in the automobile industry122. In addition, various tetrazole-based

compounds have good coordination properties and are able to form stable complexes

with several metal ions 123. This ability is successfully used in analytical chemistry for

the removal of heavy metal ions from liquids, and in chemical systems formulated for

metal protection against corrosion 124. Furthermore, the tetrazole ring has strong

electron-withdrawing properties and, as such, tetrazolyl halides have been successfully

used in synthesis as derivatising agents for the chemical modification of alcohols 125–

130.

Tetrazoles are also particularly interesting compounds because they exhibit a

very rich photochemistry. The photochemistry of matrix-isolated unsubstituted

tetrazole was studied by Maier and co-workers and published in 1996131.

Candida albicans is an opportunistic and often deadly pathogen that invades

host tissues, undergoes a dimorphic shift, and then grows as a fungal mass in the

kidney, heart or brain. It is the fourth leading cause of hospital-acquired infection in the

Chapter-I

9

United States and over 95% of AIDS patients suffer from infections by C. albicans132.

Candida albicans is the predominant organism associated with candidiasis; but other

Candida species, including C. glabrata, C. tropicalis and C. krusei, are now emerging

as serious nosocomial threats to patient populations133. Existing antifungals can treat

mucosal fungal infections but very few treatments are available for invasive diseases.

The current antifungal therapy suffers from drug related toxicity, severe drug

resistance, non-optimal pharmacokinetics, and serious drug-drug interactions. The

common antifungal drugs currently used in clinics belong to polyenes and azoles.

Polyenes (amphotericin B and nystatin) cause serious host toxicity134 whereas azoles

are fungistatic and their prolonged use contributes to the development of drug

resistance in C. albicans and other species135,136. Because of all these striking problems,

they developed novel antifungal drugs with higher efficiency, broader spectrum,

improved pharmacodynamic profiles and lower toxicity.

Scheme-3: Potential pharmaceuticals based on tetrazole rings

Cl

NN

NN

NN

H H

OR

Antifungal

N

NN

NHN

N

O

N O

N

N

Cl

NN

N

S

HN

Angiotensin (AT1) receptor antagonist Antimicrobial

Oxadiazole Introduction:

The oxadiazole motif is an important pharmacophore within medicinal

chemistry and can be regarded as a bioisosteric, and metabolically stable, replacement

Chapter-I

10

for an ester unit. Indeed, the 1,2,4-oxadiazole is present in several notable drug

molecules, including antitussive drugs, such as Perebron137 1, and Libexin138 2, as well

as the serotonin agonist 3, for the treatment of migraine139 and L-690548, 4, for the

treatment of Alzheimer's disease.

Scheme-4: Therapeutic compounds containing the 1,2,4-oxadiazole unit

Et2N

O N

NPh

N

O N

N

CHPh2

Ph

NO

N

NH

NEt2

NN

NO

(1) (2)

(3) (4)

Data from the World Organization of Health show a significant rise in drug-

resistant tuberculosis140-142. Tuberculosis (TB) is one of the leading causes of death and

suffering worldwide among the infectious diseases. The ever increasing drug

resistance, toxicity and side effects of currently used anti-tuberculosis drugs and the

absence of their bactericidal activity highlight the need for new, safer and more

effective anti-tuberculosis drugs143-147. The computer-aided prediction of biological

activity in relation to the chemical structure of a compound is now a commonly used

technique in drug discovery148-153. Modern drug discovery also relies on the interface of

chemical and biological diversity through high throughput screening154. Generation of

functional molecular diversity to probe biological activity space requires robust

molecular scaffolds that are low in molecular weight and are easily modified to create a

variety of chemically diverse, biologically active potential drugs155-156.

Additionally, compounds containing the oxadiazole motif have been the subject

of interest as novel 5-HT3 antagonist157. A number of such compounds have been

Chapter-I

11

shown to be effective in the control of cancer chemotherapy-induced emesis158, and

evidence suggests therapeutic benefits towards migraine159, schizophrenia160, and

anxiety161.

Along with 1,2,4-oxadiazole compounds 1,3,4-oxadiazole unit containing

molecules also currently used in clinical medicine are like raltegravir (5), an

antiretroviral drug162, nesapidil (6) an anti-arrhythmic therapy163, furamizole (7) a

nitrofuran derivative that has strong antibacterial activity164 and tiodazosin (8) an

antihypertensive drug165. Therefore, considering the range of potential biological

applications, the formulation of more efficient synthetic strategies to access

functionalised compounds containing the 1,2,4-oxadiazole motif has emerged as an

attractive preparative goal.

Scheme-5: Potential pharmaceuticals based on 1,3,4-oxadiazole system

N

N

HN

O

NN

O

O

OH

HN

O

FN

N

O

OH

O

ON

N

(5) (6)

O

N N

OO

O2N

NH2

(7)

N

NMeO

MeO

NH2

N

N

O

O

NN

S

(8)

Pyrazole Introduction:

The chemistry of pyrazoles has been reviewed by Jarobe in 1967. Pyrazoles

have attracted attention of medicinal chemists for both with regard to heterocyclic

chemistry and the pharmacological activities associated with them. Pyrazole have been

studied extensively because of ready accessibility, diverse chemical reactivity, broad

Chapter-I

12

spectrum of biological activity and varieties of industrial applications. As evident from

the literature in recent years a significant portion of research work in heterocyclic

chemistry has been devoted to pyrazoles containing different alkyl, aryl and heteroaryl

groups as substituents.

Pyrazoles belong to the family of azoles, i.e. five-member ring containing only

nitrogen and carbon atoms, ranging from pyrrole to pentazole. According to Albert’s

classification, they are π-excessive, N-hetero aromatic derivatives and according to

Kauffmann’s arenology principle, as a substituted carbon, they are analogues of amines

and as substituted nitrogen they are analogues of halogens, i.e. pseudo halogens.

Synthesis of pyrazole and its N-aryl analogs has been a subject of consistent interest

because of the wide applications of such heterocycles in pharmaceutical as well as in

agrochemical industry166-168. Numerous compounds containing pyrazole moiety have

been shown to exhibit anti-hyperglycemic, analgesic, anti-inflammatory, antipyretic,

anti-bacterial and sedative-hypnotic activities169-171.

Scheme-6: Potential pharmaceuticals based on pyrazole system

NN

COOH

Cl

N

NN

CH3

H3C

O

O

OH

F

Lonazolac Pyrazole mevalonolactone

(Anti-inflammatory) (Hypocholesterolemic effect)

Chapter-I

13

NN

(CH2)3N(CH3)2

N

CH3

N

H3C

HN

Cl

OH

N

N

CH3

NHO

NCH3

Fezolamine (Antipsychotic) Granisoton

(Antidepressant) (Antagonist)

Pyrazoles belong to an important class of heterocycles due to their biological

and pharmacological activities172-173, such as anti-inflammatory174, herbicidal175,

fungicidal176, bactericidal176, plant growth inhibitory175, antipyretic177, and protein

kinase inhibitory activities178. Also, they are the key starting materials for the synthesis

of commercial aryl/hetero-arylazopyrazolone dyes179-180. Many other authors have

reported other biological activities181-185

The great importance of these oxygen heterocyclics: triazole, tetrazole,

oxadiazole and pyrazoles compounds drive us to concentrate on the development of

new compounds in the area of heterocyclic chemistry. Present thesis has been discussed

the details of synthesis and activity studies. The detailed study of this work was

reported in the later chapters.

Chapter-I

14

REFERENCES:

1. P. Savi, J. M. Pereillo, M. F. Uzabiaga, J. Combalbert; C. Picard, J. P.

Maffrand, M. Pascal, J. M. Herbert, Thromb. Haemostasis 2000, 84, 891-896.

2. (a) Murray, R. D. H.; Mendez. J.; Brown, S. A. in The Natural Coumarins:

Occurrence,Chemistry and Biochemistry; John Wiley and Sons: New York,

1982.

(b) Hepworth, J. D. In Comprehensive Heterocyclic Chemistry; Katritzky, A.

R., Rees, C.W., Eds.; Pergamon: New York, 1984; Vol. 3, pp 799-810.

(c) Hepworth, J. D.; Gabbutt, C. D.; Heron, B. M. In Comprehensive

Heterocyclic Chemistry-II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,

Eds.; Pergamon: NewYork, 1996; Vol. 5, pp 417-434.

3. Vogel, A., Gilbert’s Ann. Phys., 1820, 64, 161.

4. Guillemette, A., Justus Liebigs, Ann.Chem., 1835, 14, 324.

5. (a) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa, H.;

Takahashi, D.; Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem. Lett. 2000,

10, 59-62.

(b) Maier, W.; Schmidt, J.; Nimtz, M.; Wray, V.; Strack, D. Phytochemistry

2000, 54, 473-479.

(c) Garcia- Argaez, A. N.; Ramirez Apan, T. O.; Delgado, H. P.; Velazquez,

G.;Martinez-Vazquez, M. Planta Med. 2000, 66, 279-281.

(d) Zhou, P.; Takaishi, Y.; Duan, H.; Chen, B.; Honda, G.; Itoh, M.; Takeda,

Y.; Kodzhimatov, O. K.; Lee, K.-H. Phytochemistry 2000, 53, 689-697.

(e) Khalmuradov, M. A.; Saidkhodzhaev, A. I. Chem. Nat. Compd. 1999,

35,364.

(f) Kamalam, M.; Jegadeesan, M. Indian Drugs 1999, 36, 484-486.

(g) Tan, R. X.; Lu, H.; Wolfender, J. L.; Yu. T. T. Zheng, W. F.; Yang, L.;

Chapter-I

15

Gafner, S.; Hostettmann, K. Planta Med. 1999, 65, 64-67.

(h) Vlietinck, A. J.; De Bruyne, T.; Apers, S.; Pieters, L. A. Planta Med.

1998, 64, 97-109.

(i) Bal-Tembe, S.; Joshi, D. D.; Lakdawala, A. D. Indian J. Chem., Sect. B:

Org. Chem. Incl. Med. Chem. 1996, 35B, 518.

(j) Silvan, A. M.; Abad, M. J.; Bermejo, P.; Villar, A.; Sollhuber, M. J. Nat.

Prod. 1996, 59, 1183.

(k) Yang, Y. M.; Hyun, J. W.; Sung, M. S.; Chung, H. S.; Kim, B. K.; Paik,

W. H.; Kang, S.S.; Park, J. G. Planta Med. 1996, 62, 353.

(l) Pereira, N. A.; Pereira, B. M. R.; Celia do Nascimento. M.; Parente, J. P.;

Mors, W. B. Planta Med. 1994, 60, 99-100.

6. (a) Perfumery: Clark, G. S. Perfum. Flavor. 1995, 20, 23-34.

(b) Fluorescent chemo-sensors: Chen, C.-T.; Huang, W.-P. J. Am. Chem. Soc.

2002, 124, 6246-6247.

7. (a) Laser, technology: Sekar, N. Colourage 2003, 50, 55-56.

(b) Fluorescent indicators: Brun, M. P.; Bischoff, L.; Garbay, C. Angew.

Chem.,Int.Ed. 2004, 43, 3432-3436.

8. Rosskopf, F., Kraus, J. and Franz, G.; Pharmazie., 1992, 47, 139.

9. Valenti, P.; Fitoterapia, 1996, 68, 115.

10. Finn, J., Creaven, B. and Egan, A.; Melanoma Res., 2001, 11, 461.

11. Kawaii, S., Tomono, Y., Ogawa, M., Yoshizawa, Y.; Anticancer Res., 2001,

21, 917.

12. Kawaii, S., Tomono, Y., Ogawa, K., Sugiura, M., Yano, M., Yoshizawa, Y.,

Ito C and Furukawa, H.; Anticancer Res., 2001, 21, 1905.

13. Wang, J., Hsieh, J., Lin, L. and Tseng, H.; Cancer Lett., 2002, 183, 163.

Chapter-I

16

14. Ho, T., Purohit A., Vicker, N., Newman, P., Robinson, J., Leese, P.,

Ganeshapillai, D., Woo, L., Potter, L. and Reed, J.; Biochem. Biophys. Res.

Commun., 2003, 305, 909.

15. Finn, J., Creaven, S. and Egan, A.; Eur. J. Pharmacol., 2003, 159, 481.

16. Edenharder, R. and Tang, X.; Food Chem. Toxicol., 1997, 35, 357.

17. Ahmed, S., James, K., Owen, P., Patel, K.; Bioorg. & Med. Chem. Lett.,

2002, 12, 1343.

18. Finn, J., Kenealy, E., Creaven, S. and Egan, A.; Cancer Lett., 2002, 183, 61.

19. Chiou, F., Huang, L., Chen, F. and Chen, C.; Planta Med., 2001, 67, 282.

20. Ferrer, M., Leiton, J. and Zaton, L.; J. Protein Chem., 1998, 17, 115.

21. Hadlipavlou-Litina, D.; Arzneim-Forsch, J.; Drug Res., 2000, 50, 631.

22. Roma, G., Di Braccio, M., Carrieri, A., Grossi, G., Leoncini, G., Signorello,

G. Carotti, A.; Bioorg. & Med. Chem., 2003, 11, 123.

23. Makhija, T. and Kulkarni, M.; J. Comput. Aid. Mol. Des., 2001, 15, 961.

24. De Clercq, E.; Med. Res. Rev., 2000, 20, 323.

25. Zhao, H., Neamati, N., Pommier, Y. and Burke, R.; Jr. Heterocycles, 1997,

45, 2277.

26. Bourinbaiar, S., Tan, X. and Nagorny, R.; Acta Virol., 1993, 37, 241.

27. Vlientick, J., De Bruyne, T., Apers, S. and Pieters, A.; Plant Med., 1998, 64,

97.

28. Bruhimann, C., Ooms, F., Carrupt, A., Testa, B., Catto, M., Leonetti, F.,

Altomare, C. and Carotti, A.; J. Med. Chem., 2001, 44, 3195.

29. Yang, B., Zhao, B., Zhang, K. and Mack, P.; Biochem. Biophys. Res.

Commun., 1999, 260, 682.

Chapter-I

17

30. Wang, H., Ternai, B. and Polya, G.; Phytochemistry, 1997, 44, 787.

31. Jo, S., Gyibg, L., Bae, K., Lee, K. and Jun, H.; Plant Med., 2002, 68, 84.

32. Sardari, S., Nishibe, S., Horita, K., Nikaido, T. and Daneshtalab, M.;

Pharmazie, 1999, 54, 554.

33. Garazd, M., Garazd, L., Shillin, V. and Khliya, P.; Chem. Nat. Compounds,

2000, 36, 485.

34. Mohareb, M., Shams, Z. and Aziz, I.; J. Chem. Research (S), 1992, 154.

35. Majumdar, C., Saha, S., De, N. and Ghosh, K.; J. Chem. Soc., 1993, 715.

36. Schio, L., Chatreaux, F. and Klich, M.; Tet. Lett., 2000, 41, 1543.

37. Schiedel, S., Briehn, A. and Bauerle, P.; Angrew. Chem. Int. Ed., 2001, 40,

4677.

38. Meng, B., Shen, G., Fu, C., Gao, H., Wang, J., Wang, G. and Matsurra, T.;

Synthesis, 1990, 719.

39. Ivanova, I., Eremin, V. and Shvets, I.; Tetrahedron, 1996, 52, 9581.

40. Nicolaides, N., Fylaktakidou, C., Litinas, E. and Hadlipavlou-Litina, D.; J.

Heterocyclic Chem., 1996, 33, 967.

41. Govori, S., Rapic, V., Leci, O. and Tabakovic, I.; J. Heterocyclic Chem.,

1996, 33, 351.

42. Aziz, I.; J. Heteroatom Chem., 1996, 7, 137.

43. Emmanuel-Giota, A., Fylaktakidou, C., Hadlipavlou-Litina, D., Litinas, E.

and Nicolaides, N.; J. Heterocyclic Chem., 2001, 38, 717.

44. Oduszek, B. and Uher, M.; Synth. Commun., 2000, 30, 1749.

45. Nishizono, N., Oda, K., Ohno, K., Minami, M. and Machida, M.;

Heterocycles, 2001, 55, 1897.

Chapter-I

18

46. Ito, K., Higuchi, Y., Tame, C. and Hariya, J.; Heterocycles, 1993, 35, 937.

47. Costantino, L., Rastelli, G. and Albasini, A.; Pharmazie, 1996, 51, 994.

48. Fernandez-Puntero, B., Barroso, I., Idlesias, I. and Benedi, J.; Bio. Pharm.

Bull., 2001, 24, 777.

49. Kaneko, T., Baba, N. and Matsuo, M.; Cytotechnology, 2001, 35, 43

50. Paya, M., Halliwell, B. and Hoult, S.; Biochem. Pharmacol., 1992, 44, 205.

51. Pignatello, R., Puleo, A., Giustolisi, S., Cuzzoccrea, S., Dugo, L., Caputi, P.

and Puglisi, G.; Drug Dev. Res., 2002, 57, 115.

52. Santana, L., Uriarte, E., Fall, Y., Teijeira, M., Teran, C., Garcia-Martinez, E.

and Tolf, R.; Eur. J. Med. Chem., 2002, 37, 503.

53. Gonzalez-Gomez, M., Santana, L., Uriarte, E., Brea, J., Villlazon, M., Loza,

I., De Luca, M., Rivas, E., Montegero, Y. and Fontela, A.; Bioorg. & Med.

Chem. Lett., 2003, 13, 175.

54. Delgado, G., Olivares, S., Chavez, M. I., Ramirez-Apan, T., Linares, E. and

R.Bye; J. Nat. Prod., 2001, 64, 861.

55. Maddi, V., Raghu, S. and Rao, A.; J. Pharm. Sci., 1992, 81, 964.

56. Lazarova, G., Kostova, I. and Neychev, H.; Fitoterapia, 1993, 64, 134.

57. Nicolaides, N., Fylaktakidou, C., Litinas, E. and Hadlipavlou-Litina, D.; Eur.

J. Med. Chem., 1998, 33, 715.

58. Ghate, M., Manoher, D., Kulkarni, V., Shosbha, R. and Kattimani, S.; Eur. J.

Med. Chem., 2003, 38, 297.

59. (a) Hariprassad, V.; Talele, T. T.; Kulkarni, V. M. Pharm. Pharmacol.

Commun. 1998, 4, 365-372.

(b) Kaye, P. T.; Musa, M. A.;Nichinda, A. T.; Nocanda, X. W. Synth.

Commun.2004, 34, 2575-2589.

Chapter-I

19

60. Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina, J. H., II;

McMahon, J. B.; Currens, M. J.; Buckheit, R. W., Jr.; Hughes, S. H.; Cragg,

G. M.; Boyd, M. R. J.Med. Chem. 1992, 35, 2735-2743.

61. Patil, A. D.; Freyer, A. J.; Eggleston, D. S.; Haltiwanger, R. C.; Bean, M. F.;

Taylor, P. B.; Caranfa, M. J.; Breen, A. L.; Bartus, H. R.; Johnson, R. K.;

Hertzberg, R. P.; Westley, J. W. J. Med. Chem. 1993, 36, 4131-4138.

62. Spino, C.; Dodier, M.; Sotheeswaran, S. Bioorg. Med. Chem. Lett. 1998, 8,

3475‐3478.

63. L. Xie, Y. Takeuchi, L. M. Cosentino, A. T. Mcphail, and K.H. Lee, J. Med.

Chemistry, 2001, 44 (5), 664-671.

64. Rollinger, J. M.; Hornick, A.; Langer, T.; Stuppner, H.; Prast, H. J. Med.

Chem.2004, 47, 6248-6254.

65. Rajagopal, R.; Sheno, U. V.; Padmanabhan, S.; Sequeira, S.; Seshadri, S,

Dyes Pigments 1990, 13, 167‐175.

66. (a) von Pechmann, H. Chem. Ber. 1883, 16, 2119.

(b) von Pechmann, H.; Duisberg, C. Chem. Ber. 1884, 17, 929.

67. (a) Russel, A.; Fyre, J. R. Org.Synth. 1941, 21, 22-26.

(b) Sethna, S.; Phadke, R. Org. React. 1953, 7, 1-58.

(c) Rabjohn, N. Org. React. 1976, 24, 261-415.

(d) Sugino, T.; Tanaka, K. Chemistry Lett. 2001, 513-515.

68. E.V.O. Jhon, S.S. Israelstam, J. Org. Chem. 1961, 26, 240.

69. Jones, G. Org. React. 1967, 15, 204-599.

70. Brufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1996, 43,

1257-1266.

71. F. Bigi, L. Chesini, R. Maggi, G. Sartori, J. Org. Chem.,1999, 64, 1033.

Chapter-I

20

72. Johnson, J. R. Org. React. 1942, 1, 210-266.

73. B.J. Donnelly, D.M.X. Donnelly, A.M.O. Sullivan, Tetrahedron., 1968, 24,

2617.

74. Shriner, R. L. Org. React. 1942, 1, 1-37.

75. Narasimhan, N. S.; Mali, R. S.; Barve, M. V. Synthesis, 1979, 906-909.

76. Harayama, T.; Nakatsuka, K.; Katsuro, K.; Nishioka, H.;Murakami, K.; Fuji,

M. Chem. Express 1993, 8, 245-248.

77. I. Yavari, R. Hekmat-shoar, A. Zonouzi, Tetrahedron Lett. 1998, 39, 2391-

2392.

78. S.Z. Ahmed, R.D. Desai, Proc. Ind. Acad. Sci. 1937, 5A, 277.

79. A.K. Das Gupta, R.M. Chatterje, K.R. Das, J. Chem. Soc. 1969, 29.

80. L.L. Woods, J. Sapp, J. Org. Chem. 1962, 27, 3703.

81. G.K. Biswas, K. Basu, A.K. Barua, P. Bhattacharya, Ind. J. Chem. 1992, 31B,

628.

82. A.J. Hoefnagel, E.A. Gunnewegh, R.S. Downing, H.V. Bekkum, J.Chem.

Soc.Chem. Commun. 1995, 225.

83. B.M. Reddy, V.R. Reddy, D. Giridhar, Synth. Commun. 2001, 31 (23), 3603.

84. A.C. Khandekar, B.M. Khadilkar, Synlett. 2002, 1,152.

85. D.D. Chaudhari, Chem. Ind. 1983, 569.

86. Burger, A.; “The practice of medicinal chemistry,” Burger A, Eds. Medicinal

Chemistry, New York, New York: Wiley, 1970, 4-9.

87. Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D.

E.; Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D.

K.; Morris, J.; Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.;

Chapter-I

21

Schaadt, R. D.; Stapert, D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.

88. Machin, P. J.; Hurst, D. N.; Bradshaw, R. M.; Blaber, L. C.; Burden, D.

T.;Melarange, R. A. J. Med. Chem. 1984, 27, 503.

89. Velazquez, S.; Alvarez, R.; Perez, C.; Gago, F.; De-Clercq, D.; Balzarini, Ca

marasa M. J. Antivir. Chem. Chemother. 1998, 9, 481.

90. Biagi, G.; Calderone, V.; Giorgi, I.; Livi, O.; Scartoni, V.; Baragatti, B.;

Martinotti, E. Eur. J. Med. Chem. 2000, 35, 715.

91. Bradbury, R. H. & Rivett, J. E. J. Med. Chem., 1991, 34, 15.

92. Hirota, T., Sasaki, K., Yamamoto, T., & Nakayama, T. J. Heterocycl. Chem.,

1991, 28, 257.

93. Wasler, A., Flynn, T., & Mason, C. J. Heterocycl. Chem., 1991, 28, 1221.

94. Garcia, Y., Van Koninsbruggen, P. J., Codjovi, E., Lapouyade, R., Khan, O.,

and Rabardel, L. J. Mater. Chem., 1997, 7, 857.

95. Khan, O. & Martinez, C. J. Science, 1998, 279, 44.

96. Heindel, N. D. & Reid, J. R. J. Heterocycl. Chem., 1980, 17, 1087.

97. Vreugdenhil, W., Haasnoot, J. G., & Reedijik, J. Inorg. Chim. Acta., 1987,

129, 205.

98. Albada, G. A., Van de Graaff, R. A. G., Haasnott, J. G., & Reedijik, J. Inorg.

Chem., 1984, 23, 1404.

99. Vos, G., Ie Febre, R. A., Van de Graaff, R. A. G., Haasnott, J. G., & Reedijik,

J. J. Am. Chem. Soc., 1983, 105, 1682.

100. Mazzone, G., Bonina,F., Panico, A. M., Amico-Roxas, M., Caruso, A.,

Blandino, G., Vanella, A. Farmaco Ed. Sci., 1987, 42, 525.

101. Massa, S., Di Santo, R., Retico, A., Artico, M., Simonetti, N., Fabrizi, G., &

Chapter-I

22

Lamba, D. Eur. J. Med. Chem., 1992, 27, 495.

102. Butler, R.N. Comprehensive Heterocyclic Chemistry, II; Pergamon: Oxford,

UK, 1996, p.621.

103. Butler, R.N. Comprehensive Heterocyclic Chemistry, I; Pergamon: New

York, NY, USA, 1984, p. 791.

104. Catalan, J.; Abboud, J.L.M.; Elguero, J. Basicity and acidity of azoles. Adv.

Het.Chem. 1987, 41, 187-274.

105. Elguero, J.; Marzin, C.; Katritzky, A.R.; Linda, P. The Tautomerism of

Heterocycles; Academic Press: New York, NY, USA, 1976; p. 287.

106. Brigas, A.F. Tetrazoles. In Science of Synthesis, Houben-Weyl Methods of

Molecular Transformations; Storr, R.C., Gilchrist, T.L., Eds.; Thieme:

Stuttgard, Germany, 2004; Volume 13, pp. 861-915.

107. Koldobskii, G.I.; Ostrovskii, V.A. Khim. Get. Soed. 1988, 579-592.

108. Koldobskii, G.I.; Ostrovskii, V.A. Tetrazoles. Uspek. Khim. 1994, 63, 847-

865.

109. Koldobskii, G.I.; Ostrovskii, V.A.; Gidaspov, B.V. Khim. Get. Soed. 1980,

867-879.

110. Koldobskii, G.I.; Ostrovskii, V.A.; Poplavskii, V.S. Advances in tetrazole

Chemistry. Khim. Get. Soed. 1981, 1299-1326.

111. Ostrovskii, V.A.; Koren, A.O. Heterocycles 2000, 53, 1421-1448.

112. Katritzky, A.R.; Pozharskii, A.F. Handbook of Heterocyclic Chemistry;

Pergamon/Elsevier: Amsterdam, Netherlands, 2000; p. 377.

113. Katritzky, A.R.; Karelson, M.; Harris, P.A. Heterocycles 1991, 32, 329-369.

114. Noda, K.; Saad, Y.; Kinoshita, A.; Boyle, T.P.; Graham, R.M.; Husain, A.;

Karnik, S.S. J. Bio. Chem. 1995, 270, 2284-2289.

Chapter-I

23

115. Mavromoustakos, T.; Kolocouris, A.; Zervou, M.; Roumelioti, P.; Matsoukas,

J.; Weisemann, R. J. Med. Chem. 1999, 42, 1714-1722.

116. Toney, J.H.; Fitzgerald, P.M.D.; Grover-Sharma, N.; Olson, S.H.; May, W.J.;

Sundelof, J.G.; Vanderwall, D.E.; Cleary, K.A.; Grant, S.K.; Wu, J.K.;

Kozarich, J.W.; Pompliano, D.L.; Hammond, G.G. Chem. Biol. 1998, 5, 185-

196.

117. Hashimoto, Y.; Ohashi, R.; Kurosawa, Y.; Minami, K.; Kaji, H.; Hayashida,

K.; Narita, H.; Murata, S. J. Card. Pharm. 1998, 31, 568-575.

118. Desarro, A.; Ammendola, D.; Zappala, M.; Grasso, S.; Desarro, G.B.

Antimicrob. Agents Chemother. 1995, 39, 232-237.

119. Abell, A.D.; Foulds, G.J. J. Chem. Soc. Perkin Trans. 1 1997, 2475-2482.

120. Tamura, Y.; Watanabe, F.; Nakatani, T.; Yasui, K.; Fuji, M.; Komurasaki, T.;

Tsuzuki, H.; Maekawa, R.; Yoshioka, T.; Kawada, K.; Sugita, K.; Ohtani, M.

J. Med. Chem. 1998, 41, 640-649.

121. Sandmann, G.; Schneider, C.; Boger, P. Biosciences 1996, 51, 534-538.

122. Ostrovskii, V.A.; Pevzner, M.S.; Kofman, T.P.; Shcherbinin, M.B.;

Tselinskii, I.V. Societa Chimica Italiana: Rome, Italy, 1999; p. 467.

123. Frija, L.M.T.; Fausto, R.; Loureiro, R.M.S.; Cristiano, M.L.S. J. Mol. Cat. A

Chem. 2009, 305, 142-146.

124. Moore, D.S.; Robinson, S.D. Adv. Inorg. Chem. 1988, 32, 171-239.

125. Araujo, N.C.P.; Barroca, P.M.M.; Bickley, J.F.; Brigas, A.F.; Cristiano,

M.L.S.; Johnstone, R.A.W.; Loureiro, R.M.S.; Pena, P.C.A. J. Chem. Soc.

Perkin Trans.1 2002, 1213-1219.

126. Araujo, N.C.P.; Brigas, A.F.; Cristiano, M.L.S.; Frija, L.M.T.; Guimaraes,

E.M.O.; Loureiro, R.M.S. J. Mol. Cat. A Chem. 2004, 215, 113-120.

Chapter-I

24

127. Barkley, J.V.; Cristiano, M.L.S.; Johnstone, R.A.W.; Loureiro, R.M. S. Acta

Crystallogr.C-Cryst. Struct. Commun. 1997, 53, 383-386.

128. Cristiano, M.L.S.; Johnstone, R.A.W. J. Chem. Res. (S) 1997, 164-165.

129. Cristiano, M.L.S.; Johnstone, R.A.W. J. Chem. Soc. Perkin Trans. 2 1997,

489-494.

130. Frija, L.M.T.; Cristiano, M.L.S.; Guimaraes, E.M.O.; Martins, N.C.;

Loureiro, R.M.S.; Bickley, J.F. J. Mol. Cat. A Chem. 2005, 242, 241-250.

131. Maier, G.; Eckwert, J.; Bothur, A.; Reisenauer, H.P.; Schmidt, C. Lieb.

Annal.1996, 1041-1053.

132. Chi, H.; Yang, Y.; Shang, S.; Chen, K.; Yeh, K.; Chang, F.; Lin, J. J.

Microbiol. Immunol. Infect. 2011, 44, 369-375.

133. Pfaller, M.A.; Diekema, D.J. J. Clinic. Microbiol. 2004, 42, 4419-4431.

134. Cohen, B. Amphotericin B. Int. J. Pharm. 1998, 162, 95-106.

135. Sanglard, D. Curr. Opinion Microbiol. 2002, 5, 379-385.

136. Marr, K.A.; White, T.C.; van Burik, J.A.; Bowden, R.A. Clin. Infect. Dis.

1997, 25, 908-910.

137. F. Angelini, PCT GB924608,; Chem. Abstr., 1963, 59, 35652.

138. L. Ledniczky and I. Seres, PCT Int. Appl.WO 199904822, 1999; Chem.

Abstr., 1999, 130, 172993.

139. L. J. Street, R. Baker, J. L. Castro, M. S. Chambers, A. R. Guiblin, S. C.

Hobbs, V.G. Matassa, A. J. Reeve, M. S. Beer, D. N. Middlemiss, A. J.

Noble, J. A. Stanton, K. Scholey and R. J. Hargreaves, J. Med. Chem., 1993,

36, 1529.

140. World Health Organization. In Anti-tuberculosis Drug Resistance in the

World; The WHO/IUATLD global project on anti-tuberculosis drug

Chapter-I

25

resistance surveillance, 1997.

141. Bastian, I.; Colebunders, R. Drugs 1999, 58, 633–661.

142. Butler, D. Nature 2000, 406, 670–672.

143. Bodiang, C. K. Scott. Med. J. 2000, 45, 25.

144. Van Scoy, R. E.; Wilkowske, C. J. Mayo Clin. Proc. 1999, 74, 1038.

145. Long, R. Can. Med. Assoc. J. 2000, 163, 425–428.

146. Gazdic, A. Med. Arch. 1998, 52, 207.

147. Pozniak, A. Int. J. Tuberc. Lung Dis. 2000, 4, 993.

148. Poroikov, V. V.; Filimonov, D. A.; Borodina, Yu. V.; Lagunin, A. A.; Kos,

A. J. Chem. Inf. Comput. Sci. 2000, 40, 1349–1355.

149. Stepanchikova, A. V.; Lagunin, A. A.; Filimonov, D. A.; Poroikov, V.

V. Curr. Med. Chem. 2003, 10, 225.

150. Poroikov, V. V.; Filimonov, D. A. J. Comput. Aided Mol. Des. 2003, 16, 819-

824.

151. Geronikaki, A. A.; Dearden, J. C.; Filimonov, D.; Galaeva, I.; Garibova,

T. L.; Gloriozova, T.; Krajneva, V.; Lagunin, A.; Macaev, F. Z.;

Molodavkin, G.; Poroikov, V. V.; Pogrebnoi, S. I.; Shepeli, F.; Voronina, T.

A.; Tsitlakidou, M.; Vlad, L. J. Med. Chem. 2004, 47, 2870-2876.

152. Geronikaki, A.; Babaev, E.; Dearden, J.; Dehaen, W.; Filimonov, D.;

Galaeva, I.;Krajneva, V.; Lagunin, A.; Macaev, F.; Molodavkin, G.;

Poroikov, V.; Pogrebnoi, S.; Saloutin, V.; Stepanchikova, A.; Stingaci, E.;

Tkach, N.; Vlad, L.; Voronina, T. Bioorg. Med. Chem. 2004, 12, 6559–6568.

153. Oruc¸, E.; Rollas, S.; Kandemirli, F.; Shvets, N.; Dimoglo, A. S. J. Med.

Chem. 2004, 47, 6760–6767.

154. Collins, L.; Franzblau, S. G. Antimicrob. Agents Chemother. 1997, 41, 1004-

Chapter-I

26

1009.

155. Dimoglo, A. S.; Sim, E.; Shvets, N. M.; Ahsen, V. Mini Rev. Med. Chem.

2003, 3, 293.

156. Dimoglo, A. S.; Shvets, N. M.; Tetko, I. V.; Livingstone, D. J. Quant. Struct.-

Act. Relat. 2001, 20, 31.

157. S. J. Swain, R. Baker, C. Kneen, J. Moseley, J. Saunders, E. M. Seward, G.

Stevenson, M. Beer, J. Stanton and K. Watling, J. Med. Chem., 1991, 34,

140.

158. (a) U. Leibundgut and I. Lancranjan, Lancet, 1987, 329, 1198.

(b) P.L.R.Andrews, W. G. Rapeport and G. J. Sanger, Trends Pharmacol.

Sci., 1988, 9, 334.

159. C. Loisy, S. Beorchia, V. Centonze, J. R. Fozard, P. J. Schechter and G. P.

Tell, Cephalalgia, 1985, 5, 79.

160. B. Costall, A. M. Domerey, R. J. Naylor and M. B. Tyres, Br. J. Pharmacol.,

1987, 92, 881.

161. B. J. Jones, B. Costall, A. M. Domerey, M. E. Kelly, R. Naylor, N. R. Oakely

and M. B. Tyres, Br. J. Pharmacol., 1988, 93, 985.

162. Savarino, A. Expert Opin. Inv. Drug. 2006, 15, 1507–1522.

163. Schlecker, R.; Thieme, P.C. Tetrahedron 1988, 44, 3289–3294.

164. Ogata, M.; Atobe, H.; Kushi-Da, H.; Yamamoto, K. J. Antibiot. 1971, 24,

443-451.

165. Vardan, S.; Mookherjee, S.; Eich, R. Clin. Pharm. Ther. 1983, 34, 290-296.

166. Junjappa, H., Ila, H., Asokan, C. V.; Tetrahedron, 1990, 46, 5423.

167. Dieter, R. K.; Tetrahedron, 1986, 42, 3029.

168. Ila, H., Junjappa, H., Mohanta, P. K.; Progress in Heterocyclic Chemistry,

Chapter-I

27

Gribble, G. W., Gilchrist, T. L. (Eds.), Pergamon, New York, 2001, 13, 1.

169. Purkayastha, M. L., Ila, H., Junjappa, H.; Synthesis, 1989, 1.

170. Ila, H., Junjappa, H., Barun, O.; J. Organomet. Chem., 2001, 34, 624.

171. Mehta, B. K., Nandi, S., Ila, H., Junjappa, H.; Tetrahedron, 1999, 55, 12843.

172. Scheibye, S., El-Barbary, A. A., Lawesson, S. O.; Tetrahedron, 1982, 38,

3753.

173. Weissberger, A., Wiley, R. H., Wiley, P.; “The Chemistry of Heterocyclic

Compounds: Pyrazolinones, Pyrazolidones and Derivatives’’, John Wiley

(Ed.), New York, 1964.

174. Hiremith, S. P., Rudresh, K., Saundan, A. R. I.; Indian J. Chem., 2002, 41B,

394.

175. Joerg, S., Reinhold, G., Otto, S., Joachim, S. H., Robert, S., Klaus, L., Ger.

Offen.; DE 3, 625, 686; Chem. Abstr., 1988, 108, 167, 465.

176. Dhal, P. N., Achary, T. E., Nayak, A.; J. Indian Chem. Soc., 1975, 52, 1196.

177. Souza, F. R., Souza, V. T., Ratzlaff, V., Borges, L. P., Oliveira, M. R.,

Bonacorso, H. G., Zanatta, N., Martins, M. A. P., Mello, C. F.; Eur. J.

Pharm., 2002, 141, 451.

178. Singh, J., Tripathy, R.; PCT Int. Appl. WO, 2001, 138.

179. Karci, F., Ertan, N.; Dyes and Pigments, 2002, 55, 99.

180. Ho, Y. W.; Dyes and Pigments, 2005, 64, 223.

181. Patel, H. V., Vyas, K. A., Fernandes, P. S.; Indian J. Chem., 1990, 29B, 966.

182. Rao, M. N. A., Satyanarayana, K.; Eur. J. Med. Chem., 1995, 30, 641.

183. Menozzi, G., Colla, P. L., Merello, L., Fossa, P.; Bioorg. Med. Chem., 2004,

12, 5465.

Chapter-I

28

184. Palaska, E., Erol, D., Demirdamar, R.; Eur. J. Med. Chem., 1996, 31, 43.

185. Ming, L., Hua-Zheng, Y., Wei-Jun, F.; Chin. J. Chem., 2004, 22, 1064.