a detailed explanation of aminoglycosides and cephalosporin for medicinal chemistry and pharmacology

1. An antibiotic is a substance produced by the microorganisms, which
has the capacity of inhibiting the growth and even of destroying
other micro-organisms.
OR
An antibiotic is a naturally occuring, semi synthetic or synthetic type of agent that
destroys or inhibits growth of micro-organisms.
1

2. ANTIBIOTICS CLASSIFICATION
1. β- LACTUM ANTIBIOTICS
– PENICILLINS
– CEPHALOSPORINS
2. β- LACTAMASE INHIBITORS
3. MONOLACTAMASES
4. AMINOGLYCOSIDES
5. TETRACYCLINES
6. MACROLIDE ANTIBOITICS
7. LINOMYCINS
8. POLYPEPTIDES
9. CHLORAMPHENICOL 2

3. CEPHALOSPORIN (introduction and history)
• These are second major group of β-lactum antibiotics, broad spectrum,
penicillinase resistance antibiotics. it is bacteriocidal.
• derived from “ Acrimonium chrysogenum”.
• The cephalosporins are closely related both structurally and functionally to
the penicillins.
• These are isolated mainly from:
– Cephalosporium species
– prepared semi-sythetically ( most antibiotics since 1965)
- Giuseppe Brotzu discovered that cultures of Cephalosporium
acremonium inhibited growth of wide variety of Gram -positive and Gram-
negative bacteria.
• C. acremonium cultures inhibited the growth of Salmonella enterica (typhi), a
Gram- bug that produces a penicillinase.
• Later the Cephalosporium was isolated later in 1950’s it had 3 different
principal components.
3

4. HISTORY
• cephalosporin P (minimal antibacterial activity)
• cephalosporin N (more activity of gram negative bacteria)
• cephalosporin C (penicillinase resistant)
– cephalosporin C is an analogue of 7-ACA(7-amino
cephalosporonic acid).
– 7-ACA is most widely used lead nucleus for most of the
cephalosporin drugs.
– 7-ACA is stable to dilute acid and highly resistant to
penicillinase enzyme.
– in 2010 cephalosporin was declared for the use for people
suffereing from allergy towards penicillin 4

5. BIOLOGICAL SOURCE
• 7-ACA (semi synthetic
process to get
cephalosporin C)
• cephalosporin C
• penicillin V
• cephamycin C
• 7-ADCA(7- amino 3-
deacetoxy cephalosporonic
acid)
7-ACA
5

6. chemistry
• Cephalosporin contains a
attached to 6 membered
rings and has an acetoxy methyl group
at position 3.
• Generally broader spectrum coverage
than penicillins. Whereas original
penicillins had primarily Gram+
coverage, most cephalosporins cover
both gram positive and gram negative
bacteria.
• low toxicity compared with penicillins.
• possible modifications:
– 7-acyl amino side chain
– 3-acetoxymethyl side chain
– substitution at C-7 6

7. NOMENCLATURE
• The chemical nomenclature of the cephalosporin is slightly more
complex than even that of penicillin because of the presence of a
double bond in the dihydro thiazine ring. The fused ring system is
designed by chemical abstracts as 1-thia-5-azabicyclo [4,2,0] oct-
2-ene.
• A simplification that retains some of the systematic nature of the
chemical abstract procedure is to name the saturated bicyclic ring
system with the lactum carbonyl oxygen as cepham.
• According to this system, all of the commercially are named as 3
cepham to designate the position of the double bond.
7

8. properties of cephalosporins
• Broad spectrum activity
• they are water soluble
• M.W= 400-450
• Relatively stable to pH and temperature changes
• Nucleus of cephalosporin is 7-ACA
• Their activity is not reduced by serum
8

9. classification of cephalosporins
• Accoring to generations Cephalosporins are classified as
follows:
First Generation
Second Generation
Third Generation
Fourth Generation
Fifth Generation
9

10. FIRST GENERATION
• Exhibit good activity against gram-positive bacteria
• Most gram positive cocci
• Strepto-, Pneumo.
• examples:
– parenteral: cefazolin, cephalothin, cephaloridine.
– oral: cephalexin, cephadroxil, cephradine*.
• USES:UTIs, ear and skin inefections, pneumonia, strep throat
cefazolin cephalexin
10

11. SECOND GENERATION
• Exhibit increased activty against the gram negative
organisms, but less active than thrid generation agents.
• Less active against gram positive cocci and bacilli compared
to first generation drugs.
• examples:
– parenteral:cefoxitin^, cefotetan^, cefuroxime
– oral: cefaclor, cefprozil, cefuroxime axetil.
cefoxitin cefaclor
11

12. THIRD GENERATION
• High activity against gram negative organisms
• All are highly resistant to β-lactamases from gram negative.
• Some of the members in these group cross BBB.
Eg.ceftriaxone
• examples:
– parenterals: Cefotaxi , Ceftriax , Ceftazidime
– oral: Cefpodoxime, Cefdinir, Cefixime
ceftriaxone cefdinir 12

13. FOURTH GENERATION
• Very broad spectrum (Gm- and Gm+)
• Effective against bacterial infections resistant to earlier
drugs.
• examples:
– parenterals: cefe me, cef rome, cefozopran.
USES: skin and soft tissues infections, pneumonia,
abdominal infections, meningitis.
cefepime
13

14. FIFTH GENERATION
• Active against gram positive cocci mainly MRSA(methicillin-
resistant staphylococcus aureus).
• PRSP(penicillin-resistant S.pneumoniae).
• Examples:
– parenteral: Cefta ine, ceftobip e.
ceftaroline
14

15. Oral cephalosporins
15

16. Parenteral cephalosporins
16

17. Spectrum of Activity
Cephalosporin exhibits a uniquely potent activity against most of the species of
Klebsiella.
Differentials potencies of cephalosporin are, compared with penicillin against
different species of bacteria are probably due to:
• Resistance to inactivation by B lactamase
• Permeability of bacterial cell
• Intrinsic activity against bacterial enzymes involved in cell wall synthesis
and cross linkage.
17

18. MECHANISM OF ACTION
• peptidoglycan layer is important for cell
wall structure intergrity of bacteria.
• the final step is synthesis of
peptidoglycan is faciliated by
transpeptidase(PBP).
• cephalosporin compititively inhibit PBP as
it mimics the structure of D-ala-D-ala into
which PBP bind for cross linking of
peptidoglycan.
• as it disrupting the cross-linking process
the cell wall will lose its strength which
results in cell lysis.
cephalosporin
act as transpeptidase enzyme
inhibit traspeptidation reaction
block polypeptide synthesis
activation of autolytic enzyme
increase the permiability of cell
membrane
cell explodes and lysed
death of microorganism
18

19. STRUCTURAL ACTIVITY RELATIONSHIP(SAR)
1.7-Acylamino substitution
• The ammonium ion improves the stability of B-
lactum of cephalosporins and make active
orally. Activity against positive bacteria is
increased and gram negative is decreased by
acylation of amino group.
• When the new acyl groups are derived from
carboxylic acids, it shows good spectrum of
antibacterial action for gram-positive bacteria.
• Substitutions on the aromatic ring phenyl that
increase lipophilicity provide higher gram-
positive activity and generally lower gram-
negative activity.
• The phenyl ring in the side chain can be
replaced with other heterocycles with improved
spectrum of activity and pharmacokinetic
properties; these include thiophene, tetrazole,
furan, pyridine, and aminothiazoles.
19

20. 2. Modification in the C-3 substitution: The pharmacokinetic and pharmacodynamics depends on C-3
substituents. Modification at C-3 position has been made to reduce the degradation of cephalosporins.
– The benzoyl ester shows improved gram-positive activity, but lowered gram-negative activity.
– Pyridine, imidaozle replaced acetoxy group by azide ion yields derivative with relatively low gram negative activity.
– Displacement with aromatic thiols of 3-acetoxy group results in an enhancement of activity against gram-negative
bacteria with improved pharmacokinetic properties.
– Orally active compounds are produced by replacement of acetoxy group at C-3 position with CH3, and Cl.
other modifications:
– Methoxy group at C-7, shows higher resistance to hydrolysis by B-lactamase.
– Oxidation of ring spectrum to sulphoxide or sulphone greatly diminishes or destroys the antibacterial activity.
– Replacement of sulphur with oxygen leads to oxacepam (latamoxet) with increased antibacterial activity, because
of its enhanced acylating power. Similarly, replacement of sulphur with methylene group has greater chemical
stability and a longer half-life.
– The carboxyl group position-4 has been converted into ester prodrugs to increase bioavailability of
cephalosporins, and these can be given orally as well.
– The antibacterial activity depends on the olefinic linkage at C-3 and C-4 position.
20

21. CHEMICAL DEGRADATION OF CEPHALOSPORIN
21

22. 22

23. INTODUCTION
• Aminoglycosides are a group of antibiotics effective
against gram negative and gram positive
microorganisms.
• They are also called as as it
contains an amino cyclitol moiety to which aminosugars
are linked glycosidically.
• Derived from genus (streptomycin).
• All aminoglycosides possess one amino hexose sugar but
few possess pentose ring such as streptomycin,
neomycin, paramomycin.
• They are also effective to a great extent against 23

24. HISTORY
• 1940- Screeing of soil for
antimicrobial substances
• 1943- discovery of first aminoglycoside streptomycin
which was isolated from actinomycetes bacteria
.
• later in 1950s it was used for the treatment of
.
• streptomycin was discovered by
and received a nobel prize in
1952. 24

25. SOURCE
25

26. PROPERTIES OF AMINOGLYCOSIDES
• Highly polar and water soluble.
• they are basic and form salts with acids.
• poorly absorbed after oral administration so they are
given mostly parenteral.
• they can cross placental barrier.
• they can’t cross BBB so they are not used for meningitis
unless injected directly to CNS.
26

27. SPECTRUM OF ACVITY
• Although the aminoglycosides are as broadspectrum
antibiotics.
• they are used in treatment of serious systemic infections
caused by aerobic gram-negative bacilli.
• the choice of agent is generally between kanamycin,
gentamycin, tobramycin and amikacin
• streptomycin is most effective of the group for the
chemotherapy of TB, brucellosis, tularemia, and yersinia
infections.
27

28. MECHANISM OF ACTION
• Aminoglycosides are bactericidal antibiotics
• transport of aminoglycoside through the bacterial cell wall
and cytoplasmic membrane.
• binding to ribosomes resulting in inhibition of protein
synthesis.
• streptomycin binds to , but other
aminoglycosides bind to additional sites on 50s subunit,
as well as to 30s-50s interface.
28

29. STREPTOMYCIN (1944)
• Streptomycin is chiefly employed
in the in
conjunction with other drugs such
as isoniazid and rifampicin.
• Streptomycin and penicillin exert
a synergistic action against bacteria
and are usually employed together
in the treatment of subacute
bacterial endocarditis caused by
Streptococcus faecalis
• It exerts bacteriostatic action in
low concentrations and bactericidal
in high concentrations against a
plethora of Gram-negative and
Gram-positive organisms.
29

30. SAR OF Streptomycin
• The ‘drug’ serves as a triacidic base due to the presence of two characteristic chemical
entities, namely: (a) two strongly basic guanido moieties ; and (b) rather weakly basic
methylamino function.
• Reduction of aldehyde to alcohol results in a compound dihyrostreptomycin activity is similar
to streptomycin but producing severe deafness.
• Oxidation of aldehyde group to a oxime,semicarbazone, phenylhydrazone derivatives results
in inactive analogues.
• Oxidation of -CH3, group in α-streptose to a methylene hydroxy gives an active analogous.
• Modification of amino methyl group in the glucosamine by demethylation and replace by
larger alkyl groups reduces activity.
• In N-methyl-L-glucosamine(-NHCH3, group) is very essential for the acivity.
• Guanidino groups streptidine ring are essential. Replacement of guanidino groups reduces
the antibacterial activity.
30

31. NEOMYCIN(1949)
• Isolated from cultures of
along with
antifungal substance Fradicin
• Neomycin is mostly used in a wide
variety of local infection such as
burns, ulcers, wounds,
conjunctivitis, etc.
• It is also employed as an adjuvant
in topical steroid preparations to
control secondary infections in the
case of inflammatory disorder.
31

32. SAR OF NEOMYCIN
• The structures of
have been established.
• The absolute configurational structures of neomycin and
neamine have been reported.
• It has been demonstrated that neamine could be obtained
by the methanolysis of neomycin B and C respectively,
whereby the glycosidic linkage existing between D-ribose
and deoxystreptamine undergoes cessation.
32

33. KANAMYCIN (1957)
• Isolated from cultures of
.
• the least toxic member in the market
is kanamycin A.
• The use of kanamycin is normally
restricted to the infections related to
the intestinal tract, such as: bacillary
dysentery; systemic infections caused
due to Gram-negative bacili, such as :
Klebsiella,Proteus, Enterobacter, and
Serratia spp., which have developed
resistance to some other antibiotics. 33

34. SAR OF KANAMYCIN
.
• Kanamycin A is the ‘drug’ available for therapeutic usage. It has been proved
that the vital point of difference amongst the kanamycins resides solely in the
sugar residues strategically linked to the glycosidic oxygen at the C-4
position of the central deoxystreptamine.
• Kanamycins do not essentially possess the D-ribose residue. In all the three
structural presence of kanosamine entity is found to be attached
glycosidically at the C-6 position of deoxystreptamine i.e., 3-D-glucosamine.
• They also differ in the substituted D-glucoses which are observed to be
attached glycosidically at the C-4 position of the inherent deoxystreptamine
ring.
34

35. SAR of Aminoglycoside Antibiotics
• The aminoglycosides consist of two or more amino
sugars joined in glycoside linkage to a highly
substituted 1,3-diaminocyclo hexane (aminocyclitol),
which is a centrally placed ring. The ring is a 2-deoxy
streptamine in all aminoglycosides except streptomycin
and dihydrostreptomycin, where it is streptidine.
• Thus,
– In kanamycin and gentamycin families, two amino sugars
are attached to 2-deoxy streptamine.
– In streptomycin, two amino sugars are attached to
strepidine.
– In neomycin family, there are amino sugars attached to 2-
deoxy streptamine.
• The aminoglycoside antibiotics contain two important
structural features. They are amino sugar portion and
centrally placed hexose ring, which is either 2-
deoxystreptamine or streptidine.
35

36. 36
1. Amino sugar portion
i. The bacterial inactivating enzymes targets C-6 and C-2 position, and
the substitution with methyl group at C-6 increases the enzyme
resistance.
ii. Cleavage of 3-hydroxyl or the 4-hydroxyl or both groups does not
affect the activity.
2. Centrally placed hexose ring (aminocyclitol ring)
Various modifications at C-1 amino group have been tested. The
acylation (e.g. amikacyn) and ethylation (e.g. 1-N-ethylsisomycin)
though does not increase the activity helps to retain the antibacterial
potency.

37. REFERENCES
• Burger’s Medicinal chemistry (volume 5)
• V. Alagarsamy textbook of medicinal chemistry (volume 2)
• Thripathi K.D. Essentials of medicinal pharmacology
• P. Ravi shankar slideshare ( CEPHALOSPORINS)
• P. Ravi shankar slideshare ( aminoglycosides)
• Ashraful Islam Rayhan slideshare (cephalosporin
antibiotics)
• Dr. yashodha krishna slideplayer (aminoglycoside
antibiotics) 37

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