Medicinal Organic Chem part 2 (Sir Jan's Notes)

Cell Wall

Site of Action?
Bacitracin
Cephalosporin
Cycloserine
Penicillins
Vancomycin

Cell Membrane

Site of Action?
Amphotericin B
Nystatin
Polymyxins

Ribosomes

Site of Action?
chloramphenicol

50s subunit

Site of action?
Erythromycin
lincomycin

30s unit

Site of action?
aminoglycosides
tetracyclines

Nucleic acids

site of action?
actinomycin
griseofulvin

DNA and/or RNA

Site of action?
Mitomycin C
Rifampacin

Bacitracin

Mucopeptide synthesis

Cephalosporin

Cell wall cross-linking

Cycloserine

Synthesis of cell wall peptides

Penicillins

Cell wall cross-linking

Vancomycin

Mucopeptide synthesis

Amphotericin B

Membrane function

Nystatin

Membrane function

Polymyxins

Membrane integrity

Aminoglycosides

Protein synthesis and fidelity

R group:

1. Electron withdrawing groups
→ L nucleophilicity of carbonyl oxygen → T stability
2. Bulky groups provides resistance to B-lactamase
3. Polar groups make the structure more hydrophilic

Ertapenem

Benzoic acid contributes to high protein binding and prolongs the half-life of the drug

Teicoplanin

A glycopeptide from Actinoplanes teichomyceticus
• MOA: long alkyl chain anchors the antibiotic to the outer surface of the cell membrane
• Use: treatment of gram-positive infections

Ring 2

SAR: Aminoglycosides

Modifications of ________ (deoxystreptamine) functional groups are possible without
appreciable loss of activity in most of the aminoglycosides.

tetracycline

• Broadest spectrum of the antibiotics
• Have activity against gram positive & negative, spirochetes & atypical bacteria
• *Chlortetracycline- Streptomyces aureofaciens
• DOC: lime disease, ricketsiz

tetracycline

Binds to the 30s subunit of ribosomes which prevents aminoacyl-tRNA from binding to the mRNA ribosome complex

Dalfopristin

interferes with the transfer of the peptide chain from one tRNA to the next

1,4 dihydro-4-oxo-3 pyridine carboxylic acid

Quinolone SAR
nucleus?

Enzyme inhibitor
•Products containing divalent and trivalent metal

Interactions of quinolones

Allylamines

MOA: inhibit squalene epoxidase

epipodophyllotoxins

• semisynthetic derivatives of podophyllotoxin, isolated from mayapple root
• MOA: inhibits Topoisomerase II
• Drugs: Etoposide, Teniposide

Beracizumab

inhibits human vascular endothelial
growth factor (VEGF), preventing
angiogenesis

Mechanisms of Antibacterial Action

• Inhibition of cell wall synthesis
• Inhibition of protein synthesis
• Inhibition of cell metabolism
• Inhibition of nucleic acid transcription and replication
• Interactions with plasma membrane

acylamido & Cis-stereochemistry

in penicillin
___ side chain & ____is essential

Cephalosporin C

Contains an unstable bicyclic system
• Beta-lactam & dihydrothiazine
• Nucleus: 7-Aminocephalosporanic acid (7-
ACA)

Cystein & Valein

cephalosporin C precursors?

Cefalexin

used for UTI in pregnant

Aminoglycosides

Bind to 30s ribosomal subunit to prevent the reading of the mRNA

Amikacin

semi synthetically derived from Kanamycin
• first prepared in Japan

macrolides

Binds to the 50s ribosomal subunit, inhibiting translocation.

Clarithromycin

• methylated erythromycin
• More stable in gastric acid and has improved oral absorption
• Use: treatment of ulcers causes by H. pylori

Roxithromycin

Semisynthetic macrolide derived from erythromycin (+N-oxime side chain)

Pritinamycin

source: Streptomyces pristinaespiralis

Sparfloxacin

Quinolone SAR
Lowest photosensitivity

Tuberculoid Leprosy (TT)

• Well demarcated, dry patch
• Minimal disfigurement
- No leonine facies
- No claw-shaped hands
- No pendulous ear lobes
• Good immune response (high resistance)

Ketoconazole (Nizoral)

Used in systemic fungal infections (before), topical (now) needs acidic pH to be absorbed
• s/e, interactions: hepatoxicity, antiandrogenic effects, enzyme inhibitor
• reduced production of testosterone, impotence, loss of libido, gynecomastia, dec. sperm count

Carbachol

More stable ester, resulting to long-acting effect • Used for glaucoma

alkyl

SAR: ACh
Addition of _______ group • less prone to susceptibility & more selective to muscarinic than nicotinic

benign neoplasm

does not invade surrounding tissues

G2 phase

• DNA synthesis ceases. RNA & other enzymes (e.g., topoisomerase I & II) are produced to prepare for cell duplication

Chloramphenicol

Protein synthesis

Erythromycin

Protein synthesis

Lincomycins

Protein synthesis

Tetracyclines

Protein synthesis

Actinomycin

DNA and mRNA synthesis

Griseofulvin

Cell division, microtubule assembly

Mitomycin C

DNA synthesis

Rifampin

mRNA synthesis

Bactericidal

Type of activity?
Bacitracin
Cephalosporin
Cycloserine
Penicillins
Vancomycin
polymycins
aminoglycosides
rifampicin

Fungicidal

Type of action?
Amphoterecin B
Nystatin

Bacteriostatic

Type of action?
Chloramphenicol
erythromycin
lincomycin
tetracyclines

Pancidal

Type of Action?
Actinomycin
Mitomycin C

Fungistatic

Type of action?
Griseofulvin

B lactam antibiotics

penicillin is a?

Alexander Fleming

Penicillin is discovered by?

Penicillium notatum

old name of penicillin

Penicillium chrysogenum

new name of penicillin

Florey & Chain

P. notatum and P. Chrysogenum are isolated by? by freezdrying/lyophilization

Penicillin

Contains an unstable bicyclic system (b-lactam & Thiazolidine ring

cysteine and Valine

Precursors of penicillin

half open book

shape of penicillin

acid stability

SAR of penicillin
Addition of electron withdrawing group

penicillin's resistant

SAR of penicillin
Addition of bulky groups

Increase spectrum activity

Addition of amino group

sulfur

in penicillin
___ is usual but not essential

Thiazolidine

in penicillin
5-membered saturated ring contains nitrogen. The geminal dimethyl group at C-2 position is a characteristic of the penicillin

Carboxylic group

1. Is usually ionized to form sodium of potassium salts.
2. Bind amino group of Lys at binding site
3. Is important for activity which is reduced it modified to alcohol or ester

B-lactam ring

in penicillin
___ strain is essential

Bicyclic system

confers further strain to B-lactam ring
increase strain --> increase activity → increase instability

Carbonyl oxygen:

Is electrophilic because the lone pair electrons on N is not provided for resonance.
Thus =0 is ready for nucleophilic attack

Pen G

Gen Name?

Pen G

Chem Name?

Pen V

Gen name?

Phenoxymethylpenicillin

Chem name?

Methicillin

Gen Name?

2,6-Dimethoxyphenyl-penicillin

Chemical name?

nafcillin

Gen Name?

2-ethoxy-1-naphthyl-penicillin

Chem Name?

amoxicillin

Gen Name?

D-a-amino-p-hydroxybenzylpenicillin

Chem name?

Cyclacillin

Gen Name

1-aminocyclohexyl-penicillin

Chem Name

Carbenicillin

Gen Name?

a-carboxybenzyl-penicillin

Chem Name?

Ticarcillin

Gen Name?

a-carboxy-3-thienhyl-penicillin

chem name

piperacillin

Gen Name

a-(4-Ethyl-2,3-dioxo-1-
piperazinylcarbonyl-
amino)benzylpenicillin

Chem Name?

Mezlocillin

Gen Name?

a-(1-Methanesulfonyl-2-
oxoimidazolidino-
carbonylamino)benzyl-
penicillin

Chem Name?

Oxacillin

Gen Name?

5-Methyl-3-phenyl-4-isoxazoly|penicillin

Chem Name?

cloxacillin

Gen Name?

5-Methyl-3-(2-
chlorophenyl)-4-isoxazoly|penicillin

Chem Name?