ANTIBIOTICS[PENICILLINS] MEDICINAL CHEMISTRY BY RAVISANKAR

Dr. P. RAVI SANKAR
M. Pharm, Ph.D.
Professor & HOD
Vignan pharmacy college,
Vadlamudi- Guntur, A.P, India.
PENICILLINS

““AntibioticsAntibiotics are defined as chemical substances orare defined as chemical substances or
compounds produced by various species of microorganismscompounds produced by various species of microorganisms
such as bacteria and fungi, which in low concentrationssuch as bacteria and fungi, which in low concentrations
destroy, kill or inhibit the growth of other species ofdestroy, kill or inhibit the growth of other species of
microorganisms.”microorganisms.”
Greek wordsGreek words anti = against ; bios = life.anti = against ; bios = life.
Vuillemin to define antibiotics literally meaning “againstVuillemin to define antibiotics literally meaning “against
life”life”
In 1942 Waksman proposed the widely cited definition that “an antibiotic is aIn 1942 Waksman proposed the widely cited definition that “an antibiotic is a
substance produced by microorganisms, which has the capacity of inhibiting thesubstance produced by microorganisms, which has the capacity of inhibiting the
growth and even of destroying other microorganisms”.growth and even of destroying other microorganisms”.
 The word antibiotic came from the wordThe word antibiotic came from the word antibiosisantibiosis a terma term
coined incoined in 18891889 by Louis Pasteur'sby Louis Pasteur's pupilpupil Paul VuilleminPaul Vuillemin whichwhich
means a process by whichmeans a process by which life could be used to destroy lifelife could be used to destroy life..
However, by acylating it with various acid derivatives, more thanHowever, by acylating it with various acid derivatives, more than
50,00050,000 semisynthetic penicillins have been made, of whichsemisynthetic penicillins have been made, of which less thanless than
3030 are currently used in medicine.are currently used in medicine.
DEFINITION
:

Requirements for a substance to be considered as an antibioticRequirements for a substance to be considered as an antibiotic

-It should have a-It should have a wide spectrumwide spectrum of activity with theof activity with the ability to destroyability to destroy
or inhibitor inhibit many different species of pathogenic organisms.many different species of pathogenic organisms.
 -It should be-It should be eliminated completelyeliminated completely from the body.from the body.
 -It should-It should not produce adverse and side effectsnot produce adverse and side effects..
 -It should-It should antagonizes the growthantagonizes the growth or survival of one or more speciesor survival of one or more species
of microorganisms.of microorganisms.
 -It should be-It should be highly effectivehighly effective in low concentrations.in low concentrations.
 -It should be-It should be nonallergenicnonallergenic to the host.to the host.
 -It should-It should notnot eliminate theeliminate the normal floranormal flora of the host.of the host.
 -It should be-It should be able to reachable to reach the part of the human body wherethe part of the human body where
the infection is occurring.the infection is occurring.
 -It should be-It should be inexpensiveinexpensive andand easy to produceeasy to produce..
 -It should be-It should be chemically-stablechemically-stable (have a long shelf-life).(have a long shelf-life).
 -It is a product of metabolism (although it may be duplicated or even-It is a product of metabolism (although it may be duplicated or even
have been anticipated by chemical synthesis).have been anticipated by chemical synthesis).

 HHistory of antibiotics can be described inistory of antibiotics can be described in two segmentstwo segments early history and modernearly history and modern
historyhistory..
 Most important is the discovery of penicillin by SIRMost important is the discovery of penicillin by SIR Alexander Fleming.Alexander Fleming.
 EARLY HISTORYEARLY HISTORY::
 During ancient timesDuring ancient times ::
 Long ago before 20Long ago before 20thth
century there was no proper treatment for diseases.century there was no proper treatment for diseases.
The diseases caused byThe diseases caused by Mycobacterium tuberculosis, Mycobacterium lepraeMycobacterium tuberculosis, Mycobacterium leprae were not identifiedwere not identified
..
 Over 2,500Over 2,500 years ago , Chinese usedyears ago , Chinese used plants and moldy cheese usedplants and moldy cheese used to treat infected wounds.to treat infected wounds.
 As early as 500 to 600 BC, molded curd of soybean was used in Chinese folk medicine to treatAs early as 500 to 600 BC, molded curd of soybean was used in Chinese folk medicine to treat
boils and carbuncles.boils and carbuncles.
 The ancientThe ancient Egyptians used honey + lint (softEgyptians used honey + lint (soft cotton cloth covering and protecting wounds)+cotton cloth covering and protecting wounds)+lardlard
(melted fat of pigs) used as ointment(melted fat of pigs) used as ointment for dressing wounds.for dressing wounds.
 EgyptiansEgyptians have often been foundhave often been found onions in body cavities of mummiesonions in body cavities of mummies. They used onions,. They used onions,
garlic and radish herb therapeutically. Infact they havegarlic and radish herb therapeutically. Infact they have anti-infective properties.anti-infective properties.
 GreeksGreeks and Indians usedand Indians used mouldsmoulds and other plants to treat infections.and other plants to treat infections.
 InIn Greece and Serbia, moldy breadGreece and Serbia, moldy bread was traditionally used to treat wounds andwas traditionally used to treat wounds and
infections.infections.
 Warm soilWarm soil was used bywas used by RussiansRussians to cure infected wounds.to cure infected wounds.
 Sumerian doctorsSumerian doctors gave patientsgave patients beer soup mixed with turtle shells and snakebeer soup mixed with turtle shells and snake
skinsskins..
 Babylonian doctorsBabylonian doctors healed the eyes using a mixture ofhealed the eyes using a mixture of frog bile and sour milkfrog bile and sour milk ..
Sri Lankan armySri Lankan army usedused oil cake (sweetmeat)oil cake (sweetmeat) to serve as antibacterial.to serve as antibacterial.

TREATMENT OF INFECTIOUS DISEASES PRIOR TO ANTIBIOTICS.
Centuries earlier, humans had learned to use crude preparations for the
topical treatment of infections.

Modern HistoryModern History Late 1800’s = Search for antibiotics began with the growing acceptance of the germ theory ofLate 1800’s = Search for antibiotics began with the growing acceptance of the germ theory of
disease(disease(Louis Pasteur was one of the first recognized physicians who observed that bacteria could beLouis Pasteur was one of the first recognized physicians who observed that bacteria could be
used to kill other bacteria)used to kill other bacteria)
 1871 = The surgeon joseph lister found urine contaminated with1871 = The surgeon joseph lister found urine contaminated with
mould couldn't kill the bacteria.mould couldn't kill the bacteria.
 1890’s = German doctors Rudolf emmerich, oscar low made1890’s = German doctors Rudolf emmerich, oscar low made
pyocyansepyocyanse from microbes. It was the first antibiotic usedfrom microbes. It was the first antibiotic used
in hospitals but the drug did not work.in hospitals but the drug did not work.
 1909 =First modern chemotherapeutic agent1909 =First modern chemotherapeutic agent SALVARSANSALVARSAN for thefor the
treatment of syphilis.(Paul Ehrlich)treatment of syphilis.(Paul Ehrlich)
 19281928 = Scottish bacteriologist= Scottish bacteriologist Sir Alexander Fleming discovered enzymeSir Alexander Fleming discovered enzyme
lysozyme and the antibiotic substance penicillin.lysozyme and the antibiotic substance penicillin.
 1932 = Gerhard Domagk discovered1932 = Gerhard Domagk discovered ProntosilProntosil a prodrug.a prodrug.
 1936 = Sulfanilamide the first synthetic sulfonamide in human medicine.1936 = Sulfanilamide the first synthetic sulfonamide in human medicine.
 1940 =1940 = Invention of Modern Drug Discovery: Ehrlich & The Magic Bullet means
compound that selectively targets a disease causing organism while having
no negative effect on human tissue.no negative effect on human tissue.
 1940 =First therapeutic use of penicillin by Floury.1940 =First therapeutic use of penicillin by Floury.
 1944 = Selman waksman made Streptomycin from soil bacteria.1944 = Selman waksman made Streptomycin from soil bacteria.
 1948 = Chlortetracycline.1948 = Chlortetracycline.
 1957 = Nystatin (fungal infections)1957 = Nystatin (fungal infections)
 1970’s = New 4-quinolones(pipemidic acid,oxolinic acid,cinoxacin)1970’s = New 4-quinolones(pipemidic acid,oxolinic acid,cinoxacin)
 1980 =Norfloxacin, the first fluoroquinolone.1980 =Norfloxacin, the first fluoroquinolone.
 1980 =Enroflocacin.1980 =Enroflocacin.
 1998 =Smithkline Beecham patented Amoxicillin/clavulanate potassium tablets1998 =Smithkline Beecham patented Amoxicillin/clavulanate potassium tablets
the first sold antibiotic under the trade names of Amoxil and trimox.the first sold antibiotic under the trade names of Amoxil and trimox.

 CLASSIFICATIONCLASSIFICATION :: Antibiotics are classified in many ways based on chemical structure, source,itsAntibiotics are classified in many ways based on chemical structure, source,its
spectrum of activity and Mechanism of action (MOA).spectrum of activity and Mechanism of action (MOA).
 *Based on the chemical structure:*Based on the chemical structure:
 1.1.β-lactam antibioticsβ-lactam antibiotics : Penicillin's, Cephalosporin's, carbapenams, monobactams.: Penicillin's, Cephalosporin's, carbapenams, monobactams.
 2.2. Amino glycoside antibioticsAmino glycoside antibiotics : Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin,: Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin,
Amikacin.Amikacin.
 3.3. TetracyclinesTetracyclines:: Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline,Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline,
methacycline, meclocycline.methacycline, meclocycline.
 4.4. Macrolide antibioticsMacrolide antibiotics :: (i.e., large macrolide structure)(i.e., large macrolide structure)::EryErythromycin,thromycin, ClariClarithromycin,thromycin, AziAzithromycinthromycin,, RoxiRoxithromycin.thromycin.
 55.. PolypeptidePolypeptide antibioticsantibiotics : Actinomycin, Bacitracin, Colistin, Polymyxin B, tyrothricin: Actinomycin, Bacitracin, Colistin, Polymyxin B, tyrothricin
 6.6. Polyenes:Polyenes: Amphotericin B, Nystatin.Amphotericin B, Nystatin.
 7.7. Lincomycin:Lincomycin: Clindamycin.Clindamycin.
 8.8. MiscellaneousMiscellaneous: Chloramphenical, Novobiocin, Mupirocin, Fucidic acid.: Chloramphenical, Novobiocin, Mupirocin, Fucidic acid.
 *Based on the source*Based on the source :: They are divided in toThey are divided in to
 Natural antibioticsNatural antibiotics :: Penicillium chrysogenum-Penicillium chrysogenum---- Penicillin.--- Penicillin.
 Bacillus subtilisBacillus subtilis --------------- Bacitracin.--------------- Bacitracin.
 Bacillus polymyxaBacillus polymyxa ------------- Polymyxin.------------- Polymyxin.
 Stryptomyces griseus-Stryptomyces griseus---------- Stryptomycin.--------- Stryptomycin.
 Streptomyces aureofaciensStreptomyces aureofaciens ---Chlortetracyclines---Chlortetracyclines
 Streptomycers erythreusStreptomycers erythreus -------Erythromycin-------Erythromycin
 Streptomyces venezulae-Streptomyces venezulae------- Chloramphenicol.------ Chloramphenicol.
 Semisynthetic antibioticsSemisynthetic antibiotics : These antibiotics are commercially synthesized by adding chemical: These antibiotics are commercially synthesized by adding chemical
compounds, amides etc., to the natural antibiotics. In these the main part of the chemical structure iscompounds, amides etc., to the natural antibiotics. In these the main part of the chemical structure is
obtained from the micro-organisms which are then modified by adding various chemical moieties as the sideobtained from the micro-organisms which are then modified by adding various chemical moieties as the side
chain.chain.
 Ex:Ex: Ampicillin, Amoxacillin, Oxacillin, Cloxacillin, Dicloxacillin, Carbencillin. Methicillin.Ampicillin, Amoxacillin, Oxacillin, Cloxacillin, Dicloxacillin, Carbencillin. Methicillin.
 **Spectrum ActivitySpectrum Activity ::
 Broad spectrumBroad spectrum: These antibiotics inhibit the growth of wide range (i.e. More than one species) of: These antibiotics inhibit the growth of wide range (i.e. More than one species) of
microorganisms. Some antibiotics can inhibit both Gram- positive and Gram-negative bacteria.microorganisms. Some antibiotics can inhibit both Gram- positive and Gram-negative bacteria.
 EX:EX: Cephalosporins, Chloramphenicol, Tetracycline’sCephalosporins, Chloramphenicol, Tetracycline’s..
 Narrow spectrumNarrow spectrum:: These antibiotics are effective mainly against a single species of microorganism eitherThese antibiotics are effective mainly against a single species of microorganism either
 Gram +ve (or) Gram –ve bacteria. EX: -Gram +ve (or) Gram –ve bacteria. EX: - Bacitracin, Nystatin, PenicillinBacitracin, Nystatin, Penicillin..

 Antibiotic activityAntibiotic activity :Based on their activity against different m.o’s they are divided in to:Based on their activity against different m.o’s they are divided in to
 a. Antibacterial antibiotics:a. Antibacterial antibiotics: The chemotherapeutic agents which kill or inhibit the growth of bacteriaThe chemotherapeutic agents which kill or inhibit the growth of bacteria
 are called antibacterial antibiotics. (penicillins, cephalosporins, tetracyclines, aminoglycosides)are called antibacterial antibiotics. (penicillins, cephalosporins, tetracyclines, aminoglycosides)
 1.1. Bactericidal antibioticsBactericidal antibiotics :: These are more effective in killing harmful microorganisms particularlyThese are more effective in killing harmful microorganisms particularly
bacterialbacterial
species. (species. (Kill the bacteria directlyKill the bacteria directly)) ExamplesExamples are …..are …..
22. Bacteriostatic antibiotics:. Bacteriostatic antibiotics: These are effective in abolishing or preventing the growth ofThese are effective in abolishing or preventing the growth of
bacterial species. (bacterial species. ( stop the bacteria from growingstop the bacteria from growing ):):
EX: Tetracyclines, Chloramphenicol, Clindamycin.EX: Tetracyclines, Chloramphenicol, Clindamycin.
b.b. Antifungal antibioticsAntifungal antibiotics : Griseofulvin, Amphoterisin B, Nystatin.: Griseofulvin, Amphoterisin B, Nystatin.
c .c . Anthelmintic agentsAnthelmintic agents : Ivermectin.: Ivermectin.
d.d. Anticancer antibioticsAnticancer antibiotics : Bleomycin, Dactinomycin, Doxorubicin.: Bleomycin, Dactinomycin, Doxorubicin.
Based on Mechanism of action (MOA) :Based on Mechanism of action (MOA) :
Cell wall synthesis inhibitorsCell wall synthesis inhibitors : Penicillins, Cephalosporins, Carbapenams, Aztreonam.: Penicillins, Cephalosporins, Carbapenams, Aztreonam.
Microbial cell membrane inhibitors :Microbial cell membrane inhibitors : Polymyxin B and E, Colistin, Polyene, Imidazole.Polymyxin B and E, Colistin, Polyene, Imidazole.
Protein synthesis inhibitors:Protein synthesis inhibitors: Aminoglycosides, Macrolides, Tetracyclines.Aminoglycosides, Macrolides, Tetracyclines.
Penicillins and Cephalosporins Are Very cidal For Microbes
Penicillins Cephalosporins
Aminoglycosides
Vancomycin
Fluoroquinolones
Mietronidazole

Beta-lactam antibiotics will be examined in fourBeta-lactam antibiotics will be examined in four
groups, includinggroups, including penicllinspenicllins, cephalosporins,, cephalosporins,
monobactams, and carbapenems.monobactams, and carbapenems.
The beta-lactam ring is joined to a five-memberedThe beta-lactam ring is joined to a five-membered
thiazolidine ring in penicillin,thiazolidine ring in penicillin,
Six-membered dihydrothiazine ring inSix-membered dihydrothiazine ring in
cephalosporins.cephalosporins.
In carbapenems, the beta-lactam ring is alsoIn carbapenems, the beta-lactam ring is also
joined to a five-membered ring, although it isjoined to a five-membered ring, although it is
carbocyclic.carbocyclic.
Monobactams have a monocyclic betalactamMonobactams have a monocyclic betalactam
structure, and the side sulfo-group is joined to astructure, and the side sulfo-group is joined to a
nitrogen atom.nitrogen atom.
All of these contain a four-membered beta-lactamAll of these contain a four-membered beta-lactam
ring, which is necessary for exhibiting antibacterialring, which is necessary for exhibiting antibacterial
activity.activity.
Four groups Beta-lactam antibiotics

 Penicillin was discovered inPenicillin was discovered in 19281928 byby Alexander FlemingAlexander Fleming, who, who
noticed that one of his experimental cultures ofnoticed that one of his experimental cultures of staphylococcusstaphylococcus
was contaminated with mold, which caused the bacteria towas contaminated with mold, which caused the bacteria to
lyse. Since mold belonged to the familylyse. Since mold belonged to the family PenicilliumPenicillium, he named, he named
the antibacterialthe antibacterial substancesubstance penicillin.penicillin.
 About a decade later, a group of researchers at OxfordAbout a decade later, a group of researchers at Oxford
University isolated a crude substance made up of a few low-University isolated a crude substance made up of a few low-
molecular substances, which were penicillins (molecular substances, which were penicillins (F, G, K, O, V,F, G, K, O, V,
XX).).
PENICILLINSPENICILLINS

Penicillium mould
(penicillium notatum)

Historical background of penicillinsHistorical background of penicillins
 Alexander Fleming was born in Loudon, Scotland on 6 August,Alexander Fleming was born in Loudon, Scotland on 6 August,
1881 in a farming family.1881 in a farming family.
 He carried on his schooling atHe carried on his schooling at regent streetregent street polytechnicpolytechnic after hisafter his
family moved to London in 1895.family moved to London in 1895.
 He joinedHe joined St. Mary's medical schoolSt. Mary's medical school and became research assistantand became research assistant
to renowned Sir Almroth Wright, after he gotto renowned Sir Almroth Wright, after he got distinctiondistinction in 1906.in 1906.
 He completed his degreeHe completed his degree (M.B.B.S.)(M.B.B.S.) withwith gold medalgold medal in 1908 fromin 1908 from
the University of London and lectured at St. Mart till 1914.the University of London and lectured at St. Mart till 1914.
 He served asHe served as captaincaptain during theduring the World War IWorld War I and worked inand worked in
battlefield hospitals in France. After the war he returned to St. Marybattlefield hospitals in France. After the war he returned to St. Mary
in 1918 and got elected asin 1918 and got elected as Professor of bacteriology in 1928.Professor of bacteriology in 1928.
 He discovered natural antiseptic enzyme in 1921, which he namedHe discovered natural antiseptic enzyme in 1921, which he named
lysozymelysozyme. This substance existed in tissues and secretions like. This substance existed in tissues and secretions like
mucus, tears and egg-white but it did not have much effect on themucus, tears and egg-white but it did not have much effect on the
strongly harmful bacteria.strongly harmful bacteria.
 It was in 1928 when he observed while experimenting onIt was in 1928 when he observed while experimenting on influenzainfluenza
virusvirus that a common fungus inhibiting the growth of organism.that a common fungus inhibiting the growth of organism.

 It was aIt was a Serendipitous observation(fortuitous accident)Serendipitous observation(fortuitous accident) i.e (happeningi.e (happening
by chance) in his laboratory in the basement of St. Mary's Hospital inby chance) in his laboratory in the basement of St. Mary's Hospital in
London ( now part of imperical college).London ( now part of imperical college).
 On Friday, September 28, in 1928, Fleming left the lid off of one ofOn Friday, September 28, in 1928, Fleming left the lid off of one of
his Petri dishes for several weeks, and a fungal spore landed on it (thehis Petri dishes for several weeks, and a fungal spore landed on it (the
culture became contaminated). After returning from vacation, Flemingculture became contaminated). After returning from vacation, Fleming
noticed that hisnoticed that his StaphylococcusStaphylococcus culture was contaminated with thisculture was contaminated with this
fungus but instead of throwing the Petri dish away, hefungus but instead of throwing the Petri dish away, he carefullycarefully
examined it first.examined it first.
 There was an inhibited bacterial growth around the mould. FlemingThere was an inhibited bacterial growth around the mould. Fleming
concluded that the mould (fungal colony) was releasing aconcluded that the mould (fungal colony) was releasing a
antibacterial substance which was spreading into the surrounding areaantibacterial substance which was spreading into the surrounding area
where the bacterial colonies were dying. i.e. lysing the bacteria.where the bacterial colonies were dying. i.e. lysing the bacteria.
 He grew a pure culture and discovered that it was aHe grew a pure culture and discovered that it was a PenicilliumPenicillium
mould, now known to bemould, now known to be Penicillium notatum.Penicillium notatum.
 Penicillium mould must be secreting an antibacterial substance,Penicillium mould must be secreting an antibacterial substance,
which he isolated first in crude form of the active substance andwhich he isolated first in crude form of the active substance and
named it as penicillin.named it as penicillin.

 This newly discovered active substance(penicillin) was effectiveThis newly discovered active substance(penicillin) was effective
even when diluted up toeven when diluted up to 800800 times.times.
 Unfortunately, the substance was alsoUnfortunately, the substance was also unstable and Fleming wasunstable and Fleming was
unableunable to isolate and purify the compoundto isolate and purify the compound. He therefore came to. He therefore came to
the conclusion that penicillin was too unstable to be used clinically.the conclusion that penicillin was too unstable to be used clinically.
 Florey and Chain in 1938Florey and Chain in 1938 by using processes such asby using processes such as freeze-dryingfreeze-drying
and chromatographyand chromatography which allowed isolation of pure form ofwhich allowed isolation of pure form of
penicillins.penicillins.
 Fleming, Florey, and Chain shared theFleming, Florey, and Chain shared the 1945 Nobel Prize1945 Nobel Prize for theirfor their
medicinal work on penicillin.medicinal work on penicillin.
 In june 1942 availability of penicillin was just to treat 10 patients.In june 1942 availability of penicillin was just to treat 10 patients.
 After fermentation research 2.3 million doses had been increased inAfter fermentation research 2.3 million doses had been increased in
U.S.U.S.

Commercial production of antibioticsCommercial production of antibiotics
The general scheme may be divided into six stepsThe general scheme may be divided into six steps
1.1. Preparation of a pure culture of the desired organism for use in inoculation of thePreparation of a pure culture of the desired organism for use in inoculation of the
fermentation medium.fermentation medium.
2.2. Fermentation, during which the antibiotic is formed.Fermentation, during which the antibiotic is formed.
3.3. Isolation of the antibiotic from the culture medium.Isolation of the antibiotic from the culture medium.
4.4. Purification.Purification.
5.5. Assays for potency, sterility, absence of pyrogens, and other necessary data.Assays for potency, sterility, absence of pyrogens, and other necessary data.
6.6. Formulation into acceptable and stable dosage forms.Formulation into acceptable and stable dosage forms.
1943 the mass production of penicillin began.
As the production increased the cost dropped
Correspondingly.
When penicillin was first available, 100,000
units sold for $20. currently, the same quantity
costs less than a penny

 Once the penicillin is released from the fungal cells, the compoundOnce the penicillin is released from the fungal cells, the compound
is isolated from the fermenter's contents and purified by specialis isolated from the fermenter's contents and purified by special
biochemical processes.biochemical processes.
 Such commercial production results in more than 100,000,000Such commercial production results in more than 100,000,000
pounds of penicillin production per year.pounds of penicillin production per year.
Bulk production of pencillins

Biological sources of penicillinBiological sources of penicillin
 The first naturally occurring benzyl penicillin (penicillin G is alsoThe first naturally occurring benzyl penicillin (penicillin G is also
referred to asreferred to as gold standard penicillingold standard penicillin ) was obtained by the) was obtained by the
fermentation of fungusfermentation of fungus Penicillium notatumPenicillium notatum..
 At present it is obtained from a highly yielding strain calledAt present it is obtained from a highly yielding strain called
PenicilliumPenicillium chrysogenumchrysogenum and other penicillum species.and other penicillum species.
 30 different biosynthetic penicillin's have been isolated from various30 different biosynthetic penicillin's have been isolated from various
strains ofstrains of Penicillium notatiumPenicillium notatium andand Penicillum chrysogenum.Penicillum chrysogenum.
The overall shape of the
molecule is like a half-open book
The three-dimensional shape of penicillin.

5 Classes of Penicillins
Natural Penicillins (Fermentation derived penicillins)
Penicillin G ,Penicillin V
Semi synthetic Penicillinase Resistant Penicillins (parenteral)
Methicillin
Nafcillin
Isoxazolyl Penicillins (Cloxacillin / Dicloxacillin / Oxacillin / Flucloxacillin)
Amino penicillins ( Semisynthetic penicillinase sensitive broad spectrum penicillins)
Ampicillin , Amoxicillin
Carboxy penicillins ( Synthetic penicillins sensitive to broad spectrum, Parenteral
penicillins.)
Carbencillin, Carbencillin phenyl, Carbencillin indanyl. Ticarcillin
Ureidopenicillins
Piperacillin , Mezlocillin, Azlocillin

Penicillin G (Benzylpenicillin)Penicillin G (Benzylpenicillin)
 Penicillin G is also referred to asPenicillin G is also referred to as gold standard penicillingold standard penicillin..
 Penicillin G is not acid resistant it is acid sensitive.Penicillin G is not acid resistant it is acid sensitive.
 3 reasons for the acid sensitivity of penicillin G.3 reasons for the acid sensitivity of penicillin G.
 11.. Ring strainRing strain. ( 4 membered betalactam ring + 5 membered thiazolidine ring) As a result penicillins. ( 4 membered betalactam ring + 5 membered thiazolidine ring) As a result penicillins
suffers large angle and torsional strains. Acid catalyzed ring opening relieves these strains by breakingsuffers large angle and torsional strains. Acid catalyzed ring opening relieves these strains by breaking
open the more highlyopen the more highly ββ –lactam ring.–lactam ring.
 22.. Highly reactive corbonyl groupHighly reactive corbonyl group.. The resonance stabilization is impossible for theThe resonance stabilization is impossible for the ββ –lactam ring because–lactam ring because
of the increase in angle strain that would result in having a double bond withinof the increase in angle strain that would result in having a double bond within ββ –lactam ring. So the–lactam ring. So the
angle of theangle of the ββ –lactam ring constrained to 90–lactam ring constrained to 9000
. So the lone pair is localized on the N atom, and the. So the lone pair is localized on the N atom, and the
carbonyl group is more electrophilic than one would expect for a tertiary amide.carbonyl group is more electrophilic than one would expect for a tertiary amide.
 Influence of the acyl side chainInfluence of the acyl side chain: Acyl group open up the lactam ring . So Penicillin G has a self-destruct: Acyl group open up the lactam ring . So Penicillin G has a self-destruct
mechanism built in its structure.mechanism built in its structure.
Benzylpenicillin is broken down by stomach acidBenzylpenicillin is broken down by stomach acid
and destroyed by staphylococcus penicillinase.and destroyed by staphylococcus penicillinase.
So it can be given by IV.So it can be given by IV.
Therapeutic uses:
Drugs of the penicillin group are effective for infections caused by Gram-positive bacteria
(streptococcus, pneumococcus, and others), spirochaetae, and other pathogenic microorganisms.
Drugs of this group are ineffective with respect to viruses, mycobacteria tuberculosis, fungi, and
the majority of Gram-negative microorganisms.
Benzylpenicillin is the drug of choice for infections caused by sensitive organisms. This includes streptococci
infections (except enterococci), gonococci, and meningococci that do not produce beta-lactam anaerobes.
Benzylpenicillin is used for croupous and focal pneumonia, skin infections, soft tissue and mucous membranes,
periotonitis, cystisis, syphilis, diphtheria, and other infectious diseases.
Benzyl group
N
S
COOH
H
CH3
CH3
HH
O
HNCH2C
O

N
S
COOH
H
CH3
CH3
HH
O
HNCH2C
O
O
It withdraws the electrons away
from the corbonyl oxygen and
reduce the tendency to act as a
nucleophile
Phenoxy methyl Penicillin ( Penicilln V)
•By placing electron with drawing group in the side chain which could draw
electrons away from the corbonyl oxygen and reduce its tendency to act as
a nucleophile.
•Penicillin- V has electro –ve oxygen on the acyl side chain with electron
withdrawing effect. It has more acid stability than penicillin G .
•It is more stable in acid in the stomach, so it can be given orally.
•Infact acid sensitivity can be solved by having an electron withdrawing group
on the Acyl side chain.
PENICILLIN- V

N
S
COOH
H
CH3
CH3
HH
O
HNCH2C
O
OCH3
OCH3
Strategy is putting
two ortho- methoxy
groups on the aromatic
ring.
Bulky groups
"Steric shields” can be added to penicillins to protect them from bacterial Betalactamase
(peicillinase) enzymes.
By placing bulky groups on the side chain, bulky groups can prevent the betalactamase or
penicillinase enzyme to Reach the beta lactamase or penicillinase active site.
Because of betalactamases bacteria can gain resistance to penicillin.
Betalactamases hydrolyse the ester link and open the pencillin. 1000 penicillin molecules
are hydrolysed per second.
Infact steric shield should not be too bulkey. If it is too bulkey it also prevents the penicillin
from attacking the transpeptidase target enzyme.
It should not be too small enough.. Methicillin is also not a ideal drug. Infact methicillin has
no electron withdrawing group on the side chain. Methicillin is acid sensitive and has to be
injected.
Penicillinase resistant penicillins
METHICILLIN
OC2H5
R Group
Nafcillin.
(Narrow spectrum Antistaphylococcal
penicillins)
Methicillin in USA not ued clinically
Methicillin produces Interstitial Nephritis (damages the kedney).
Nafcillin also some times produces Interstitial Nephritis.
it also Produces Neutropenia (Low level of Neutrophils)

Isoxazoyl Penicillins
Penicillinase- resistant penicillins or β- lactamase- resistant penicillins
R1 R2
Oxacillin H H
Cloxacillin Cl H
Dicloxacillin Cl Cl
Flucloxacillin Cl F
N
S CH3
CH3
COOH
O
HN
O
N
O
CH3
R1
R2
H
H H
Bulkyand electron
withdrawing
group
Isoxazolyl ring
The incorporation of an isoxazolyl ring in to the penicillin side chain lead to orally active
compounds which were stable to β-lactamase enzymes of S. aureus.
The isoxazolyl ring acts as the steric shiels but it is also electron-withdrawing, giving the
structure acid stable.
The β-Lactamase resistant penicllins tend to be comparatively
lipophilic molecules that do not penetrate well into Gram –ve
bacteria.
α- acyl carbon could be part of an aromatic ( phenyl or
Naphthyl or heteroaromatic (e.g., 4-isoazoyl) system.

 To sum up acid resistant penicillins would be the drugs of first choice against an infection.
 If the bacteria proved resistance due to the presence of a Penicillinase enzyme
 Penicillin resistant S. aureus therapy would be changed to penicillinase resistant penicillins.
 Hydrophobic groups on the side chain(pen-G) favor gram +ve but Poor activity against gram-
ve.
 Enhancement of gram -ve activity is found if hydrophilic Groups – NH2, - OH, -COOH are
attached to the alpha carbon from the carbonyl group on the side chain. Those Penicillins have
useful activity against gram +ve and gram -ve.
 Hydrophilic groups on the side chain have little effect on Gram-positive activity (e.g.
penicillin T) or cause a reduction of activity (e.g. penicillin N)
 However, they lead to an increase in activity against Gram-negative bacteria.

The acidic stability of the ampicillin also attributes the electron withdrawing character of the primary
amino group which prevents the hydrolysis of the β-lactum bond. It is susceptible to degradation by
β-lactamase enzymes. Hence it is given in Combination with inhibitors like Sulbactum.
Hydrophobic groups on the side chain( Ex: penicillin G) favor activity against Gram-positive bacteria
Hydrophilic groups on the side chain have increase in activity against Gram –negative bacteria.
If the hydrophilic group is (NH2,OH,COOH group) attached to the carbon, alpha to the carbonyl group on the
side chain. All have an alpha hydrophilic group which aids the passage of these penicillins through the porins of
the Gram-ve Bacterial outer cell membrane.
Uses: Ampicillin and Amoxicillin HELPS to clear the Enterococci.
H – Haemophilus Influenzae.
E – Escherichia Coli.
L – Listeria monocytogenes.
P- Proteus.
S – Salmonella Typhi.
Amino Penicillins ( Ampicllin, Amoxicillin )
AMPICILLIN
N
S CH3
CH3
COOH
O
HN
O
C
H
H H
NH2
H

Amoxicillin (Amoxil) (p-hydroxy Ampicillin)
Amoxicillin is the very similar in structure like ampicillin, the only difference being
an extra phenol group on amoxicillin.
*similar spectrum of activity to penicillin G, but more active against Gram-ve bacteria
*Acid resistant due to the –NH2 group and therefore orally active.
*Non toxic, *Sensitive to β-lactamase (No shield).
---Can cause diarrhea due to poor absorption through the gut wall, is due to dipolar nature of the molecule
It has both free carboxylic acid and amino function. This problem can be solved by using a prodrug
Pivampicillin, talampicillin, bacampicillin are prodrugs of ampicillin. acyloxymethyl esters are used to mask the
-COOH groups. Its spectrum of activity is increased when administered with clavalunic acid.
Amoxicillin + clavalunic acid = Augmentin tablets.
Broad spectrum activity is associated with the
presence of an alpha hydrophilic group on the acyl side chain
of penicillin. Extra phenol group is present on amoxicillin.
If you compare with ampicillin, amoxicillin Is better absorbed
through gut wall.
Uses:
Bronchitis
Pneumonia
Typhoid
Enteric fever
Gonorrhea.
Urinary tract infections.
N
S CH3
CH3
COOH
O
HN
O
C
H
H H
NH2
H
HO

Ampicillin synthesis:
A method of directly acylating 6-APA with phenylglycine chloride hydrochloride
Ampicillin
Amoxicillin synthesis:
The direct reaction of D-()-2-(4-hydroxyphenyl) glycine chloride hydrochloride with
trimethylsylil ester of 6-APA
Amoxicillin

Nomenclature of PenicillinsNomenclature of Penicillins
Nomenclature of penicillins was done in different systemsNomenclature of penicillins was done in different systems..
Chemical abstract system(CAS):
•According to this system penicillins are numbered starting from “S” atom.
Sulphur atom is assigned the 1st
position and “N” atom is assigned number 4.
1
2
34
56
7
Bicyclic ring system
1-thia-4-azabicyclo [3.2.0] heptane
United States Pharmacopoeia (USP system):
•The USP system of naming penicillins is the reverse of CAS.
•According to this system the nitrogen atom is given the 1st
position and “S” atom
is assigned the 4th
position.
1 2
3
4
56
74-thia-1-azabicyclo [3.2.0] heptane
1 2
2
34
56
7
1
2
3
4
56
7

As derivatives of Penam:
Unsubstituted bicyclic system together with amide
corbonyl group has been named as penam.
According to this method penicillins are named as
4- Thia-1-azabicyclo[3.2.0] heptane-7-one.
4. As derivatives of penicillanic acid:
In this method penicillins are named as derivatives of penicillanic acid ring system
with 5- acyl amino -2,2’-dimethyl penam -3- carboxylic acid.
1
5. As derivatives of penicillins (on the basis of “R” group) … TRIVAL SYSTEM
In this system 6-corbonyl amino penicillanic acid portion of the molecule is named
as penicillin and the different penicillins are distinguished on the basis of “R” group
on the acyl amino side chain.
4
56
7
This system of naming of penicillins is simple and serves as a good measure for naming and comparing
closely related penicillin structures. However this system is not well suited for compounds having the

Stereo chemistryStereo chemistry The penicillin molecule contains three chiral carbon atoms at C-3, C-5 andThe penicillin molecule contains three chiral carbon atoms at C-3, C-5 and
C-6.C-6.
 All natural and synthetic penicillins have the same absolute configurationAll natural and synthetic penicillins have the same absolute configuration
about these three centers.about these three centers.
 The 6The 6thth
carbon atom bearing the acyl amino group has the L-configuration,carbon atom bearing the acyl amino group has the L-configuration,
where as the carbon to which the carboxyl group was attached has thewhere as the carbon to which the carboxyl group was attached has the
D- configuration.D- configuration.
 Thus the acyl amino group and carboxyl group are trans to each other, withThus the acyl amino group and carboxyl group are trans to each other, with
the formerthe former αα and latter in theand latter in the ββ orientation relative to penam ring.orientation relative to penam ring.
 The absolute stereochemistry of the penicillins was designated asThe absolute stereochemistry of the penicillins was designated as
3S:5R:6R.3S:5R:6R.
 The atoms composing the 6-aminopenicillanic acid are biosyntheticallyThe atoms composing the 6-aminopenicillanic acid are biosynthetically
derived from two amino acids, L-cysteine and D-valine.derived from two amino acids, L-cysteine and D-valine.

Reactions: Hydrolysis of penicillins by hot and cold dilute mineral acidReactions: Hydrolysis of penicillins by hot and cold dilute mineral acid

There are also a variety of acylases that have been isolated from some bacteria, and
these enzymes cleave the acylamino sidechain of the antibiotic, a modification which also

The principle of chemotherapy or the
magic bullet involves the design of
chemicals that show selective toxicity
against bacterial cells rather than
N
S
COO
H
CH3
CH3
HH
O
HNCR
O
Thiazolidine
ring
β-Lactam
ring
Cis orientation of hydrogens
(stereochemistry) are essential
Bicyclic system
essential
Free corboxylate essential
Amide essential or
acylaminoside chain
essential
Strained β-lacturm
ring,which is necessary
for exhibiting
antibacterial activity
(The corboxylate ion binds
to the charged ammonium
ion of a lysine residue in the
binding site)
Sulfur is usual but not
essential
Presence of one
α-orientation and
one β-orientation
is essential for activity
Presence of N is essential
any modification upon
nitrogen it will results lack
of activity.
Highly reactive
ketonic group at
7th
position also
essential any
modification lack
of activity.
Amino group present
on the 6th
position
should be trans which
is very essential.
1
2
34
56
7
Bicyclic system confers further strainon
β-lactam ring. Greater the stran, the greater
the activity,but greater the instability of the
molecure to other factors.
6-Aminopenicillanic acid
The “R”group
determines the
Stability and
Improved spectrum
of activity and
Pharmacokinetic
advantages.
BASIC CHEMISTRY= β-LACTRUM RING + THIAZOLIDINE RING
STRUCTURE - ACTIVITY RELATION SHIP (SAR) OF PENICILLINS
GENERAL STUCTURE OF PENICILLIN OR PENICILLIN CORE STRUCTURE
PENICILLIN NUCLEUS OR BASIC STRUCTUREOF PENICILLIN
cysteine
(aminoacid)
By
Prof. Ravisankar
Site of penicillinase action(break in beta lactum ring
(that bond is broken by betalactamase or penicillinase
Enzyme.(the bond b/n C and N is broken by ß-lactamase (or) penicillinase
enzme.
Valine

Key features of structure
 1. β-lactam ring
 a. "Lactam" is a word for any cyclic amide (the word "lactone" is used for
a cyclic ester)
 b. a β-lactam means that the nitrogen is joined to the carbon which is beta
to the carbonyl
 c. this creates strain in the ring, since it is a four membered ring
 d. b-lactam becomes good acylating agent for active site serine of
penicillin binding
 protein
 2. Carboxylate:
 a. Negatively charged at neutral pH
 b. Anchors drug in active site pocket (positively charged)
 3. Acylamide side chain:
 a. Necessary for biological potency
 b. Proper stereochemistry of attachment to ring essential for activity
 c. Variation at side chain can dramatically affect biological activity against
various strains of bacteria
 D. Common Early Penicillins
 1. Penicillin G had to be administered parenterally, since it isn't acid stable.
 2. Penicillin V has more acid stability, and can be administered orally

Penicillins are….
a group of antibiotics that contain 6-amino penicillanic acid side chain attached
to the 6-amino group.
•The penicillin nucleus is the chief structural requirement for biological activity.
•The side chain structure determines the many of the antibacterial and
pharmacological characterstics.
•The strained β-lactum ring is essential.
•Penicillin contains β-lactum ring is fused with thiazolidine ring.
•The free carboxylic acid is essential. The carbolated ion is binds to the charged
ammonium ion of lysine residue in the binding site.
•The bicyclic system is important. The greater the strain, the greater the activity.
•The acyl amino side chain is essential.
•Sulfur is usual but not essential.
•The cis- stereo chemistry of bicyclic ring with respect to the acyl amino side chain is
important.
•Oxidation of sulphur to a sulfone or sulfoxide will decrease the activity.
•The methyl groups at position 2 are essential.
•β- lactum corbonyl group at position “7” is must.
•The carboxylic acid is changed to an alcohol or ester activity is decreased.
•“N” at position 4 is must for antibacterial activity.
•Penicillin molecule contains a ‘3’ chiral carbon atome c-3,c-5,c-6. Disruption of
•These spacial arrangements results in loss of activity.

 SAR of “R” group:SAR of “R” group:
 C-6 amino west end substitution:C-6 amino west end substitution:
The design and development of the west-end substituents hasThe design and development of the west-end substituents has
been aimed at strengthening of activity, stability, resistance, absorption and distribution.been aimed at strengthening of activity, stability, resistance, absorption and distribution.
 Placing the electron withdrawing group in the side chain which could draw electrons awayPlacing the electron withdrawing group in the side chain which could draw electrons away
from the carbonyl oxygen and reduce the tendency to act as a nucleophile and allows afrom the carbonyl oxygen and reduce the tendency to act as a nucleophile and allows a
greater stability and oral availability. Ex: penicillin V, Ampicillin.greater stability and oral availability. Ex: penicillin V, Ampicillin.
 Stereic shields can be added to penicillin to protect them from bacterial β-lactamase enzymes.Stereic shields can be added to penicillin to protect them from bacterial β-lactamase enzymes.
 By placing bulky groups on the side chain it prevent the penicillin from entering theBy placing bulky groups on the side chain it prevent the penicillin from entering the
penicillinase or β-lactamase active site.penicillinase or β-lactamase active site.
 Infact if the stereic shield was too bulky then it also prevents the penicillin fromInfact if the stereic shield was too bulky then it also prevents the penicillin from
attacking the transpeptidase target enzyme, It should be ideal shield.attacking the transpeptidase target enzyme, It should be ideal shield.
but it should not be too small enough…but it should not be too small enough…
Ex: Methicillin.Ex: Methicillin.
 Indeed Methicillin has no electron with drawing group on the side chain. It is acid sensitiveIndeed Methicillin has no electron with drawing group on the side chain. It is acid sensitive
and has to be injected.and has to be injected.
 Incorporation of isoxazolyl ring in to the penicillin side chain lead to the development ofIncorporation of isoxazolyl ring in to the penicillin side chain lead to the development of
better penicillinase resistant agents. In fact isoxazolyl ring acts as the stereic shield but alsobetter penicillinase resistant agents. In fact isoxazolyl ring acts as the stereic shield but also
electron withdrawing group giving the structure acid stability.electron withdrawing group giving the structure acid stability.
Ex: Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin.Ex: Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin.

 Broad spectrum activity is associated with the presence ofBroad spectrum activity is associated with the presence of αα-hydrophilic-hydrophilic
group on the acyl side chain of penicillin.group on the acyl side chain of penicillin.
 Enhancement of Gram –ve activity is increased hydrophilic groupEnhancement of Gram –ve activity is increased hydrophilic group
(-NH(-NH22,OH,-COOH group), attached to the Carbon,,OH,-COOH group), attached to the Carbon,αα to the carbonyl groupto the carbonyl group
on the side chain. These penicillin's are having useful activity against bothon the side chain. These penicillin's are having useful activity against both
remove and gram-Vet bacteria are known as broad spectrum antibiotics.remove and gram-Vet bacteria are known as broad spectrum antibiotics.
EX: Ampicillin and Amoxicillin.EX: Ampicillin and Amoxicillin.
 The spectrum of activity was further extended with introducing strongThe spectrum of activity was further extended with introducing strong
acidic group is attached to the carbonacidic group is attached to the carbon αα- to the carbonyl group on the side- to the carbonyl group on the side
chain.chain.
αα - carboxy penicillins are broad spectrum penicillins and wider range of- carboxy penicillins are broad spectrum penicillins and wider range of
gram-ve activity than ampicillin.gram-ve activity than ampicillin.
EX: Carbencillin,Ticarcillin.EX: Carbencillin,Ticarcillin.
 The acylation of the ampicillin west-end amine functionality withThe acylation of the ampicillin west-end amine functionality with
certain polar groups leads to cyclic urea derivatives.certain polar groups leads to cyclic urea derivatives.
 Urido penicillins have a urea functional group atUrido penicillins have a urea functional group at αα-position. In fact they-position. In fact they
are more active than the carboxy Penicillins against streptococci andare more active than the carboxy Penicillins against streptococci and
Haemophilus species. Presence of urea group gives improved penetrationHaemophilus species. Presence of urea group gives improved penetration
in to gram-ve species.in to gram-ve species.
EX: Azocillin, Mezlocillin, Piperacillin.EX: Azocillin, Mezlocillin, Piperacillin.

Plasma membrane
Peptidoglycan cell wall
(rigid coating around the membrane)
Lipopolysaccharide layer
(LPS)
Gram +ve Gram –ve
Thick Thin
One of the major difference between 2 types of bacteria is the amount of peptidoglycon
They have on the cell wall.
Gram +ve bacteria has a lot of peptidoglycon and this actually holds the gram stain in
That’s why it is gram +ve.
Gram –ve bacteria has a very thin layer of the peptidoglycon and gram stain leaks out
Cell membrane (or)
Outer membrane
Since the penicillin's inhibits peptidoglycon synthesis it is much better an attacking gram+ve bacteria such as
Staphylococci, and streptococci than gram –Ve bacteria like E-coli.
(cell wall in
Gram-positive bacteria
consists of
50-100 peptidoglycan layers)
(Gram –ve
Bacteria cell wall
Consists of only
2 layers.)

Beta-lactam antibiotics are relativelyBeta-lactam antibiotics are relatively
non-toxic to humans why?non-toxic to humans why?
 One of the important point is penicillin is acting as a mimicOne of the important point is penicillin is acting as a mimic
for a D-Ala-D- Ala moiety, this provides another explanationfor a D-Ala-D- Ala moiety, this provides another explanation
for its lack of toxicity.for its lack of toxicity.
 There is no D-Ala- D-Ala amino acids or D-Ala- D-AlaThere is no D-Ala- D-Ala amino acids or D-Ala- D-Ala
segments in any human protein. That’s why any of the body'ssegments in any human protein. That’s why any of the body's
serine protease enzymes does not recognize penicillin.serine protease enzymes does not recognize penicillin.
 As a result penicillin is only selective for bacterialAs a result penicillin is only selective for bacterial
transpeptidase enzyme and ignored by the body’s own serinetranspeptidase enzyme and ignored by the body’s own serine
protease.protease.

Mechanism of action of penicillinsMechanism of action of penicillins
 The primary mechanism of the action of beta-lactam antibiotics is the inhibition of synthesis ofThe primary mechanism of the action of beta-lactam antibiotics is the inhibition of synthesis of cell walcell wall ofl of
bacteria, which causes them to quickly die.bacteria, which causes them to quickly die.
 The cell membrane protects bacteria cells from lysis, which can occur as a result of different osmotic pressuresThe cell membrane protects bacteria cells from lysis, which can occur as a result of different osmotic pressures
between the cytoplasm and the surrounding medium..between the cytoplasm and the surrounding medium..
 The main component of bacterial cell membranes is a mixed polymer known asThe main component of bacterial cell membranes is a mixed polymer known as murein or peptidoglycanmurein or peptidoglycan..
Peptidoglycon is a long polysaccharide chain that is cross-linked with short peptides.Peptidoglycon is a long polysaccharide chain that is cross-linked with short peptides.
 Polysaccharide chains are made up of two varying aminosugars—Polysaccharide chains are made up of two varying aminosugars—N-acetylglucosamineN-acetylglucosamine
andand N-acetylmuraminic acidN-acetylmuraminic acid. There are significant differences between Gram +ve and Gram –ve bacteria. The. There are significant differences between Gram +ve and Gram –ve bacteria. The
cell wall in Gram +ve bacteria consists ofcell wall in Gram +ve bacteria consists of 50-10050-100 peptidoglycon layers where as Gram –ve bacteria itpeptidoglycon layers where as Gram –ve bacteria it
consists onlyconsists only 2 layers2 layers..
 Beta-lactam antibiotics specifically bind with a number of proteins of cytoplasmic membranes known asBeta-lactam antibiotics specifically bind with a number of proteins of cytoplasmic membranes known as
penicillin-binding proteins (PBP).penicillin-binding proteins (PBP).
 The enzyme responsible for the cross-linking reaction is known as theThe enzyme responsible for the cross-linking reaction is known as the transpeptidase enzyme.transpeptidase enzyme.
 Beta-lactam antibiotics must pass through the outer layer of the cell in order to get the desired PBP to theBeta-lactam antibiotics must pass through the outer layer of the cell in order to get the desired PBP to the
surface of the membrane.surface of the membrane.
 About 30 enzymes are involved in the overall biosynthesis of cell wall but final cross linking reaction which isAbout 30 enzymes are involved in the overall biosynthesis of cell wall but final cross linking reaction which is
inhibited by penicillin. This leads to a cell wall framework that is no longer interlinked. As a result, the wallinhibited by penicillin. This leads to a cell wall framework that is no longer interlinked. As a result, the wall
becomes fragile and can no longer prevent the cell frombecomes fragile and can no longer prevent the cell from swelling and bursting.swelling and bursting.
 It has been proposed thatIt has been proposed that penicillin has a conformation which is similarpenicillin has a conformation which is similar to the transition state conformationto the transition state conformation
taken up by thetaken up by the D-Ala- D-Ala moietyD-Ala- D-Ala moiety during cross linking reaction. The enzyme mistakes penicillin for D-during cross linking reaction. The enzyme mistakes penicillin for D-
Ala- D-Ala and binds to the active site.Ala- D-Ala and binds to the active site.
 Once bound, penicillin is subjected toOnce bound, penicillin is subjected to nucleophilic attack by serinenucleophilic attack by serine. The enzyme can attack the. The enzyme can attack the ββ- lactam rung- lactam rung
of penicillin and open it in the same way as it did with the peptide bond. However penicillin is a cyclic and asof penicillin and open it in the same way as it did with the peptide bond. However penicillin is a cyclic and as
a result the molecule isa result the molecule is not split in twonot split in two and nothing leaves the active site.and nothing leaves the active site.

 Transpeptidase connects the little peptide chains perpendicular to the NAM chains.Transpeptidase connects the little peptide chains perpendicular to the NAM chains.
 Without the grid the rapidly growing bacteria can’t maintain the strong cell wall.Without the grid the rapidly growing bacteria can’t maintain the strong cell wall.
 There is a high pressure inside the cell i.e. 10-20 atm. pressure which means if the cell wall isThere is a high pressure inside the cell i.e. 10-20 atm. pressure which means if the cell wall is
not present, the rigid coating bacteria can swell and burst.not present, the rigid coating bacteria can swell and burst.
 β – lactam antibiotics like penicillins act by inhibiting the transpeptidase (or) PBPs byβ – lactam antibiotics like penicillins act by inhibiting the transpeptidase (or) PBPs by
covalently bonding to the serine residues within the active sites and prevent the cell wallcovalently bonding to the serine residues within the active sites and prevent the cell wall
synthesis.synthesis.

(Peptidoglycan cell wall)
N-acetylglucosamine
N-acetylmuramic acid
Transpeptidase located
within the cell membrane
are responsible for
cross linking the
Peptidoglycon chains
Transpeptidases
(Penicillin Binding Proteins)
In order to make the rigid grid,
There is an enzyme called
Transpeptidase, which
connects
the Little peptide strings
perpendicular to the
NAM and NAG chains.
Cell membrane
PBP’S (or) transpeptidase help to build
Or construct maintain the peptidoglycon
Layer.

Cross-linking of bacterial cell walls inhibited by penicillin

 Sugars contained in the cell wall structure of bacteria.Sugars contained in the cell wall structure of bacteria.
 N-acetylglucosamine (NAG)N-acetylglucosamine (NAG)
 N- acetylmuramic acid (NAM)N- acetylmuramic acid (NAM)
PEPTIDOGLYCAN STRUCTURE OF BACTERIAL CELL WALLS

Mechanisms of transpeptidase crosslinking and penicillin inhibition.

 Microbial resistance toMicrobial resistance to ββ-lactam antibiotics-lactam antibiotics like penicillins, cephalosporins occurslike penicillins, cephalosporins occurs
mainlymainly due to the production of an enzyme known asdue to the production of an enzyme known as ββ-lactamases.-lactamases.
 ββ-lactamases act by breaking the-lactamases act by breaking the ββ-lactam ring by catalyzing the hydrolysis of-lactam ring by catalyzing the hydrolysis of ββ--
lactum ringlactum ring, which results in the loss of antibacterial property of antibiotics. Thus, which results in the loss of antibacterial property of antibiotics. Thus
micro-organisms exhibit resistance.micro-organisms exhibit resistance.
 The presence of (The presence of (ββ-lactamase enzymes is the most important mechanism-lactamase enzymes is the most important mechanism
by which bacteria gain resistance to penicillin. (by which bacteria gain resistance to penicillin. (ββ-Lactamases are-Lactamases are
enzymes which have mutated from transpeptidase.enzymes which have mutated from transpeptidase.
 Unlike the transpeptidase enzyme, (Unlike the transpeptidase enzyme, (ββ-lactamases are able to hydrolyse-lactamases are able to hydrolyse
the ester link and shed the ring-opened penicillin. They do this sothe ester link and shed the ring-opened penicillin. They do this so
effectively thateffectively that 1000 penicillin molecules are hydrolysed per second1000 penicillin molecules are hydrolysed per second..
β -LACTAMASE DEACTIVATION OF PENICILLIN

The agents Clavalunic acid, sulbactam and tazobactam have
also been developed as β-lactamase inhibitors.
Sulbactum + Ampicillin = Unasyn.
Amoxycillin + Clavulanic acid = Augmentin
Ticarcillin + Clavulanic acid = Timentin
β-lactamase inhibitors are β-lactam structures that have negligible antibacterial
activity but inhibit β -lactamases.
They can be administered along with penicillins to protect them from
β -lactamases and broaden(increase) their spectrum of activity.
β-lactamase inhibitors such as Clavulanic acid, Sulbactam, Tazobactum act as suicide
substrates for β-lactamase enzymes.
Suicide substrates are agents which are converted to highly reactive species when they
undergo an enzyme-catalyzed reaction. They form covalent bonds to the enzyme and
inhibit irreversibly.

 However, there are various types of (However, there are various types of (ββ -lactamase enzyme-lactamase enzyme
produced by both Gram-positive and Gram-negative bacteria whichproduced by both Gram-positive and Gram-negative bacteria which
vary in their substrate selectivity.vary in their substrate selectivity.
 Some are selective for penicillins (Some are selective for penicillins (penicillinases)penicillinases),,
 some for cephalosporins (some for cephalosporins (cephalosporinases)cephalosporinases)
 and some forand some for bothboth penicillins and cephalosporins.penicillins and cephalosporins.
 The differing levels of enzyme and their differing affinities forThe differing levels of enzyme and their differing affinities for
differentdifferent ββ-lactams account for the varying susceptibilities of Gram--lactams account for the varying susceptibilities of Gram-
 negative bacteria to differentnegative bacteria to different ββ-lactams.-lactams.

 Clavulanic acid:Clavulanic acid:
clavalunic acid was isolated from streptomyces clavuligerus by Bechams inclavalunic acid was isolated from streptomyces clavuligerus by Bechams in
1976.1976.
It has weak and unimportant antibiotic activity, but it is powerful andIt has weak and unimportant antibiotic activity, but it is powerful and
irreversible inhibitor of most β-lactamases and as such it is now usedirreversible inhibitor of most β-lactamases and as such it is now used
in combination with penicillins such as amoxicillinin combination with penicillins such as amoxicillin( Augmentin)( Augmentin)
 The structure of clavulanic acid was the first example of a naturally occuringThe structure of clavulanic acid was the first example of a naturally occuring
β-lactam ring that was not fused to a sulfur-containing ring.β-lactam ring that was not fused to a sulfur-containing ring.
 It is fused instead to an oxazolidine ring structure.It is fused instead to an oxazolidine ring structure.
ESSENTIAL REQUIREMENTS FORESSENTIAL REQUIREMENTS FOR ββ-lactamase inhibition are:-lactamase inhibition are:
 StrainedStrained ββ-lactam ring.-lactam ring.
 Enol ether.Enol ether.
 The double bond of the enol ether has the Z configuration(Activity is reducedThe double bond of the enol ether has the Z configuration(Activity is reduced
but not eliminated if the double bond is E)but not eliminated if the double bond is E)
 No substitution at C-6No substitution at C-6
 R- Stereochemistry at positions 2 and 5.R- Stereochemistry at positions 2 and 5.
 Carboxylic acid group.Carboxylic acid group.

Resistance to penicillinResistance to penicillin
 Penicillins have been used widely, and often carelessly. As a result,Penicillins have been used widely, and often carelessly. As a result,
penicillin-resistant bacteria have evolved and have become an increasingpenicillin-resistant bacteria have evolved and have become an increasing
problem.problem.
 Bacterial strains vary in their susceptibility to penicillin. Some species, suchBacterial strains vary in their susceptibility to penicillin. Some species, such
as streptococci, are quite vulnerable, whereas a bacterium likeas streptococci, are quite vulnerable, whereas a bacterium like PseudomonasPseudomonas
aeruginosa is particularly resistantaeruginosa is particularly resistant. Other species, such as Staphylococcus. Other species, such as Staphylococcus
aureus, are initially vulnerable, but acquire resistance when they are exposedaureus, are initially vulnerable, but acquire resistance when they are exposed
to penicillin over a period of time. There are several reasons for this variedto penicillin over a period of time. There are several reasons for this varied
susceptibility.susceptibility.
 P. aeruginosa is a difficult organism to treat because it has an intrinsicP. aeruginosa is a difficult organism to treat because it has an intrinsic
resistance to a wide variety of antibacterial agents including many penicillins,resistance to a wide variety of antibacterial agents including many penicillins,
cephalosporins, tetracyclines, quinolones, and chloramphenicol.cephalosporins, tetracyclines, quinolones, and chloramphenicol.
 There are two reasons for this. The outer membrane of the cell has a lowThere are two reasons for this. The outer membrane of the cell has a low
permeability to drugs, and even if a drug does enter the cell, there is an effluxpermeability to drugs, and even if a drug does enter the cell, there is an efflux
system which can pump it back out again.system which can pump it back out again.
 Nevertheless, there are drugs that have proved effective against the organism,Nevertheless, there are drugs that have proved effective against the organism,
in particular aminoglycosides such as tobramycin or gentamicin, andin particular aminoglycosides such as tobramycin or gentamicin, and
penicillins such aspenicillins such as ticarcillin.ticarcillin. These are often given in combination withThese are often given in combination with
each other.each other.

High levels of β-lactamase productionHigh levels of β-lactamase production
In some Gram-negative bacteria, excess quantities of transpeptidase areIn some Gram-negative bacteria, excess quantities of transpeptidase are
produced, and penicillin is incapable of inactivating all the enzymeproduced, and penicillin is incapable of inactivating all the enzyme
molecules present.molecules present.
Transport back across the outer membrane of Gram-negative bacteriaTransport back across the outer membrane of Gram-negative bacteria
There are proteins in the outer membrane of some Gram- negative bacteriaThere are proteins in the outer membrane of some Gram- negative bacteria
which are capable of pumping penicillin out of the periplasmic space,which are capable of pumping penicillin out of the periplasmic space,
thus lowering its concentration and effectiveness. This is known as anthus lowering its concentration and effectiveness. This is known as an
efflux process.efflux process.
Mutations and genetic transfersMutations and genetic transfers
Mutations can occur which will affect any or all of the above mechanismsMutations can occur which will affect any or all of the above mechanisms
such that they are more effective in resisting the effects of (3-lactams.such that they are more effective in resisting the effects of (3-lactams.
Affinity of the transpeptidase enzyme to penicillinAffinity of the transpeptidase enzyme to penicillin
Early strains of Staphylococcus aureus contained transpeptidase enzymesEarly strains of Staphylococcus aureus contained transpeptidase enzymes
which had a high affinity for penicillin and were effectively inhibited.which had a high affinity for penicillin and were effectively inhibited.
Penicillin-resistant strains of Staphylococcus aureus acquired aPenicillin-resistant strains of Staphylococcus aureus acquired a
transpeptidase enzyme called penicillin binding protein (PBP) 2a, whichtranspeptidase enzyme called penicillin binding protein (PBP) 2a, which
has a much lower affinity to penicillins.has a much lower affinity to penicillins.
BACTERIAL RESISTANT TO PENICILLIN.

 Penicillin’s may be used to treat infections such as urinary tract infections.Penicillin’s may be used to treat infections such as urinary tract infections.
 Septicaemia, meningitis, intra-abdominal infection, respiratory infections, ear,Septicaemia, meningitis, intra-abdominal infection, respiratory infections, ear,
nose and throat infections.nose and throat infections.
 Skin and Soft tissue infections. Examples of infectious micro organisms (bacteria)Skin and Soft tissue infections. Examples of infectious micro organisms (bacteria)
that may respond to penicillin therapy includethat may respond to penicillin therapy include
 * Streptococcal infections* Streptococcal infections
* Pneumococcal infections* Pneumococcal infections
* Meningococcal infections* Meningococcal infections
* Gonorrhoea* Gonorrhoea
* Syphilis* Syphilis
* Diphtheria* Diphtheria
* Tetanus and gas gangrene* Tetanus and gas gangrene
DRUG OF CHOICE for *Anaerobic anthrax*DRUG OF CHOICE for *Anaerobic anthrax*
* Actinomycosis* Actinomycosis
* Trench mouth* Trench mouth
* Rat bite fever* Rat bite fever
* Listeria monocytogenes* Listeria monocytogenes
* Pasteurella multocida* Pasteurella multocida

 Penicillins are available only with a prescription. Penicillin’s are useful againstPenicillins are available only with a prescription. Penicillin’s are useful against
infections in many parts of the body, including the mouth and throat, skin andinfections in many parts of the body, including the mouth and throat, skin and
soft tissue, tonsils, heart, lungs, and ears. For example, dentists often prescribesoft tissue, tonsils, heart, lungs, and ears. For example, dentists often prescribe
penicillin to prevent infections after dental surgery.penicillin to prevent infections after dental surgery.
 Biosynthetic penicillins are important in chemotherapy. They are used inBiosynthetic penicillins are important in chemotherapy. They are used in
treating streptococcal sore throat, tonsillitis, pneumococcal pneumonia,treating streptococcal sore throat, tonsillitis, pneumococcal pneumonia,
endocardities caused by some streptococci, syphilis, gonorrhoea, meningococcalendocardities caused by some streptococci, syphilis, gonorrhoea, meningococcal
infections and infections that are caused by some anaerobic organisms.infections and infections that are caused by some anaerobic organisms.
 The drug Augmentin, for example, contains a combination ofThe drug Augmentin, for example, contains a combination of
amoxicillin(500mg) and a β-lactamase inhibitor, clavulanic acid (125mg)amoxicillin(500mg) and a β-lactamase inhibitor, clavulanic acid (125mg) usedused
in the treatment of Feverish patients with neutropenia from cancerin the treatment of Feverish patients with neutropenia from cancer
chemotherapy.chemotherapy. It is also useful in treating the sinusitis. Animal/human biteIt is also useful in treating the sinusitis. Animal/human bite
wounds, otitis media in children.wounds, otitis media in children.
 There are several types of penicillins, each used to treat different kinds ofThere are several types of penicillins, each used to treat different kinds of
infections.infections.
 These drugs will not work for, flu, and other infections caused by viruses.These drugs will not work for, flu, and other infections caused by viruses.

 Adverse/toxic effects of penicillins:-
 Although most penicillins are safe for the majority of people, some people may
experience side effects. Once an individual is allergic to one penicillin, he or
she is most likely allergic to all of the penicillins.
 The most serious allergic reaction is anaphylaxis that can be fatal which is not
treated properly.
 a severe allergic reaction that can cause skin rash, itching, difficulty breathing,a severe allergic reaction that can cause skin rash, itching, difficulty breathing,
shock, and unconsciousness.shock, and unconsciousness.
 An early sign of anaphylaxis is a feeling of warmth and flushing. If any ofAn early sign of anaphylaxis is a feeling of warmth and flushing. If any of
these occurs, the medicine should be stopped and emergency help soughtthese occurs, the medicine should be stopped and emergency help sought
immediately.immediately.
 Anaphylactic shock occurs more frequently after parenteral administration butAnaphylactic shock occurs more frequently after parenteral administration but
can occur with oral use.can occur with oral use.

After 7 days this allergy occurred her after penicillin has been
taken for throat Infection. That is Late hypersensitivity.

Nausea Dizziness Headache
In((inflammation
of blood vessels)
Skinrashes fever Bronchospasm
(Constriction of the
Airways of the
Lungs)
Angioodema(swelling of lips, face and
tongue)

Less common side effects of penicillins are
 1. Nausea 2. Diziness 3. Head ache 4. skin rashes 5. Bronchospasm 6. vasculitis 7.
inflammation of blood vessels 8. constriction of the airways of the lungs 9. fever
10. Angioedema or swelling of lips, face and tongue.
 Other most common side effects are mild diarrhoea, vomiting, headache, vaginal
itching and discharge, sore mouth or tongue, or white patches in the mouth or on
the tongue. These problems usually go away as the body adjusts to the drug and do
not require medical treatment unless they continue or they are bothersome.
 Occasionally, certain types of penicillin may cause the tongue to darken or
discolour. This condition is temporary and will go away when the medicine is
stopped.
 Effect on GITEffect on GIT: Broad spectrum penicillins like Ampicillin, when administered: Broad spectrum penicillins like Ampicillin, when administered
orally, alters the bacterial flora in the intestines and leads to GIT disturbances likeorally, alters the bacterial flora in the intestines and leads to GIT disturbances like
diarrhoea .diarrhoea .
 On rare occasions some types of penicillin may cause severe abdominal or stomachOn rare occasions some types of penicillin may cause severe abdominal or stomach
cramps, pain, or bloating or severe or bloody diarrhoea. Other rare side effectscramps, pain, or bloating or severe or bloody diarrhoea. Other rare side effects
include fever, increased thirst, severe nausea or vomiting, unusual tiredness orinclude fever, increased thirst, severe nausea or vomiting, unusual tiredness or
weakness, weight loss, seizures, or unusual bleeding or bruising .weakness, weight loss, seizures, or unusual bleeding or bruising .
 Over dosage/Acute ToxicityOver dosage/Acute Toxicity - Acute oral penicillin overdoses are unlikely to- Acute oral penicillin overdoses are unlikely to
cause significant problems other than GI distress, but other effects are possible .Incause significant problems other than GI distress, but other effects are possible .In
humans, very high dosages of parenteral penicillin’s, especially in patients withhumans, very high dosages of parenteral penicillin’s, especially in patients with
renal disease, have induced CNS effects.renal disease, have induced CNS effects.

Hypersensitivity or allergic reactions :
 Hypersensitivity to penicillin’s is caused by the degradation
products of penicillins. The degradation products of
penicilloic acid, sodium benzyl penicilloate (of β-lactum
ring) binds ie combines to serum proteins initiating an IgE
and initiates the IgE mediated inflammatory reactions
 It occurs in about 5-8% of the patients and according to
estimation, 300-500 people have been dieing each year form
penicillin induced anaphylaxis.
 Hypersensitivity reactions are classified into
 A) Immediate Hypersensitivity
 b) Accelerated Hypersensitivity
 C) Late Hypersensitivity

 A)A) Immediate hypersensitivityImmediate hypersensitivity:: -- This occursThis occurs within 20 minwithin 20 min. of parenteral. of parenteral
administration of penicillin and is characterized by the prurities, skinadministration of penicillin and is characterized by the prurities, skin
rashes, wheezing, rhinitis, sneezing.rashes, wheezing, rhinitis, sneezing.
 These reactions are transformed in to anaphylaxis (extreme from ofThese reactions are transformed in to anaphylaxis (extreme from of
immediate hypersensitivity reaction) that it is characterised by hypotensiveimmediate hypersensitivity reaction) that it is characterised by hypotensive
shock, angioneurotic oedema, choking, loss of consciousness and finallyshock, angioneurotic oedema, choking, loss of consciousness and finally
death.death.
 Serious anaphylaxis reactions require immediate emergency treatment withSerious anaphylaxis reactions require immediate emergency treatment with
ephedrine, oxygen, IV steroids and airway management, includingephedrine, oxygen, IV steroids and airway management, including
intubations should also be administered as indicated.intubations should also be administered as indicated.
 B)B) Accelerated HypersensitivityAccelerated Hypersensitivity:: - It occurs- It occurs within few hourswithin few hours afterafter
penicillin has been administered. Accelerated hypersensitivity reactions arepenicillin has been administered. Accelerated hypersensitivity reactions are
characterized by skin rashes, fever, urticaria, angioneurotic oedema. Deathcharacterized by skin rashes, fever, urticaria, angioneurotic oedema. Death
is a rare consequence.is a rare consequence.
 c)c) Late HypersensitivityLate Hypersensitivity:: It occursIt occurs after 72 hoursafter 72 hours after penicillin hasafter penicillin has
been administered. This reaction is mediated by IgE and IgM antibodiesbeen administered. This reaction is mediated by IgE and IgM antibodies
and manifested byand manifested by utricaria, skin rashes similar to measles, localutricaria, skin rashes similar to measles, local
inflammation, serum sickness and coomb’s positive haemolytic anaemiainflammation, serum sickness and coomb’s positive haemolytic anaemia

Penicillin's advantages and disadvantagesPenicillin's advantages and disadvantages
 Penicillin's disadvantagesPenicillin's disadvantages::
 Acid liability - most of these drugs are destroyed by gastric acid.Acid liability - most of these drugs are destroyed by gastric acid.
 Short duration of action - because of this short half-life, the penicillin's must be at shortShort duration of action - because of this short half-life, the penicillin's must be at short
intervals, usually every 4 hours.intervals, usually every 4 hours.
 Lack of activity against most gram-negative organisms.Lack of activity against most gram-negative organisms.
 Drug hypersensitivity - about 10 % of population has allergy.Drug hypersensitivity - about 10 % of population has allergy.
 Many patients experience GI upset.Many patients experience GI upset.
 Painful if given intramuscularly.Painful if given intramuscularly.

penicillin's advantagespenicillin's advantages::
 Bactericidal against sensitive strains.Bactericidal against sensitive strains.
 Relatively nontoxic.Relatively nontoxic.
 Have excellent tissue penetration.Have excellent tissue penetration.
 Efficacious in the treatment of infections.Efficacious in the treatment of infections.
 Relatively inexpensive in comparison with other antibiotics.Relatively inexpensive in comparison with other antibiotics.
 Newer penicillin's are resistant to stomach acid, such as penicillin v, or have a broaderNewer penicillin's are resistant to stomach acid, such as penicillin v, or have a broader
spectrum, such as Ampicillin and Amoxicillin.spectrum, such as Ampicillin and Amoxicillin.

 KEY POINTSKEY POINTS
 Penicillins have a bicyclic structure consisting of aPenicillins have a bicyclic structure consisting of a ββ-lactam ring fused to a-lactam ring fused to a
thiazolidine ring. The strained (thiazolidine ring. The strained (ββ-lactam ring reacts irreversibly with the-lactam ring reacts irreversibly with the
transpeptidase enzyme responsible for the final cross-linking of the bacterial celltranspeptidase enzyme responsible for the final cross-linking of the bacterial cell
wall.wall.
 Penicillin analogues can be prepared by fermentation or by a semi-syntheticPenicillin analogues can be prepared by fermentation or by a semi-synthetic
synthesis from 6-aminopenicillanic acid.synthesis from 6-aminopenicillanic acid.
 Variation of the penicillin structure is limited to the acyl side chain. Penicillins canVariation of the penicillin structure is limited to the acyl side chain. Penicillins can
be made more resistant to acid conditions by incorporating an electron-withdrawingbe made more resistant to acid conditions by incorporating an electron-withdrawing
group into the acyl side chain.group into the acyl side chain.
 Steric shields can be added to penicillins to protect them from bacterialSteric shields can be added to penicillins to protect them from bacterial ββ-lactamase-lactamase
enzymes.enzymes.
 Broad-spectrum activity is associated with the presence of an cc-hydrophilic groupBroad-spectrum activity is associated with the presence of an cc-hydrophilic group
on the acyl side chain of penicillin.on the acyl side chain of penicillin.

ANTIBIOTICS[PENICILLINS] MEDICINAL CHEMISTRY BY RAVISANKAR

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ANTIBIOTICS[PENICILLINS] MEDICINAL CHEMISTRY BY RAVISANKAR