Antibiotics Sulfonamides

8/18/2019 Antibiotics Sulfonamides

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Chemical classification of antibiotics

I. Sulfonamides

II. β-Lactams: include penicillins and

cephalosporins

III. Aminoglycosides: amino sugars suchas streptomycins, kanamycins,neomycins, gentamycins

IV. Polypeptides: such as tyrothiricin andpolymyxin

VI. Tetracyclines:

VII.Fused ring systems

VIII.Lincomycins

IX. Polyenes: Antifungal sucand amphotericins

X. Unclassified antibiotics

•Chemical classification of antibiotics is usually of limited value due to high variability.

• Structurally similar antibiotics derived from different microorganisms may have similamechanism of action.


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Sulfonamides (Sulfa or sulpha drugs)

Diseases like pneumonia, meningitis, dysentry etc., could not be treated effectively

discovery of sulfa drugs which were suitable for internal use against gram+ bacteri

p-aminobenzenesulphonamide (sulfanilamide) was initially synthesized in 190

intermediate for azo dyes, later on, it was observed that it is effective against strepto

In 1935, a red dye (4-sulfonamide-2′, 4′ -diaminoazobenzene) was prepared and

properties against infections and named Prontosil

The inactivity of prontosil as antibacterial agents in vitro suggests that it should be

another metabolite to exert its antibacterial activity in vivo.

Due to resistance development, only few sulfonamides are still in use such as (sul+t


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•

Sulfonamides inhibit DHPS by competing PABA.

• some bacteria can resist sulfonamide competition by making more Pcell membrane permeability to sulfonamide or by getting mutated D


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Structure-activity relationship

Any substitution inthe ring abolish

activity

Should not be substituted(i.e. R 1=H), and if

substituted should bemetabolized back to 1°

amine (i.e act as prodrug)

Tvarwiim

act

Only para

substitution isallowed

The benzene ring andsulfonamide are critical and

should be directly connected

The benzene ring andsulfonamide are critical and

should be directly connected

Should be directly

connected

Only para

substitution isallowed

4

Repby

re


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Ionization ofsulfonamides

Sulfonamide group (SO2NH2) is unstable and get stabilized by losin which results in negative charge being stabilized by resonance with s

Therefore, the SO2NH2 group can be considered as HA acid similar tCOOH), phenols (benzene-OH) and thiols (-SH).

The R group in –SO2-NH-R affects the ionizability of NH. If R is elec

drawing group, the antibacterial activity and solubility of the drug is Pyrimidine is more electron withdrawing than benzene and thiazoleproduce toxic sulfonamide derivatives.

The lipid solubility inf luences the pharmacokinetic and antibacteriaso increases the half-life and antibacterial activity in vivo.


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Crystalluria and pKa of sulfonamides

Despite the good ability to treat infections, thesulfanilamide are associated with sever renal damagedue to crystallization in the kidneys

The pKa of sulfonamido group (-SO2NH-) of sulfanilamide is 10.4, thurine pH of 6 only 0.004% of sulfanilamide is ionized (water-soluble

excreted in urine. The precipitated sulfanilamide in urine lead to crystalluria.

Sodium bicarbonate was administered before each dose of sulfanilamimprove solubility and thus excretion in urine.

nchanged (63%)


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Case study: Sulphathiazole

(metabolism problem)

Kidn

• Acetylation of N4 of sulfonamide ↓ ionization of N1 (NH) ↓so

Highly ionizable

Less ionizable

4 1

Electron withdrawing

group (pyrimidine) more soluble and less toxic

pKa=7.1

unchanged (63%)N4-acetyl (29%)N4-glucuronide (0.8%)N4-sulfate (0.5%)N1-glucuronide (3.8%)

pKa > 7.1


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Impaired Oral bioavailability of sulfonamide offeadvantage to locally treat gastrointestinal infecti

Too hydrophilic drug will not be absorbed as N4-succinyl derivatives

Too hydrophobic drug will not be absorbed as N4-benzoyl derivative

Oral bioavailability (i.e. absorption through GIT) requires balanced hydrophobic/hyd


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Sulfamethazine

naming options

4-Amino- N -(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide;

N 1-(4,6-dimethyl-2-pyrimidinyl)sulfanilamide;

2-sulfanilamido-4,6-dimethylpyrimidine.

pKa of 7.2

Cl ifi i f lf id h b i f


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Classification of sulfonamides on the basis ofChemical structure

N-substituted sulphonamide: Sulphadiazine, Sulphacetamide, Sulph • N-4 substituted sulphonamides (prodrugs): Prontosil.

• Both N-1 and N-4 substituted sulphonamides: Succinyl sulphathiazPhthalylsulphathiazole.

• Miscellaneous: Mafenide sodium.


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Classification of sulfonamides on the basis of Chemical structu

A) N-substituted sulfonamides

R 1 R 2


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B) N-4 substituted sulphonamides prodrugs)

Prontosil drug is inactive in vitro, but it is active in vivo since it is convsulphanilamide by azo reductase enzymes.

Note: Pro-drugs of amines are occasionally prepared by incorporating them in to an azo li

action of azo reductase the amino compounds are released in vivo.

Azo reductase

4-sulfonamide-2′, 4′ -diaminoazobenzene


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B) N-4 substituted sulphonamides prodrugs)

Sulphasalazine by the action ofazo reductase

releases the 5-amino salic(5-ASA) and sulphapyridine. The generation of anti-inflammatory salicto absorption prevents the systemic absorption of the agents and enhanconcentration of it in active site (intestine). Therefore, sulphaslazine is treat inflammatory bowel syndrome due to the released 5-ASA.

pKa=6.5

pKa=2.3

LogP =2.3

pKa=8.4

LogP =0.35

Low absorption from GITDue to low lipophilicity

pKa

Low aMostly


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C) Both N-1 and N-4 substituted

R 1 R 2

l f f lf d h b f h l


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D) Miscellaneous

It is NOT a true sulfanilam

as it is not inhibited by P

action involves a mechanisof true sulfanilamide-type c


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Mechanisms of Microbial Resistance

to Sulfonamides

The indiscriminate use of sulfonamides has led to the emerresistance strains of bacteria.

Resistance is likely through:- compensatory increase in biosynthesis of PABA.- Mutations at dihydropteroate synthase

- Decrease cell membrane permeability to sulfonamides.- Active efflux of sulfonamides outside the cell- acquisition of another copy of DHPS through plasmid tra


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Antibiotics Sulfonamides

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