24 Med Chem Antihistamines, Antivirals/Protease Inhibitors, and Antimycobacterials

Ethylenediamine

pharmacophore of antihistamines

has ethylene with 2 nitrogens (1 on either side) as well as 2 aryl rings (1 w/ a carbon spacer)

Identify the pharmacophore

Histamine

Identify the pharmacophore

ethanolamine ether pharmacophore of antihistamines

Identify the pharmacophore

Histamine

imidazole ring with a ethylamine

Identify the structure

Piperazine antihistamine

Identify the pharmacophore

Piperazine

Identify the pharmacophore

Tricyclic antihistamine

Identify the pharmacophore

Variation in structure with piperidine/piperazinepharmacophore (CYP2D6/CYP3A4 metabolism, except fexofenadine)

What is the structural difference between between sedation and non-sedating antihistamine

pyridine of the antimycobacterials (isoniazid here)

pharmacophore?

drug class?

pyrazine pharmacophore (pyrazinamide here) -- mimics nicotinamide

pharmacophore?

what molecule does this agent mimic?

isoniazid

ethionamide

which anti-TB agents are anti-mycolates that inhibit mycolic acid synthesis of the cell wall?

ethambutol

Identify the structure

Carbons 1, 8, 21, and 23 oxygens are key

• 1, 8 chelate Zn+2

• 21, 23 form hydrogen bonds in DDRP

What carbons are the key moieties for rifamycin antibiotics?

Rifamycin

Identify the drug class?

Macrolide Antibiotics

Identify the drug class?

Amantadine

Identify the drug

Rimantadine

Identify the drug

many lack a 3' OH group

what makes NRTIs chain terminators? do they all exhibit this structural component?

NRTIs

Identify the class

1=ethylenediamine

2=ethanolamine ether

3=alkylamine

4=ethanolamine ether

5=tricyclic antihistamine

6=ethylenediamine

Identify the drugs below as either ethylenediamine, ethanolamine ether, alkylamine, or tricyclic antihistamine agents.

Piperidine

Identify the pharmacophore

Pyridine

Identify the pharmacophore

Piperidine and piperazine

__________ and _________ are the backbones of antihistamine

Pyridine

Shown below are two small molecule drugs used in the treatment of M. tuberculosis infection. Identify the backbone of these agents. Piperazine, Piperidine or pyridine?

Naphthalene

OH groups are important for funtion

Shown below are two rifamycin antibiotics used in the treatment of M. tuberculosis infection. Highlight the naphthalene backbone in these. Which “functional” groups in these drugs are particularly important?

These are transition state inhibitors

They mimic neuraminic acid (sialic acid)

The ring is the sugar moiety that mimics sialic acid

Shown below are two neuraminidase inhibitors. What type of inhibitors are these, and what sugar do they mimic? Highlight that sugar moiety in their structure

Neuraminic acid (9 carbon backbone)

Identify the structure

Purine

Does this structure represent purines or pyrimidines?

Pyrimidine

Does this structure represent purines or pyrimidines?

Purine

Does this structure represent purines or pyrimidines?

Pyrimidine

Does this structure represent purines or pyrimidines?

Pyrimidine

Does this structure represent purines or pyrimidines?

1= nucleoside

2= nucleotide

3= nucleoside

4= nucleoside

5= nucleotide

6= nucleotide

Of the six molecules shown below, which represent nucleosides and which nucleotides?

Nucleotides have a phosphate group

What is the difference between nucleoside and nucleotide structures?

1= purine

2= purine

3= pyrimidine

4= pyrimidine

5= purine

6= pyrimidine

In the above molecules, which contain purine as opposed to pyrimidine bases?

Shown below are a number of drugs employed in the treatment of hepatitis. Which of these agents are acyclic agents, and which are conventional nucleoside agents? (note: one “drug” is a normal component in DNA synthesis, which you should easily identify). ANSWER SHOWN IN PICTURE

1 = acyclic agent

2 = conventional nucleoside agent

Shown below are a number of drugs employed in the treatment of hepatitis. Which of these agents are acyclic agents, and which are conventional nucleoside agents? (note: one “drug” is a normal component in DNA synthesis, which you should easily identify). ANSWER SHOWN IN PICTURE

1 = acyclic agent

2 = conventional nucleoside agent

Normal DNA constituent

Identify structure

NRTIs lacks a 3' hydroxyl- moiety needed for chain propagation

What is the difference between NRTIs and a normal DNA constituent?

1=DNA

2=RNA

Bottom right OH makes it RNA

Shown below are two ribose sugars. Which do you predict is found in DNA and RNA. Why?

HIV protease inhibitor

- sp3-hybridized hydroxyl-carbon mimics transition state that occurs in hydrolysis of a peptide bond by HIV protease

Identify the class

NNRTI

Identify the class

Fusion (Entry) Inhibitor

Identify the class

HIV integrase inhibitors

Identify the class

Hydroxyl- moiety

Shown below are 3 HIV protease inhibitors, whose function is to mimic the transition state of the catalytic site of the enzyme. What is the key region (or functional group) that enables this mimicking of the transition state?

Naphthalene; Rifamycin antibiotics

Identify the structure. What class is this seen in?

A and B

In this grouping of first and second generation antihistamines, which contain a piperazine backbone? (select all that apply)

c. 1=ethylenediamine; 2=ethanolamine ether; 3=alkylamine

Which is the one true association of antihistamine with pharmacophore?

a. 1=ethylenediamine; 2=phenothiazine; 3=ethylenediamine

b. 1=ethanolamine ether; 2=ethylenediamine; 3=alkylamine

c. 1=ethylenediamine; 2=ethanolamine ether; 3=alkylamine

d. 1=alkylamine; 2=ethanolamine ether; 3=phenothiazine

e. 1=ethanolamine ether; 2=ethylenediamine; 3=phenothiazine

A and C

Which of the following contain the naphthalene backbone indicative of rifamycin antibiotics?

False

In ritonavir, the thiazole rings bind critical aspartic acid residues that results in inhibition of the HIV protease? True or False

d. It contains a pyrimidine base.

Which is the one false statement tenofovir disoproxil?

a. It is a prodrug.

b. It is an acyclic agent.

c. It contains a purine base.

d. It contains a pyrimidine base.

e. It is a non-nucleoside agent.

C

Which is the alkylamine antihistamine?

d. it contains a piperazine backbone

Which is the one true statement concerning cetirizine?

a. it is a piperidine antihistamine

b. it contains a pyridine ring

c. it contains a lactone

d. it contains a piperazine backbone

d. it contains a piperazine ring

Which is the one false statement concerning lasmiditan, an investigational agent for migraine?

a. it contains a pyridine ring

b. it contains a piperidine ring

c. it contains a benzamide backbone

d. it contains a piperazine ring

C and F

Which are false structure pharmacophore associations?

c. it contains a pyridine ring

Which is the one false statement concerning levocabastine?

a. it contains a cyano- group

b. it contains a cyclohexane ring

c. it contains a pyridine ring

d. it contains a piperidine ring

c. antihistamine

The one non- "antimycolate" falls into which drug class based on pharmacophore?

a. antibiotic

b. antiparasitic

c. antihistamine

d. antimycobacterial

b. its 10 carbon backbone mimics neuraminic acid

Which is the one false statement concerning zanamivir?

a. it is a nueraminidase inhibitor

b. its 10 carbon backbone mimics neuraminic acid

c. it is a viral early replication inhibitor

d. it contains a guanidine moiety

a. it contains a phtalic acid pharmacophore

Which is the one false statement concerning rifapentine?

a. it contains a phtalic acid pharmacophore

b. it contains a piperazine structure

c. it is an antimycobacterial

d. it inhibits DNA dependent RNA polymerase

d. it is a nucleoside antiviral

Which is the one false statement about tonofovir disoproxil?

a. it is a prodrug

b. it is an acyclic antiviral

c. it contains a purine base

d. it is a nucleoside antiviral

c. it is an NRTI

Which is the one true statement concerning zalcitabine?

a. it contains a purine base

b. it lacks the 5'-hydroxyl moiety

c. it is an NRTI

d. it contains the expected 3'-hydroxy moiety

d. it is predominantly found in DNA

Which is the one false statement about uridine?

a. it contains a pyrimidine base

b. it possesses 2', 3', 5'- hydroxyl - moieties

c. it is predominantly found in RNA

d. it is predominantly found in DNA

D

Which of these HIV protease inhibitors would you predict to have reduced activity?

d. three are nucleotides

Which is the one true statement concerning these adenosine compounds?

a. four are nucleotides

b. all contain pyrimidine bases

c. two are nucleotides

d. three are nucleotides

b. RNA

Referring to the previous question, which nucleic acid would contain these analogs?

a. DNA

b. RNA

c. antihistamine

This pharmacophore schematic indicates which class of drug?

a. antimycobacterial

b. antiparasitic

c. antihistamine

d. antibiotic

d. it contains a 2'-hydroxyl-group

Identify the one false statement concerning stavudine?

a. there is an alkene at the 2', 3' carbon

b. it contains a 5'-hydroxyl group

c. its base is thymine

d. it contains a 2'-hydroxyl-group

B and D

Which are NOT rifamycin drugs based upon pharmacophore?

B and E

Which are ethanolamine ether antihistamines?

c. acetylcholine

The backbone of which neurotransmitter is in the ethanolamine ether antihistamine?

a. epinephrine

b. serotonin

c. acetylcholine

d. norepinephrine

False

The isopropyl- groups of ritonavir bind an active site aspartate of HIV protease. True or False?

3

Which is the correct number of purines in the figure?

D

Which one drug can NOT be an HIV protease inhibitor?

c. it shares the 9 carbon backbone of sialic acid

Which is the one true statement about zanamavir, an early replication inhibitor?

a. it shares the 8 carbon backbone of sialic acid

b. it shares the 10 carbon backbone of sialic acid

c. it shares the 9 carbon backbone of sialic acid

d. it shares the guanidine backbone of sialic acid

c. the 3' carbon has the azide moiety

Identify the one true statement about zidovudine?

a. the 1' carbon has the azide moiety

b. the 2' carbon has the azide moiety

c. the 3' carbon has the azide moiety

d. the 5' carbon has the azide moiety