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Bio-Active Heterocyclic Compounds

As Potential Antimicrobial Agents

A Thesis SubmittedTo

BHAVNAGAR UNIVERSITY

UNDER THE GUIDANCE OF

Dr. N. C. DESAI

(PROFESSOR IN CHEMISTRY)

UNIVERSITY DEPARTMENT OF CHEMISTRYBHAVNAGAR UNIVERSITY

BHAVNAGAR- 364 002 (INDIA)

Date : 17/05/08


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Objective

The fundamental goal of this work

is to try to assist the chemist in hissearch for what to make next.


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Contents Synopsis General introduction

Studies on 4-oxo-quinazoline and 4-oxo-thiazolidine derivatives

Studies on 5-imidazolonederivatives

Studies on [1,2,4]-triazolederivatives

Biological evaluation andCharacterization of compounds

Conclusion


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General Introduction

Medicinal chemistry is the design and synthesis

of novel drugs, based on an understanding of howthey work at the molecular level. A useful drug mustinteract with a molecular target in the body and alsobe capable of reaching that target.

Most of the activity in this discipline is directedto new natural or synthetic organic compounds.

A logical approach to the study of drugs andtheir activities is the recognition of the basicprinciples behind the biochemical events leading todrug actions.


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Perspectives of Drugs

In a broad sense Medicinal Chemistry is a science ofDrugs.

It deals with the exogenously administratedchemical molecules with living systems.

The fundamental objective of drug research is tolearn the cellular language in order to devisemeaningful and specific message.

Pharmacotherapy is usually concerned with twofactors:

Drug and Organism


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Drugs Discovery Our society is faced with challenges such as new disease like AIDS,

drug resistance, and aggressive agriculture pest control processes,which can have a chemical agreement.

To design new drug with improved properties and diminished side-effects, and to assess the safety of some chemicals.

The assessment of the risk of chemicals released to the environment

and the evolvement of environmentally benign synthesis method isstrongly required.

There is also a demand on scientific methods that replace or at leastrefine and reduce the use of laboratory animals.

It should be Cost effective.

Many of the concepts and methodologies applied to the design ofmedicinally interesting compounds


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Drugs DevelopmentIt takes on average about 12-15 years to develop a drug from

an idea through to a product that can be sold for use in patients.

A little more than half of this time is spent testing the drug inthe laboratory (known as 'pre-clinical' testing).

The remaining is spent testing the product in humans (known as'clinical testing) and having the data reviewed by the regulatory

authorities.


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Agents

Selective toxicity

Antimicrobial spectrum No side effects

No killing effect on normal flora

No inactivation

Solubility in body fluids Sufficient concentration of the drug in target tissues

Low break-down rate of drug

No development of drug-resistance

Stable viability

Easily availability at affordable cost/price


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Different Possible Route For Synthesis of4-Oxo-quinazoline Moiety

N

N

R

O

R'

CO2CH3

NH2

N

RCl

R'

NH

O

R'

NO2

reflux,2 days

N

O

R

O

(CH3CO)2O

COOH

NHCOR

COOH

NH2

Formamide

RCOCl

(i)

(ii)

(iii)( A )

(v)

(vi)

COOH

NH2

RCONHR'

SOCl2 / DMF

HCl / R-CH2OHSnCl2

(i)

H2NR'

(R, R' =H)

Anthranilic acid is heated with excess of formamide in presence ofthionyl chloride, water is expelled and a nearly quantitative conversion of4-oxo-quinazoline (A) is achieved. (A) are the formal condensation productsof anthranilic acid and amides, and these can also be prepared in this fashionthrough the Niementowski (1866-1925) quinazolinone synthesis.


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Pharmaceutical Importance of4-Oxo-quinazolines

N

NCl

H2NO

2S

O

H

CH3

CH3

Zaroxolyn (metolazone) is a currently available drug inmarket which belongs to quinazoline class havingdiuretic/antihyper-tensive potency.

NH

N

N OH

O

O

N

N

O

O

NH

OH

Shingo Hirai and coworkers synthesized Quinazolinone typealkaloids, febrifugine and isofebrifugine isolated from Dichroafebrifuga roots, show powerful antimalarial activity against

Plasmodium falciparum.


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Chemistry and Mechanism of4-Oxo-thiazolidines

Most of the thiazolidines have been prepared by thecondensation of the required aldehydes with hydrazides and2-sulfanyl acetic acid. Here, electronegative sulphur acquiresnegative charge, which in turn is responsible for the attractionbetween sulphur and the electropositive imino carbon. To maintainthe stability carbon breaks the -Bond with nitrogen atom, leading

to the development of negative charge on nitrogen. This reactivenitrogen attacks on the carbonyl carbon, which has positive chargethus eliminating hydroxy group and forming the Thiazolidinonering. The hydroxyl group and the hydrogen atom releasedcombines together to give a water molecule.

O OH

H

HS

N

Ar

R

N

S

O Ar

R

H


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N

N

CH3

O

S

O

O

N

S

ArO

R

Pharmaceutical Importance of4-Oxo-thiazolidines

N C Desai et al have synthesized several 4-oxo-quinazoline and thiazolidine derivatives and

tested them for their anti HIV, anticancer andantitubercular activities.

Shanker and coworkerssynthesized several quinazolinesas potential anti-inflammatory

agents. Panamkant and Saksenasynthesized 2-phenyl-3-p-(2 -ethyl-3 -aryl-4 -oxo- thiazolin-2 -yl)phenyl quinazolin-4-onesand studied their antimicrobial

activity.

N

NN

C6H5

O SO


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Reaction Scheme of 4-Oxo-quinazoline

COOH

NH 2

COCl

CH3

N

O

O

CH3

Pyridine

0-4oC, 2 hrs.

N

N

OCOOC2H5

CH3

NH 2

COOC2H5

Pyridine

NH 2NH 2H2O

++

Methanol, 6-7 hrs.N

N

CH3

O NHNH 2

O

Compound C Compound B

Compound A

8-9 hrs.


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N

N

CH3

NH

N

SO

O

O R

SHCH 2COOH

1:4 Dioxane, 6-7 hrs.

Where, Ar = Different aryl groups

N

N

CH3

NH

N

SO

O

O

Ar

R

Ar H

O

NaOMe, 8-9 hrs.

N

N

CH3

O NHNH 2

O

Methanol, 6-7 hrs.

Compound C

(1) (2)R-CHO

Compound D

Compound E

Reaction Scheme of 4-Oxo-thiazolidines


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N NN

N N

NH

Cl

HO

n-BuLosartan

Studies on 5-Imidazolone Derivatives

Many of the azoles comprise the ring system of several

natural and synthetic compounds which are important for theliving systems and also as important drugs, dyes andagricultural chemicals.

IMPORTANT ANTIBACTERIAL AND ANTIFUNGAL DRUGS

One of these {2-butyl-5-chloro-3-[2-(1H-tetrazol-5-yl)- biphenyl-4-ylmethyl] -3H-imidazol-4-yl}methanol[Losartan] is undergoing extensiveclinical evaluation. This pioneer work

initiated a flurry of activity inpharmaceutical research, and manyother nonpeptide orally active AT1angiotensin-II receptor antagonists havebeen reported.

Diff P ibl R F S h i f


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X

OH

CH3O

CHO+

CONH

COOH CH3COONa

(CH3CO)2O

X

OH

CH3O

N O

O

X

OH

CH3ON N

O Zeolite (Y-H)

Ar-NH 2

Where X = Br / I

R

(A) (B)

(C)(D)

Different Possible Route For Synthesis of5-Imidazolone Moiety

N O

Ar

OR

NH

R NH

O

Ar

O

R1

R1-NH2K2CO3 POCl3

N N

O

R1

Ar

R

R1-NH2

Ethanol

Ar = -C6H5, R = Different aryl groups, R1 = Alkyl or aryl groups

4-arylidine-imidazolin-5-ones

Amides of acylamino acrylic acids

S A Siddiqui et al introducedsome new imidazolone (D),

synthesized by the condensation ofaromatic and substituted aromaticamines with 5-oxazolonederivatives (C) in presence of (Y-H)Zeolite. The 5-oxazolone derivativesare prepared by the condensation ofhippuric acid with 5-bromo/iodo-4-

hydroxy-3-methoxy benzaldehyde inpresence of sodium acetate andacetic anhydride.

S f T f ti f


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Sequence of Transformation ofImidazolone From Oxazolone

(a)Cyclisation of hippuric acid and aromatic aldehydes to form Oxazolones.

(b)Proton abstract by base results in the generation of carbanion.

(c) Carbanion attacks on carbonyl carbon of aldehyde, followed by

dehydration .

(d)Ring opening by attack of amine.

(e)Ring closure results in the formation of imidazolone ring.

N O

Ar O

N

H

H Ar

N

OH

N

H

Ar

OAr

N NAr

Ar O

.. ..

Ph ti l I t f


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N

N

O

Ph

NH

N

N

O

CH3

C6H5

Pharmaceutical Importance of5-Imidazolone Derivatives

Imidazolone ring system is of biological and chemical interest since long. The

imidazolinones are associated with a wide range of therapeutic activities such asanticonvulsant, sedative and hypnotic, potent CNS depressant, antihistamine,antimalarial, bacteriocidal, fungicidal, anti-inflammatory, MAO inhibitory,antiparkinsonian, antihypertensive and anthelmintic.

Hooshang et al synthesized 3-methyl-2-{[5-oxo-2-phenyl-4-(phenylmethylene)(2-

imidazolinyl)]amino}-3- hydroquinazolinones which is an important compound inchemistry and pharmacology.


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Reaction Scheme of 5-Imidazolone

N O

OAr

+

Pyridine

CONHCH 2COOH

AnhydrousCH3COONa

(CH3CO)2O

Ar H

O

N

N

O

NHH2N

O

R

+

Where, Ar = Different aryl groups,

N

N

O

NH

O

NN

Ar O

R

R = 3-Nitrophenol, 4-Nitrophenol

N-benzoyl amino acetic acid

150oC, 6-8 hrs.


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Studies on [1,2,4]-Triazole Derivatives

The presence of additional nitrogen atoms in the five-membered ring has important effects on the properties of the

ring system.

Triazoles have been found to exhibit properties such asanticonvulsant, analgesic, anti-inflammatory, herbicidal,

anthelmintic, CNS depressant, antitumor agent and

tranquilizing. Fluconazole, Ribavirin, Triazolam, Itraconazole,

Viramidine, Voriconazole and Terconazole are leading

N-substituted 1,2,4-triazole derivatives and these are used on

tropical antifungal infections.


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N N

NH

1

2

3

45

Molecular Geometry of [1,2,4]-TriazoleStudies carried out at 1600C proves the molecular dimensions

as shown in following table for one unit of a pleated sheet linked

by hydrogen bridges. Slightly different values are obtained atroom temperature or in substituted aromatic triazoles.

aThe numbering refers to annular centers in 1,2,4-triazole.

Angle () Bond Bond length (m)

5-1-4 110.2 1-2 135.9

1-2-3 102.1 2-3 132.3

2-3-4 114.6 3-4 135.9

3-4-5 103.0 4-5 132.44-5-1 110.1 5-1 133.1

N(4)-H 103.0

C(2)-H 93.0

C(5)-H 93.0

Diff t P ibl R t F S th i f


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Et3N

+

PhCN

N

NN

Ar

Ph

Ph

N

NN

Ph

Ph

Ph

H

Ph

N

NN

Ph

Ph

Ph

O

PhCH NPh

PhC N NPh-

PhNCO

PhC NNHPh

Cl

C-halobenzylidenephenylhydrazones

Nitrilimines

Different Possible Route For Synthesis of[1,2,4]-Triazole Moiety

Route (1) 1,3-dipolar cycloadditionsleading to a great variety of heterocyclic

systems are applicable to the synthesis oftriazoles and derivatives. Nitriliminesformed by dehydro-halogenation of C-halobenzylidenephenylhydrazones, whichreact with phenylcyanide, phenylisocyanate and benzylidenephenylamine to

afford triazoles derivatives.


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Route (2) Ring closure of acylderivatives of semicarbazides,thiosemicarbazides or aminoguanidinesin alkaline solutions is a method widelyapplied for the preparation of 1,2,4-triazoles. Gehlen reported that 3-hydroxy-5-alkyl1,2,4-triazoles areproduced in 65-75% yield by thismethod.

N

NH

O

NH 2

OR'KHCO3

NH

N

N

OH

Where R'=H, C6H5

h i l f


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Where W = H, CH3, F, OH, CH2OH, Ph

X = O, CH2, NR3. R3 = H/Cl/6 alkyl

Y = phenyl, naphthyl

NNH

NH

SWXY

Svensson et al synthesized2,4-dihydro-[1,2,4] triazole-3-thione.

These compounds are inhibitors of theenzyme myeloperoxidase (MPO) andare thereby particularly useful in thetreatment of prophylaxis of

neuroinflammatory disorders.

Pharmaceutical Importance of[1,2,4]-Triazole Derivatives

R.R.Kamble et al have developeda 3-substituted-2-aryl-5-methyl- 5-thioxo- [4,4-bi-4H-1,2,4-triazol]-

3(1H,2H)-ones and found intresingproperties, such as antinociceptive,anticancer and plant growth regulativeactivities.

N

N

N N

N

NHR

O S

CH3 R'

Where R=Aryl groups, R'=Alkyl groups

Commercially Available [1 2 4] Triazoles As


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N N NN

N

O

H3C

CH3

O O

OH

NN

N

Cl Cl4. Itraconazole

OH

NN

N

N

N

N

F

F

1. Fluconazole

N

N

N

NH2

O

O

HO OH

HO

2. Ribavirin

Cl

N

N

N

N

CH3

Cl

3. Triazolam

O

HO OH

HO

N

N

N

NH2

NH

5. Viramidine

CH3

N

N

N

N

N

F

OH

F

F

O

N

N CH3

CH3

O

O

ClCl

N

NN

6. Voriconazole 7. Terconazole

Commercially Available [1,2,4]-Triazoles AsAntimicrobial Agents


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Reaction Scheme of [1,2,4]-Triazole

Where, Ar = Different aryl groups

NHNH 2

O

R

CS2KOH

C2H5OH

Compound A

S- K+

C2H5OH

Ar-CONHNH 2

NHONH

S

R

N

N

N NH

ArOSH

R

R = ,

,

,4-Chloro-1-methoxybenzeneNaphthalene

Methoxynaphthalene1-Methyl-3-nitrobenzene


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Biological Evaluation

scherichia coli (Gram negative) MTCC-443

seudomonas aeruginosa (Gram negative) MTCC-1688

taphylococcus aureus (Gram positive) MTCC-96

treptococcus pyogenes (Gram positive) MTCC-442

andida albicans MTCC-227

spergillus niger MTCC-282

spergillus clavatus MTCC-1323

ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES OF THE

COMPOUNDSSYNTHESISED IN PART - I , II & III.


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K. Nystatin

O

HOCH3

H3C

O OH OH OH

OH

OH O

OH

H3C

OH

O

OH

O O

HO

NH 2

OH

CH3

ONH

O

HO O

NH 2

H2N

O

H2N

NH

OH

Gentamycin

Important Antibacterial & Antifungal Drugs

Experimentation For Antibacterial Screening


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Characterization

We have determined the structure of thenewly synthesized compounds by their Infraredspectroscopy (IR), Gas Chromatography MassSpectroscopy (GCMS) and Proton Magnetic

Resonance Spectroscopy (PMR).


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Conclusion

Discussion of antibacterial activity

Part-I deals with the synthesis and antibacterial activities ofquinazoline which bears the 4-oxo-thiazolidine. On the basis of theresults of antibacterial activity, it has been observed that compoundsPI-07, PI-12, PII-05, PII-06, PII-07, PII-10, PII-14, PIII-05, PIII-11, PIV-01, PIV-04, PIV-06, PIV-07, PIV-09, PIV-11 and PIV-13 were found to be

moderately active. PI-07, PI-13, PII-07, PII-08, PII-11, PIII-11 and PIV-02 showed good activity against E. coli, while compound PII-01, PII-10, PII-14, PIII-02, PIII-06, PIII-07 and PIII-13 showed excellent activityagainst E. coli and P. aeruginosa.

Part-II describes the preparations and antibacterial activitiesof 5-imidazolones. From the results of antibacterial activity, it hasbeen observed that compounds PV-11, PV-12, PVI-01, PVI-03, PVI-04,

PVI-11, PVI-12, PVI-13, PVI-14, PVII-03, PVII-04, PVII-06, PVII-10,PVII-11, PVII-12, PVII-13, PVII-14, PVIII-02, PVIII-04, PVIII-10, PVIII-11,PVIII-12 and PVIII-13 are moderately active.


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Conclusion

Discussion of antibacterial activity

Compound PIV-02, PVI-04, PVI-07, PVII-03, PVII-06, PVII-10,PVII-12, PVII-14, PVIII-05, PVIII-06, PVIII-07, PVIII-12 and PVIII-14exhibit good activity. Compounds PVI-05, PVI-07, PVI-09, PVI-10 andPVIII-02 showed excellent activity against E. coli.

Part-III encompasses the preparations and antibacterialactivities of 1,2,4-triazoles. Results of antibacterial activity indicatethat compounds PIX-02, PIX-03, PIX-08, PIX-10, PIX-11, PIX-12, PX-04,PX-08, PX-09, PX-12, PXI-03, PXI-04, PXI-08, PXI-09, PXI-12, PXII-01,PXII-02, PXII-04, PXII-07 and PXII-11 are moderately active.

Compounds PIX-01, PIX-06, PX-01, PX-04, PXI-06, PXI-08, PXI-12, PXII-01, PXII-04 and PXII-11 showed good activity, whereas compoundsPX-08, PXI-10, PXII-09 showed excellent activity against E. coli.


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Discussion of antifungal activity

The results of the compounds synthesized in part 1 to 3 clearlyreveals that PIII-02, PIII-09, PIV-10, PV-12, PVI-06, PVI-13, PVIII-02, PVIII-04 and PIX-11 were found to be comparable with standard drugagainst C. albicans, A. nigerandA. clavatus.The compounds PVIII-05,PIX-06, PIX-07, PIX-10 were found to be quiet active compared tostandard drug against C. albicans while compound PVIII-05, PIX-07

and PIX-10 were found to be quiet active compared to standard drugagainstA. niger. Moreover compound PVIII-05, PIX-07 and PIX-10 werefound to be quiet active compared to standard drug against A.clavatus.

For antibacterial activity, in present protocol, 100 g/ml isconsidered as moderate activity and 50 g/ml is considered as goodactivity. 25 and 12.5 g/ml are considered as excellent as compared tothe standard drug Gentamycin. For antifungal activity, 100 g/ml isconsidered as compared to standard drug. 50 g/ml is reported asactive compared to standard drug K. Nystatin.

Conclusion


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N N NH

OO

NH

PS

OC2H5

OC2H5

Ar

SECTION : 8

N

N

N NH

Ar

OSH

SECTION : 9

PVIII -05 Where Ar = -2-OH-C10 H6

C. albicans (FBC) = 50 g/mlA. niger(FBC) = 50 g/mlA. clavatus (FBC) = 50 g/ml

PIX-06 Where Ar = -2-Cl-C6H4C. albicans (FBC) = 50 g/ml

PIX-07 Where Ar = -3-Cl-C6H4C. albicans (FBC) = 50 g/ml

A. niger(FBC) = 50 g/mlA. clavatus (FBC) = 50 g/ml

PIX-10 Where Ar = -4-NO2-C6H4C. albicans (FBC) = 50 g/mlA. niger(FBC) = 50 g/ml

A. clavatus (FBC) = 50 g/ml

In the present work, we found some of the interesting antifungalagents and we may send these compounds for the in vivo screening. Thestructures of the compounds are as under with their FBC value.


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The 2nd half of the 20th century showed a remarkable

advance in the therapy of bacterial infections.Unfortunately due to the excess use of some currently

available antibacterial agents, the bacteria begin to fight

back-developing mechanism for resisting the antimicrobial

agents. And due to this there is a urgent need to find out

some new antibacterial agents. Keeping this in mind, we

have focused on the synthesis of some bioactive molecules

like imidazolone with a quinazolone moiety, and triazole

derivatives. On the basis of the results of antimicrobial

activity, we conclude that still there is a wide scope forthese derivatives in Medicinal Chemistry and by the help of

these compounds we may generate lead molecules.

The road ahead in Medicinal Chemistry


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