ID E3_ medchem questions

bottom: miconazole

bc of more chloro groups. makes it soluble in EG and castor oil

comparing structure of econazole, which is more lipophilic

top: econazole

bottom: miconazole

;

GI distrubance/toxicity

what are the adverse effects of these structures;

nitrogen not attached to a carbon

which nitrogen forms nitrate salts;

IM

has more chloro compared to econazole, making it more soluble in EG and castor oil

how is this molecule (miconazole) given;

1. thrombophlebitis

2. puritis

3. GI upset

adverse effects of miconazole;

the butyl, 4Cs and S make it more lipophilic, therefore increasing its antifungal activity

used as a cream

what is the important point of this molecule (butoconazole nitrate);

due to removal of 5 carbon linker and placement of S it is sparingly water soluble

important point of this molecule (sulconazole nitrate);

oxime must have Z geometry

the lower the concentration the more potent this drug is

important point of this molecule (oiconazole nitrate);

best azole choice for candida glabrata

important points of this molecule (ticonazole);

broad spectrum antifungal that has oral bioavailability

depends on acidic pH for dissolution and absorption

has high tendency for hepatotoxicity

piperazine side chain increases hepatotoxicity

important points of this drug (ketoconazole)1.;

1. antacids

2. anticholinergic/H2 histamine antagonists

meds that inhibit the gastric absorption of ketoconazole;

N-deacetylketoconazole

inactive metabolite of ketoconazole that is hepatically excreted

causes hepatotoxicity;

amphotericin B

antagonized the activity of ketoconazole;

1. inhibition of cholesterol biosynthesis (results in lowering of testosterone and corticosterone levels in humans)

2. drug-drug interactions (cyclosporine, phenytoin, terfenadine metabolism will decrease and concentrations will increase

what does inhibition of lanosterol 14 alpha-demethylase in humans from the use of azoles result in;

B

predict the most active steroisomer of A-D;

cis 2S 4R

note: cis configuration is required for activity of ketoconazole

isomer of ketoconazole that is the most active;

have extended conformation and mask the ability of the imidazole functionality

cis conformation expose the imidazole to the binding site allowing for better activity

why are the trans isomers of ketoconazole less active;

triazole pharmacophore makes it highly potent

bulky alkylation of the N makes dealkylation take a longer amount of time compared to ketoconazole

what are important points of this molecule (terconazole);

dealkylation

note: all azoles that have the substitution at the piperazine ring are dealkylated for inactivation

how is ketoconazole metabolized;

the 2 triazoles

the one with an oxygen is not basic and has no antifungal acivity but increases binding affinity

the one without the oxygen is basic

like ketoconazole, requires acidic environment for absorption but has less risk of hepatotoxicity

important points of this molecule (itraconazole);

hydroxyitraconazole

note: the molecules are inactivated by N dealkylation but not on the triazole ring. dealkylation occurs on the piperazine ring

metabolite of itraconazole that is active

and it is much more active than itraconzole;

unlike ketoconazole, itraconazole is not hepatotoxic and does not induce adrenal/testicular suppression at therapeutic doses

they both inhibit CYP450, which metabolize xenobiotics and antihistamic drugs like terfenadine and astemizole

what is the difference between ketoconazole and itraconazole;

fluo-phenyl is much less toxic than chloro-fenyl

highly water soluble and can cross BBB

it does not interfere with corticosteroid or androgen biosynthesis in therapeutic doses

what is important about this molecule (fluconazole);

fluconazole

azole of choice for cryptococcal and coccidioidal meningitis;

fluorinated pyrimidine give better potency and activity versus resistant strains of aspergillus species

imadine nitrogen oxygenation results in loss of activity

causes hepatotoxicity and photophobia

H2O insoluble

what is important about this molecule (voriconazole);

oxygenation of the N of the active pharmacophore

how is this molecule inactivated;

has very long half life

excreted in feces unchanged

can cause GI and liver enzyme change

what are the important points of this molecule (posaconazole);

allylamines have less effect on mammalian cells and have less inhibition of mammalian cholesterol synthesis

azoles vs allylamines;

allylamine has antifungal activity

what are the important points of this molecule (naftifine HCl);

orally active vs onychomycoses (nail ringworm)

highly lipophilic

what are the important points of this molecule;

1. N dealkylation

2. oxidative d alination

3. hydroxination

how is this molecule inactivated;

not an allylamine but has same activity

thiocarbamate ester of beta-naphthol-m-toluidine contributes activity

what is the importance of this molecule (tolnaftate);

propionic acid and zinc propionate

propionic acid: non volatile and odorless

zinc propionate: unstable to moisture

nonirritant, nontoxic fungicide acid in sweat;

undecylenic acid

irritant and not used to mucous membranes

obtained by destructive distillation of castor oil

viscous yellow oil, with characteristic odor;

triacetin

glyceryl triacetate colorless oil with bitter taste

has fungicidal effect due to enzymatic hydrolysis by skin eserase to acetic acid;

interfere with cell membrane integrity/function in susceptible fungi

mechanism of action of phenols and related compounds;

photosensitive, must be protected from light due to I

important points of this molecule (haloprogin);

1st choice for tinea corporis, cruris, and pedis

2nd choice for onychomycoses after griseofulvin

blocks amino acid transport at low doses

important points of this moleule (ciclopirox olamine);

iodine is released in tissues

what important;

acts as a prodrug activated by fungal cytosine deaminase to 5-fluorouracil which is cytotoxic and anticancer

what important (flucytosine);

5-fluorodeoxyuridine

note: only effects fungal cells bc human cells do not have cytosine deaminase

active form of flucytosine;

contain enes in the macrocycle which differentiate them from the antibacterial macrolide erythromycins

describe polyene antifungal antibioitcs;

26 membered

size of polyene antifungals;

mycoasamine

amphoteric

hydrophilic: OHs, COOH, and sugar parts

lipophilic: 4-7 double bonds (correlates with antifungal potency and inversely correlates with degree of toxicity)

contained in all polyene antifungals;

bind sterol containing membranes, inserting into and disrupting membrane functions, leaking of essential constituents

mechanism of action of polyene antifungals;

ergosterol containing

do polyenes have a higher affinity for ergosterol containin gmembranes or cholesterol containg membranes;

false

never give IM

T/F amphotericin can be given IM;

amphotericin

antigungal that forms salts with acids and alkali but cannot be used for oral systemic uses;

dextrose

what is amphotericin infused in;

saline

destroys amphotericin;

liposomal encapsulation and lipid complexes

formulations of amphotericin that decrease its toxicity;

nephrotoxicity

limits the use of amphotericin;

natamycin

has four double bonds and one non conjugated double bond;

keratin/microtubules

what is griseofulvin attracted to;

fngistatic

action of griseofulvin;

particle size reduction and administration with fatty meals

increases the oral bioavailability of griseofulvin;

echinocandins

penicillin of antifungals;

noncompetitive inhibitor of (1,3)-beta-d-glucans synthase

results in inhibition of cell wall synthesis

mechanism of action of echinocandins;

caspofungin

semisynthesit canalog of echinocandin from culture of the fungus glarea lozoyensis;

c. saline will destroy amphotricin soluble colloidal solution

why amphotericin B solution will not be compatible with saline IV

a. saline will degrade amphotricin liposomal conjugates

b. saline will form amphotricin toxic monosodium salt

c. saline will destroy amphotricin soluble colloidal solution

d. saline will form insoluble amphotericin B sodium salt;

d

;

a

;

b

;

c

;

b

;

a

which should be conjugated with Na deoxycholate or liposome encapsulations before its systemic use;

d

which is not opitcally active;

e

which possesses a bis-triazole pharmacophore;

b

which will be the first pass metabolite of voriconazole;