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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-halobenzylidenephenyl- hydrazones, 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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