MedChem Tetracyclines

Aureomycin

First active tetracycline metabolite isolated

chlortetracycline

Generic of Aureomycin

T

T/F Tetracyclines are considered “broad-spectrum”

fermentation, chemical transformations

How are tetracyclines obtained and produced from natural products?

octahydronaphthacene

Tetracyclines are derivatives of what molecule?

tigecycline

What tetracycline was marketed as a glycylcycline?

T

T/F Tigecycline has increased spectrum of activity and reduced susceptibility of resistance compared to minocycline.

4 4a 5 5a 6 12a

Locations of chiral carbons on tetracyclines

amphoteric

Tetracyclines will form with either acids or bases, and exist mainly as zwitterions in solution. Therefore they are ____

2.8-3.3

Typical pKa range of pKa₁

_7.2-7.8

Typical pKa range of pKa₂

_9.1-9.7

Typical pKa range of pKa₃

HCl salts

What salts of tetracyclines are most common due to their solubility and stability?

F

T/F Basic salts (using KOH or NaOH) are stable in solution.

chelation

Insoluble salts of tetracyclines are formed with divalent and polyvalent metals known as ____.

T

T/F Tetracyclines must be stabilized with excess acid to prevent crystallization out of solution.

epimerization

In pH 4-8, tetracyclines can undergo interconversion of the C-4 asymmetric center to a inactive form known as ______

anhydrotetracycline

Inactive product of a tetracycline (with a β-OH at C-6 and the ⍺-H at C-5a) dehydrated by acids and bases

Fanconi-like syndrome

The syndrome related to kidney disfunction associated with the use of expired tetracyclines

anhydrotetracycline, anhydro-4-epitetracycline

Expired tetracycline by-products linked to kidney disfunction

lactone

Inactive structure formed by base catalyzed degradation of tetracyclines

tetracycline-calcium orthophosphate complexes

What complexes are formed by the binding of tetracyclines to Ca²⁺ causing yellow discoloration of teeth?

T

T/F Tetracyclines are present in breast milk and cross the placenta

bacteriostatic

Are tetracyclines bactericidal or bacteriostatic?

30S ribosomal subunit

Tetracyclines bind to what subunit to inhibit microbial translation?

aminoacyl tRNA

Binding of the 30S ribosomal subunit to what molecule is prevented by tetracyclines?

Mg

Tetracyclines and aminoacyl tRNA require what molecule to bind to the ribosome?

comparative cytology

Tetracyclines have limited mammalian cell membrane penetration. This is an example of what kind of selective toxicity?

passive diffusion, active transport

How do tetracyclines enter bacterial cells?

exclusion

Bacterial resistance due to presence of tetracycline binding proteins at the cell surface is an example of what type of resistance?

target modification

Bacterial resistance due to synthesis of proteins that associate with ribosomes allowing for protein synthesis to continue in the presence of tetracyclines is an example of what kind of resistance?

tetracyclines

What class of antibiotics have the broadest spectrum of activity?

F

T/F Tetracyclines are a good choice during life-threatening infections

Candida albicans

A superinfection of what organism can be caused by incomplete absorption of tetracyclines?

S. aureus, P. aeruginosa

Superinfections of what organisms can be caused from prolonged use of tetracyclines?

T

T/F The amide at C-2 must be present for a tetracycline to be active

alpha

The dimethyl amine at C-4 must be present for a tetracycline to be active. Does this substituent need to have alpha or beta stereochemistry?

cis

Does the fusion of the A/B ring of a tetracycline need to be cis or trans isomer to be active?

11a

Alkylation at what location makes a tetracycline inactive?

12a

Esters of what hydroxyl group make a tetracycline inactive?

1 2 3 4 10 11 11a 12 12a

What locations cannot be violated in order to preserve tetracycline activity?

decrease

What effect do polar substituents at C5 and C6 have on the partition coefficient (P) of tetracyclines?

C6-OH

Removal of what group on a tetracycline causes an increase in the partition coefficient (P)?

high

Does a tetracycline with a high or low partition coefficient (P) have lower renal clearance and prolonged duration of action?

lipid soluble

Do polar or lipid soluble tetracyclines have better distribution into poorly vascularized tissue?

doxycycline hyclate

What is the most used tetracycline. (has QD dosing)

monohydrochloride hemiethanolate hemihydrate

Chemical name for doxycycline hyclate

oxytetracycline

Based on the image, which drug would have the lowest partition coefficient (P), and therefore have the most renal clearance and shortest duration of action?

tetracycline, doxycycline, minocycline

Doxycycline (P=0.95), minocycline (P=1.1), tetracycline (P=0.056). Rank in order from shortest duration of action to longest.