Dr.

Harish & Purvi Kakrani

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Contents 
Introduction  Classification  Isolation  Structure

Determination  Stereochemistry  Biological Activity

Dr. Harish & Purvi Kakrani

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INTRODUCTION« 

A chemical compound acting against life is called an µAntibiotic¶,obtained either from natural source or by a synthetic method. term µAntibiotic¶ has been derived from the word ³antibiosis´ which according to biological concept means survival of fittest means a process in which one organism may destroy another to preserve itself.
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The 

The

word µAntibiotic¶ was first introduced by vuillemin in 1889 and defined by waksman and latter modified by benedict &langlykke.

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DEFINITION OF ANTIBIOTIC: ³It is a chemical substance produced by or derived from living cell which is capable ,in small concentration ,of inhibiting the life process or even distroying the microorganism.´

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Conditions for chemical compound being an antibiotic.

1)Originally µAntibiotic¶ must have been a product of metabolism although it might have been synthesized. 2) If µAntibiotic¶ is a synthetic product then it should be a structural analogue of naturally occurred µAntibiotic¶. 3) The µAntibiotic¶ must be effective at low concentration. 4)The µAntibiotic¶ must be antagonise the growth and/or survival of microorganism.

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In

order for a particular µAntibiotic¶ to act as a therapeutic agent,it has to satisfy the following conditions:

1) It 2) It 3) It

must be effective against a pathogen. must not cause significant toxic effect. should be stored for a long time period without loss of its activity. 4) Its stability must be high so that it can be isolated and processed into suitable forms of dosage which are readily absorbed in to human body.
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IMPORTANCE OF ANTIBIOTIC: Clinically effective in protozoal infection and fungal infection. Carcinostatic activity Antitumour activity Antibacterial activity Antiviral activity Important tool for study of biochemical cellular mechanism
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‡

‡ ‡ ‡ ‡ ‡

Three ¶ANTIBIOTICS· should be discussed here« PENICILLIN  STREPTOMYCIN  GRISEOFULVIN 

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CLASSIFICATION...
First classification(the broad based classification): a) Broad spectrum Antibiotics: PENICILLINS Tetracycline Chloramphenicol b) Relative broad spectrum Antibiotics: Ampicillin Cephalosporin 

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c) Narrow spectrum Antibiotic:

STREPTOMYCIN(gm -ve) GRESEOFULVIN(antifungal) Amphotericin  Second classification(type of bacteria can antibiotic destroy): a) Effective against Gm +ve bacteria: PENICILLIN Erythromycin Bacitracin
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b) Effective against Gm ±ve bacteria:

STREPTOMYCIN Neomycin Gentamicin c) Effective against both Gm +ve & Gm ±ve: Ampicillin Cephalosporin Tetracycline Chloramphenicol
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Third classification (chemical structure): a) PENICILLIN and related Antibiotics: PENICILLIN SEMISYNTHETIC PENICILLIN b) Aminoglycoside antibiotics: STREPTOMYCIN Neomycin c) Macrolide Antobiotics: Erythromycin 

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d) Tetracycline Antibiotics: Tetracycline Oxytetracycline Chlorotetracycline e) Peptide Antibiotics: Bacitracin Gramicidin f) Chloramphenicol and its synthetic analogues
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g)Antifungal Antibiotics: GRISEOFULVIN Amphotericin h) Unclassified Antibiotics: Cycloserine Fusidic acid Vancomycin

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PENICILLIN

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PENICILLIN POWDER

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µPenicillin¶ is the first antibiotic discovered by alexander flemming .  It was first extracted from P.notatum then P.chrysogenum but now by biofermentation process.  It is also known as beta lactam antibiotics.  The basic structure of Penicillin consists of thiazolidine ring(A) fused with beta lactam ring(B).both these unit form the 6-amino penicillinamic acid. 

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Penicillin has simillarity with L-cysteine and D-valine

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CLASSIFICATION« 
Acid

resistant Penicillin: Penicillin V Phenethicillin  Penicillinase resistant Penicillin: Methicillin Oxacillin  Extended spectrum Penicillin: Ampicillin Amoxicillin
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Reversed

spectrum Penicillin: Temocillin  -lactamase inhibitors: Clauvanic acid Sulbactam

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ISOLATION« 
Various

culture method known which are used to produce Penicillin.  The strains of Penicillin species are grown in a nutrient medium which is obtained from sugary materials and proteinous substance.  P .chrysogenum (NRRL 1951,Stanford 25099,X-1612,176) are widely used strains for the commercial production of Penicillin.
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Typical nutrient medium for penicillin Component Corn steep liqour solid Lactose Glucose CaCO3 KH2PO4 Edible oil Penicillin precursor
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% 3.5 3.5 1 1 0.4 0.25
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Penicillin produced on larger scale by 3 methods:  Liquid surface culture method  Bran method  Submerged method 

In all these methods submerged method is widely used.

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Liquid surface method:The molases containing pH 7-8 is used as medium for microorganisms.After few days the growth of microorganism starts and after 6-7 days,concentration of Penicillin become 0.3-0.4 mg/ml.This method mainly used for lab.studies.  Bran method:The use of moist bran is considered to be substrate for mould growth and resultant Penicillin may be extracted in a liquid or Penicillin containing bran. 

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Submerged culture method:This is widely used method for commercial production of Penicillin.In this method P.chrysogenum is used for the culture.Here culture and culture medium are taken in large tanks.The medium is agitated by a stream of sterile air at 24 c for 2-3 days.After that fermentation vessel is sealed and positive air pressure is maintained.under this condition mould grows throughout the bulk of liquid.
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After

fermentation the contents of vessel should be rapidly cooled and mycellium filtered on sterile rotary filter.  Adjust the pH of fitrate depends upon the nature of solvent extraction that carried out with amyl or butyl alcohol now pet.ether is added and shaken with dil.Na2CO3,adjust the pH 6-7 and rapidly freeze evaporated to yield Nasalt.
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STRUCTURE DETERMINATION«
From analytical data the molecular formula of Penicillin is C9H11N2O4SR. As Penicillin forms mono salts it should be revealed that it contains carboxyl group. From the chemical test it has been proved that penicillin does not contain free amino group.

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When

penicillin are hydrolysed by hot dilute inorganic acids,they degraded to the equimolar amount of Dpenicillimine and penilloaldehyde. C9H11N2O4SR+2H2O C5H11NO2S+C3H4NO2R+CO2 

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Structure
‡ ‡

of D-Penicillamine: Molecular formula of Penicillamine is C5H11NO2S. Penicillamine gives colour reaction with sodium nitroprusside this reveals that it contains thiol group so it is probably substituted cysteine.

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‡

When Penicilline is treated with diazomethane, it is converted into its methyl ester.the later compound when treated with aqueous solution of mercuric chloride gives methyl ester of Penicillamine.this reaction reveals that carboxyl group in Penicillamine is carboxyl group in penicillin itself.

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‡

‡

Like cysteine D-Penicillamine also react with acetone to yield isopropylidene derivative.the later compound does not contain a free amino or thio group and reconverted into Penicillamine on hydrolysis. Further the oxidation of Penicillamine with bromine water gives sulphonic acid. So, D-Penicillamine is , dimethylcysteine,which is confirmed by its synthesis.
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‡ ‡

Structure of Penilloaldehyde: Molecular formula of Penilloaldehyde found to be C3H4NO2R. When hydrolysed vigorously,all Penilloaldehyde yields a substituted acetic acid and amino acetaldehyde.this reaction reveals that Penilloaldehyde are acyl derivatives of amino acetaldehyde.

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The latter structure of Penilloaldehyde has been confirmed by its synthesis from corresponding acid chloride and aminoacetal.  RCONHCH2CHO+H2O RCOOH+ NH2CH2CHO  RCOCl+NH2CH2CH(OC2H5)2 RCONHCH2CHO.
‡

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D-Penicillimine - Penilloaldehyde

Penicillin

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‡

Mode of linking of Penicillamine and Penilloaldehyde: When Penicillin is hydrolysed with dilute alkali it yields Penicilloic acid which is dicarboxylic acid and readily eliminates a CO2 to yield monocarboxylic acid,Penilloic acid.this suggests that in Penilloic acid one of the carboxyl group is in position with respect to electrone attracting group.
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‡

When Penilloic acid hydrolysed with aqueous mercuric chloride,yields Penicillamine and Penilloaldehyde.this type of hydrolysis is characteristic of compound having a thiozolidine ring.

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‡

‡

if ( ) is the structure of Penilloic acid then the structure of Penicilloic acid represented as (ii) (iii) and (iv)are also possible structures of Penicillin.

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Desulphurisation

of benzyl penicillin with raney nickel to yield desthiobenzylpenicillin which on hydrolysis by acid gives desthiobenzylpenicilloic acid it proves existance of -lactam ring in Penicillin.

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The

infrared spectral studies of oxazolone and -lactam structure,and correlation between various band and functional group is worked out.  This could be understood by considering the methyl ester and Nasalt of benzylpenicillin.

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Ir maxima of methyl ester & Na-salt benzyl penicillin
Ir maxima of Ir maxima methyl ester of Na-salt 3333 1770 1748 1684 1506 3333 1770 1613 1681 1515
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assignment NH- group -lactam >C=O 2 amide 2 amide
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The

ir spectra of number of -lactam & fused thiazolidine -lactams are recorded.  The -lactam do not exhibit band at 1770 cm while the other exhibit band at 1770 cm ,this explain the 5th band so it would be concluded that (iv) is the correct structure for penicillin.

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So Finally Structure of Penicillin

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STEREOCHEMISTRY« 
Penicillin

contains a 4 membered lactam ring which is fused through the nitrogen and tetrahedral carbon to a second heterocyclic ring.  All the natural Penicillin are strongly dextrorotatory .  It has been denoted that there are 8 stereoisomers of benzyl penicillin,achieved by changing the orientation of three carbon in structure namely 4,10,14.
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Stereoisomer of benzylpenicillin

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The

incorporation of an ionized or polar group at the - position of the side chain benzyl carbon atom of benzylpenicillin imparts clinical activity against Gm ±ve bacilli.  If we were to find the stereochemistry of cyclisation which forms the lactam ring in Penicillin,we would have to synthesized cysteine with chiral tritium labelling at C-3 by cisaddition of H atom to an olefin of well defined stereochemistry.
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3-D Structure of penicillin

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BIOLOGICAL ACTIVITY« 
Penicillin

inhibits bacterial cell wall formation.the cell wall of bacteria is essential for their normal growth and development.  Peptidoglycan is a component of the cell wall and provides rigid mechanical stability by virtue of its highly crossed linked lattice work structure.

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Penicillin

inhibits the enzymetranspeptidase that brings about cross linking between 5th glycine of the already existing peptidoglycan in the cell wall and 4th amino acid of newly formed peptidoglycan.  In addition, to the peptidoglycan synthesis,Penicillin also inhibits penicillin binding proteins at the cell wall causing lysis of the bacterial cell through autolysing enzymes.
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Penicillin

is bactericidal in action.In its presence the bacterial cell wall become soft and finally undergoes lysis.  It is more effective on actively multiplying organisms.

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STREPTOMYCIN

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STREPTOMYCIN POWDER

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Ineffectiveness

of Penicillin towards Gm ±ve organisms leading to search for newer antibiotics.  Streptomycin was developed as a result of a well planned scientific research by waksman and coworkers in 1944.

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It

was first isolated from Streptomyces griesus by schatz & waksman in 1944.  It is active against Gm ±ve, Gm +ve organism including acid fast bacteria.  Streptomycin and other related antibiotics like kanamycin,Tobramycin,Framycetin etc. are termed as aminoglycoside antibiotics

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chemically

aminoglycoside antibiotics,consists of two or more amino sugars joined in glycosidic linkage to a hexose nucleus.  This hexose is either Streptidine(in streptomycin)or 2-Deoxy streptamine(in other aminoglycoside antibiotics).

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The

number of the amino sugars attached are also different.  kanamycin ,Gentamicin,Tobramycin consists two amino sugars,neomycin consists three aminosugar.

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ISOLATION« 
Initially,Streptomycin

was prepared by surface culture technique but now a days submerged culture technique is widely used.  The yield of Streptomycin depends greatly on medium used.the addition of corn steep liquor, meat extract, soyabean meal enhances the yield.  The medium composed of glucose ,1% peptone, 0.3% meat extract, Nacl 0.5% in water.
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The

culture solution is kept in large vats. The growth of micro organism begins at 24-28 C and maximum yield achieved after 3-5 days.  After seperating mycellium and other wastes,Streptomycin is extracted from filtrate, either by adsorption on charcoal or on base exchangable resin.  Sreptomycin is eluted from column by means of dil.aqueous or alcoholic mineral acid,then purify it by passing
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through ion exchangable resin.  The pure form of Streptomycin has been isolated as sulphate or crystalline double salt of calcium chloride.  To get sterile drug crystaline Streptomycin is dissolved to yield 25% solution which is free from impurity by passing through seitz filter and then freeze dried then transferred aseptically to small vials.
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STRUCTURE DETERMINATION«
From essential analytical data molecular formula of Streptomycin has been found to be C21H39N7O12. As Streptomycin form tri hydrochloride, this shows that its three N atoms must be strongly basic in nature.  C21H39N7O12 +3Hcl C21H39N7O12.3Hcl
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When Streptomycin is hydrolysed in strongly acid solution,it yields one molecule of Streptidine and one molecule of Streptobiosamine.(folkers et al)  Streptomycin+H2O Streptidine+ Streptobiosamine. On the other hand alkaline hydrolysis gives maltol which is believed to be derived from one of the fragment of Streptobiosamine.
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‡ ‡

Structure of Streptidine: From analytical data molecular formula is found to be C8H18N6O4. When it is oxidised with pottasium permenganate,it yields two molecules of guanidine it reveals that Streptidine has two guanidino groups.

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‡

When Streptidine is subjected to alkaline hydrolysis,it yields Streptamine and ammonia.(brink et al) Streptidine+4H2O 4NH3+2CO2 Streptamine+ 

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‡As Streptamine is obtained by alkaline hydrolysis of Streptidine,the following structure may be assigned to Streptidine.this structure is confirmed by its synthesis from Streptamine(wolfrom et al)

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‡

Streptidine is not opticaly active,therefore it was assigned mesoconfiguration with two guanidino group in a cis position.

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‡ ‡

Structure of Streptobiosamine: From analytical study the molecular formula found to be C13H23NO9. When Streptomycin is subjected to methanolysis then hydrolysed finally acetylated,the penta acetate of NMethyl L-glucosamine which on hydrolysis yields N-Methyl Lglucosamine.

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‡ When Streptomycin is reacted with methanolic hydrochloric acid it gives Streptidine di hydrochloride and methyl streptobiosamine dimethyl acetal.
‡

When methyl Streptobiosamine dimethyl acetal is subjected to drastic alkaline hydrolysis yields methyl acetal,indicating the presence of methyl amino group.
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‡

On the other hand less drastic degradation of the Methyl Streptamine by means of acetic anhydride and hydrochloric acid yields N-Methyl glucosamine and Streptose so it would be concluded that Streptobiosamine may be glycoside of N-Methylglucosamine and Streptose.

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‡

When N-Methylglucosamine is treated with phenylhydrazine,it yields a phenylhydrazone.the later can be converted in to phenylosotriazole which has same m.p and an equal but opposite specific rotation as of Dglucose phenylosotriazole.

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‡

When Streptobiosamine is oxidised with bromine,it yields a product which on hydrolysis yields Streptosonic acid monolactone.the lactone is converted into amide which consumes two moles of periodic acid ,indicating the presence of three hydroxyl group.so the structure of Streptosonic Acid Diamide,Streptosonic Acid Monolactone and Streptose may be written as follows:
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Streptobiosamine

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Streptidine

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Streptamine

N-Methylglucosamine Streptose Streptobiosamine

Streptidine

Streptomycin
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‡

Point of linkage between Streptidine and Streptobiosamine: In 1948-49 merck group of chemist established the point of linkage between Streptidine and Streptobiosamine by carried out hydrolysis of benzolyated streptomycin very carefully without disturbing the ester linkage to yield optically active heptabenzoylstreptidine.
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‡

The oxidation product clearly established the structure of dibenzoyl derivative it reveals that ±OH group is adjacent to one of the carbon attached to the guanidino group of streptidine.

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‡

‡

‡

C1 of Streptose unit is involved in linkage between Streptidine and Streptobiosamine. But later compound do not have substituents on C1 it means that substituent must be present for maltol production. Hence,C1 of Streptose is linked glycosidically to the C4 of the Streptidine to yield following structure of Streptomycin.
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Point of linkage between Streptidine and Streptobiosamine.

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Structure of Streptomycin

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STEREOCHEMISTRY« 
Streptomycin

has two important structural features namely aminosugar portion and centrally placed hexose ring.  If Amino sugar portion at C-6 or C-2 position,serve as major target sites for bacterial inactivating enzyme.  If modification at C-1 carbon of centrally placed hexose ring,helps to retain the antibacterial potency.
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Chair conformation

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Streptidine is not optically active.therefore,it was assigned mesoconfiguration with two guanidino groups in a cis position.

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Point of linkage

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3-D structure of Streptomycin

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BIOLOGICAL ACTIVITY« 
It

is bactericidal in therapeutic dose and bacteriostatic in lower dose.it interferes with protein synthesis.  The initial event is penetration of drug into the cell.  The 30s subunit of cell ribosomes is primarily affected which in turn causes inhibition of protein synthesis.it also causes elongation of the cell without permiting final division.
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Ribosomal protein synthesis is inhibited by aminoglycoside by three ways: 1)They interfere with the initiation complex of peptide formation. 2)They induce misreading of the code on the mRNA template. 3)They cause a break up of polysomes into non-functional monosomes. 

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Before producing inhibition of protein synthesis ,it is necessary for aminoglycoside to enter into cytosol of the bacteria by diffusion through aqueous channel or energy dependent electrone transport.

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Non functional proteins produced due to effect of Streptomycin,may be incorporated into the cell membrane leading to further stimulation of aminoglycoside transport and leakage of small and larger molecule.this is the reason of bactericidal action of Streptomycin.

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GRISEOFULVIN
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GRISEOFULVIN POWDER

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Griseofulvin

is an antifungal agent produced by the cultures of P.griseofulvum other penicillium species including P.notatum,P.paltatum.  Grisoefulvin is the drug of choice for widespread or itractable dermatophyte infection.

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Griseofulvin contain neither sulphur nor nitrogen,but contains chlorine.chlorine is supplied as pottasium chloride throughout its production,otherwise the product is dechlorogriseofulvin which is identical to griseofulvin.

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ISOLATION« 
The

principle in Griseofulvin fermentation is to encourage early growth and then,by nutrient limitation,to maintain a cell population just within the aeration potential of the fermentor.  Griseofulvin remains intracellular,at harvest it is the cell that are significant and the filtrate is no of use.the cell can be easily removed by fitration.
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The first step in the recovery of Griseofulvin is to extract the cell with acetone.  The resulting extract is subjected to concentration,thus a crude product is obtained. 

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This

crude product is washed with further organic solvent to remove acetone soluble impurities.  The washed Griseofulvin is redissolved in acetone and solution is mixed carefully with water so it would be precipitated.the large volume of acetone used are recovered for further use.
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STRUCTURE DETERMINATION« 

There is no particular details about structure determination for Griseofulvin. From essential analytical data molecular formula of Griseofulvin is C17H17ClO6. By the usual chemical test it has been shown that Griseofulvin do not have free amino or thiol group.
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Initial inspection of structure of Griseofulvin shows the alternative oxygenation pattern and also methyl group which identifies the start of the polyketide chain.

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From IR spectra studies of Griseofulvin the principal peaks at wave number 1220,1611,1210,1583,1135,800(KBr disc). From Mass spectral studies of Griseofulvin principal peaks acc. to m/z 138,352,215,310,214,69,321,354.

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Structure of Griseofulvin

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BIOLOGICAL ACTIVITY« 
A prominent

morphological menisfastation of the action Griseofulvin is the production of multinucleate cells as the drug inhibit fungal mitosis.the explanation for this phenomenon appears to come from the studies of effects on mammalian cells of higher concentration of the antibiotic.
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Griseofulvin causes disruption of mitotic spindle by interacting with polymerized microtubules,thus action similar to colchicine and vinca alkaloids.

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Griseofulvinµs

binding site on microtubular protein is distinct.there is evidence that it binds to a microtubule associated protein in addition to its binding to tubulin.  Here,by destruction of microtubules responsible for the synthesis of various substance.

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REFERANCE« 

Kar Ashutosh,Pharmacognosy & Pharmabiotechnology 2nd revised edition;New age international publisher. Page:568-694. Kokate C K,Purohit A P,Pharmacognosy,27th edition;Nirali prakashan Page:585-87. Agarwal O P,Organic Chemistry of Natural Products Vol.2,28th edition;Goel publication merut. Page:98-122.
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Comprehensive Medicinal Product,vol 4. Page:100-02. Peter K,Volhardt C,Organic Chemistry: Structure & Function, 3rd edition;W H Freeman & Company,New york Page:898,1102. Indian Pharmacopoiea¶96 vol-1,Published by controller of publication,Delhi.Page:353. British Pharmacopoiea¶93 vol.1 International edition,Page:316,635.
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Devik Paul,A Biosynthetic Approach to Medicinal Natural Product,2nd edition;Willey publication Page:78,437-444,478-480. Patel A H,Industrial Microbiology,Macmillan India ltd, Page:112-22. Manfred Wollf,Berger¶s Medicinal Chemistry &Drug discovery vol2:Therapeutic Agent ,5th edition; Page:46672,642-44. Kar Ashutosh,Medicinal Chemistry;2nd edition, New age publication Page:455-61.
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Manfred Wollf,Berger¶s Medicinal Chemistry &Drug discovery vol 4:Therapeutic agent;5th edition Page:28593. Goyal R K, Element of Pharmacology 14th edition 2004-05;B S Shah Prakashan, Page:486-88,500-02,530. Rang &Dale,Pharmacology,5th edition;elsevier publication,page:63947,666-69.
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Clarke¶s Isolation &Identification of Drug in Pharmaceutical Body Fluid and Postmorterm Material,2nd edition;The Pharmaceutical press.Page:645. Foye Willium,Williams A David,Principal of Medicinal Chemistry 4th edition;B I Waverly Pvt ltd,New Delhi.Page:1190-93,1222. Tripathi K D,Essentials of Medical Pharmacology,5th edition;Jaypee Page:653-57,681-82.
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Bothra K G, Kadam S S,:Principles of Medicinal Chemistry vol 2 15th edition; Nirali Prakashan Page:69-72,84. Munson Paul,Maller,Breese: Principles of Pharmacology;Basic Concept &Clinical application, Hall publication Page:131922,1351-57,1409. Gilman,limbird;Goodman &Gilman¶s Pharmacological Basis of Therapeutics,10th edition; International edition Page:118993,1219-24,1305-06.
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