Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
66 Cards in this Set
- Front
- Back
Four criteria for good antibiotics
|
target is essential to the microorganism survival
The compound is non-toxic to humans structure and function of the target is highly conserved across a variety of spp (broad spectrum) Resistance to inhibitors not easily acquired |
|
1930s
|
observation affinity of organic dyes for bacterial cells
Testing of dyes for antibacterial activity in vivo |
|
1935
|
prontosil (red dye) antibacterial activity (in vivo)
Structure |
|
Sulfanilamide
|
first synthetic antibacterial (G+’ve bacteria)
|
|
Protonsil metabolised to
|
Sulphanilamide and 1,2,4-triaminobenzene
Structure |
|
Why not stat with primary amine than acetylate early and then deacetylate
|
Anilne primary amine will be protonated by chlorosulphonic acid thus become meta directing instead of para
The bulky acetanilide amide group is para directing because of steric hindrance. Mechanism |
|
Sulpohnamide structure activity relationship
|
Para substituted to mirror PABA
para amine & benzene for activity Amide less active that sulfonamide Monosubstitution on sulfonamide may increase activity and Disubstitution abolishes activity |
|
Sulpohnamide pH
|
lipophilicity determines their ability to get inside the bacterial cell
ionization at physiological pH to resemble PABA for better incorporated into enzyme for inhibition |
|
Sulpohnamide pKa and activity
|
Amine pKa around 4.7 in both Sulfonamides & PABA
Carboxylic acid pKa in PABA is 6.5, while the Sulfonamide has a pKa around 10.4 |
|
pka
|
pKa is the negative base-10 logarithm of the acid dissociation constant of a solution. pKa = -log10Ka. The lower the pKa value, the stronger the acid.
Suphonamide active when ionised pH at which acid or base is 50% ionised |
|
Sulphonamide active at pka
|
6.4 to 7.4 Groups attached to N are electron withdrawing which spread the electron density of sulphonamides (pka 10.4) thus lowering pka on the amine in order to move their pka toward 6.4
|
|
Sulphonamide requirements for activity
|
Sulphonamide skeleton to resemble PABA
S directly attached to benzene and para to free amine (substituted - get inactivated) Substitution of -SO3 destroys activity. Nitrogen can only be primary or secondary Heterocyclic substituents enhance activity |
|
Sulphonamide MOA
|
Sulphonamides are folate antagonists
Competitive inhibitor of dihydropteroate synthetase (DHPS) Inhibits activation of folate to its active form, tetrahydrofolate. |
|
Why Sulphonamides do not affect humans
|
Bacteria synthesize folate - form cofactors for purine, pyrimidine and amino acid synthesis
Mammals acquire folic acid from diet so they are unaffected |
|
Sulphonamide Resistance
|
increasing the concentration of PABA
change in the enzyme structure to better distinguish between PABA and the drug. uptake Folic acid from their surroundings Decrease sulphonamide permeability Destroy sulphonamide Production of altered dihydrofolate reductase |
|
Sulphonamide uses
|
treatment of acute, uncomplicated urinary-tract infections, particularly those caused by Escherichia coli. GIT infection
Eye lotions Infections of mucous membranes |
|
Sulphonamide Adverse affects
|
Crystalluria, kidney damage, Stevens-Johnson
allergic reactions, especially rashes, photosensitivity and fever. Hemolytic anemia (G6PDH deficient pts. neutropenia and thrombocytopenia |
|
Early Sulphonamide Side effect
|
Earlier solutions were to increase urine flow
increase the pH of urine to around 10 using sodium bicarbonate |
|
Suphonamide Drug interactions
|
Warfarin, phenytoin, methotrexate.
|
|
nalidixic acid
|
First quinolone Not technically a quinolone
Discovered as a by-product of chloroquine synthesis G –ve bacteria Commonly used for UTI |
|
Quinolone MOA
|
Inhibition of bacterial topoisomerase IV (G+) and topoisomerase II (G- DNA gyrase) (Not present in humans) leading to inhibition of replication and transcription
|
|
Quinolone Resistance
|
– DNA Gyrase mutations
– Cellular membrane efflux mechanisms. – Decreased number of porins in target cells |
|
Quinolone distribution
|
Wide distribution - CSF, saliva, bone, cartilage
|
|
Quinolone SAR
|
Ketone (reduction inactivates) & -COOH DNA binding
C2 enzyme substrate complexation (substitution inactivate |
|
Quinolone F at C 6
|
Increase lipophilicity and bacterial cell wall penetration and increased DNA gyrase binding because F is lipophilic
|
|
Quinolone F at C 8 (Halogen)
|
Increase drug absorption and half life
Unfortunately increase drug induced photo sensitivity via singlet oxygen and radical induction (Lomefloxacin) Methoxy at 8 reduce photo sensitivity (Gatifloxacin) |
|
Quinolone Substitution at C 7
|
Increase spectrum of activity against G -ve
Piperazine (ciprofloxacin) increase binding to GABA leading to CNS S/E Adding bulky groups at position 1 reduce GABA binding (Sparfloxacin) |
|
Quinolone Substitution at 1 (N)
|
Broadens spectrum of activity against atypical bacteria ( cyclopropyl ) Mycoplasma, clamedia and legionella species e.g Ofloxacin
Cyclopropyl substituent considered most potent substituent here |
|
Quinolone C3 asymmetric C isomer
|
S (-) isomer (levofloxacin) is twice active as Ofloxacin and 8-128 fold potent than R (+) isomer due to increased binding to DNA gyrase
|
|
Position 3 and 4
|
considered essential for DNA binding
Very few bioisosteric replacements are successful at these positions |
|
Position 7
|
interacts directly with DNA gyrase and topoisomerase IV
Optimum substituents contain 5 or 6 membered heterocyclic rings e.g. Piperazinyl moeity Methylation of piperazine increases log P |
|
1928 Fleming discovered
|
antibacterial activity of fungus (Penicillium sp.)
|
|
1938 Florey and Chain
|
isolated penicillin
|
|
1945 Dorothy Hodgkin
|
established structure by X-ray crystallography
|
|
1957 Sheehan
|
completed first total synthesis
|
|
1958 Beechams
|
isolated 6-aminopenicillinic acid (6-APA, precursor to penicillins)
|
|
1976 Beechams
|
discovered clavulanic acid – reversal of penicillin resistance
|
|
Penicillin
|
dipeptide analogs of D-ala-D-ala
inhibition of PBPs 1a & 1b and PBP3 that function as transpeptidases in the biosynthesis of the peptidoglycan |
|
PBP
|
Penicillin Binding Protein
|
|
Penicillin Mechanism of Action
|
Inhibition is result of acylation of the enzyme by attack of serine on the β-lactam ring
β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner. |
|
Why Beta lactum ring is very reactive
|
The amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl.
Bicyclic system increases b-lactam ring strain |
|
Penicillin Structure Activity Relationship
|
Amide and carboxylic acid are involved in binding
Carboxylic acid binds as the carboxylate ion Variations are limited to the side chain (R) β-lactam ring is an essential portion of pharmacophore its hydrolysis deactivates Bicyclic system increases b-lactam ring strain |
|
Beta lactum hydrolysis due to
|
β-lactamase, Alcohols and amines PRODUCING corresponding esters and amides.
|
|
Penicillin Spectrum of activity
|
Hydrophobic side chains favours activity against G+ bacteria
Increased hydrophobic character decreased G- activity, no effect on G+ Hydrophilic groups have no effect or reduction of activity on G+ but increased activity against G- bacteria |
|
Penicilin best activity
|
NH2, OH, COOH alpha to carbonyl
|
|
Penicilin hydrolysis reduced by
|
Addition of EWGs - Reduced nucleophilic character of carbonyl e.g phenoxymethyl penicillin
Steric shields can be added to protect penicillins from b-lactamases |
|
Interaction of nitrogen’s lone pair with the carbonyl group is not possible Structure
|
the bond angles are 90o instead of 120o, thus 30o ring strain prevents the overlap of the nitrogen lone
pair with the adjacent carbonyl system. Ring strain prevents the normal amide resonance from taking place in b-lactam rings |
|
penicillins and cephalosporins is very susceptible to ring-opening under strongly
acidic and basic conditions |
b-lactam carbonyl is much more
electrophilic than a normal amide - susceptible to nucleophilic attack. Nitrogen is readily protonated under acidic conditions, making the b-lactam ring sensitive to strong acids. |
|
Structural features essential for activity in penicillins
|
The bicyclic ring system containing the b-lactam is crucial, as are the cis relationship
between the two hydrogens at positions 5 and 6, a free 3-carboxylate and a 6-amide.Changing one or more of these results in a loss of activity |
|
Synthesis of penicillin analogues
|
fermentation process, in which different carboxylic acid derivatives were added to yield penicillins containing different 6-amido derivatives
relies on the isolation of 6-aminopenicillanic acid (6- APA) from fermentation media. Use acyl chlorides. |
|
Penicillin analogue synthesis by Fermentation limitations
|
not all carboxylic acids were biologically acceptable and thus only a limited number
of analogues could be prepared |
|
Penicilinase resistance mechanisms
|
•Decreased cellular uptake of pen
•Lower binding affinity of pen to PBPa •Production of β-lactamases by bacteria |
|
Overcome Penicillin resistance
|
Use of steric shields - introducing bulky groups to the side chain
|
|
How does introduction of bulky group affect activity of penicillin?
|
The additional hydrophilic groups make penetration of the gut wall difficult - infections of GI by H. pylori
administered intravenously or as a prodrug. aminopenicillins increased activity against Gram (-) bacteria by way of the import porins |
|
Effect Metal ions on penicillin activity
|
mercury, zinc, and copper, catalyse the
degradation of penicillin's Use plastic containers |
|
Effect of substituents on aromatic ring attached to the side chain amide (Structures)
|
If ring has methoxy groups at para and ortho B-lactamase stability results e.g. Methicillin IV coz its acid sensitive
If one of the methoxy groups is replace by H B-sensitivity occurs If methoxy is put between ring and penicillin B-sensitivity occurs (Phenoxymethyl penicillin) |
|
Beta lactum sensitive penicillins
|
Benzyl penicillin Gram positive) Benz-CH2-
Phenoxymethyl penicillin Benz-O-CH2- Ampicillin (Gram +ve and -ve) Benz-CH2(NH2)- Amoxycillin HO-Benz-CH2(NH2)- |
|
Ampicillin
|
Benz-CH2(NH2)- Gram -ve eff greater penetration of gram -ve bacteria due NH2 protonation thus polar but not affect gram +ve effect
NH2 get protonated thus EWD and acid stable B-lactum sensitive. |
|
Amoxycillin
|
HO-Benz-CH2(NH2)- The -OH adjust isoelectric point to more acidic value thus enhanced intestine absorption by peptide transporter transporter than Ampicllin thus less drug induced diarrhoea coz less GI flora disturbance.
|
|
Clavulanic acid
|
Combined with amoxy to prevent B-lactamases
2 rings S replaced by O and 2 -CH3 replced by =CH-CH2OH |
|
Benzyl penicillin
|
Benz-CH2- More Gram +ve because benzene ring is hydrophobic. IM injection prolonged sustained release. More acid sensitive
|
|
Phenoxymethyl penicillin (Pen V)
|
Benz-O-CH2- More acid stable than Benzyl penicillin because of the electronegative oxygen atom in C7 amide chain inhibiting Beta lactam hydrolysis thus used orally. Has the same spectrum as benzyl penicillin (Gram -ve)
|
|
Methicillin
|
2(H3C-O meta-ortho )-Benz- Acid sensitive but Beta lactamase stable. Narrow spectrum - Beta lactamase producing staphylococcus. Administered IV
Resistance - reduced uptake and altered PBP e.g. PBP2. Use Vancomycin, cotri or rifampicin |
|
Nafacillin
|
2 benzene rings fused at meta-ortho side and -CH2CH3 at other meta side of ring
Same spectrum as Methicin but more acid stable and also beta lactamase stable. |
|
Penicillin Pro-drugs mechanism
|
Ester groups attached to enhance absorption of the dipolar penicillin. The ester is hydrolysed after absorption. Ester attached to the -COOH below the penicillin molecule e.g. Talampicillin
|
|
Gram -ve bacteria resistance
|
They have a lipopolysaccharide outer membrane which prevent access to the cell wall
Penicillins only cross at porins in the outer membrane. |