DNA Inhibitors MedChem (Exam 1 Cut Off) Flashcards
1
Q
Fluoroquinolones
A
- Most commonly see ciprofloxacin
- Newer quinolones change basic groups and quinolone N-substitutions
2
Q
Patient Counseling + Quinolones
A
- Chelate complexes with polyvalent cations
- Chelate is less soluble, bioavailability, potent, and has inhibited uptake
- Old difluoros would degrade in presence of UV leading to immunotoxicity
- Normal quinolones can still cause free radical formation from UV light exposure
3
Q
Folate Synthesis
A
- Target in bacterial pathogens since humans don’t synthesize their own folate
- Through dihydropteroate synthetase (DHPS) and dihydrofolate synthetase (DHFS), creates dihydrofolate that is used for biosynthesis
- Dihydropteroate and glutamic acid create the dihydrofolate through an amide bond
4
Q
Folate Use
A
- Co-enzyme involved in thymidine purine synthesis
- Also involved in some amino acid formation
- Involved in pathways where 1-carbon fragments are added (methyls)
5
Q
Sulfanilamide Actions
A
- Competitive inhibition of DHPS where its product blocks PABA from the active site
- Become a fake dihydropteroate that inhibits DHFS where it can’t accept glutamic acid
6
Q
Sulfanilamide Host
A
- Host to many compounds including sulfonamides
- ALL active compounds are 1,4 (para) substituted on the phenyl ring
- Adding more substituents decreases activity
- Monosubstitution of the amide give MORE active compounds and improve PK, disubstitution decreases activity significantly
7
Q
Amide Protons
A
- Electron withdrawing nature of aromatic SO2 group makes amide protons weakly acidic
- Acidic due to resonance stabilization
- PABA pKa ~ 6.5 but sulfanilamide ~10.4
- Monosubstitutions at N alter pKa of remaining proton
- Ideal pKa of amide is equivalent to that of PABA which also reduces many of its side effects (crystallizing in glomerular filtrate causing kidney damage)
8
Q
Trimethoprim
A
- Analog of dihydrofolate
- Competitively inhibits dihydrofolate reductase
- Act on different point of same pathway as sulfonamides, therefore synergistic
9
Q
Trimethoprim + Sulfonamides
A
- Synergistic activity
- Also helps prevent resistance
- Less likely for a pathogen to get both required mutations at the same time
10
Q
Flagyl
A
- Metronidazole
- Nitroaromatic
- Nitro groups are not always polar
- Targets anaerobes (obligate or facultative)
- Redox-cycling agent to produce superoxide in aerobic environments
- In absence of oxygen, the nitro radical anion sticks around for further bioreduction into a C-nitroso (extremely reactive, active form)
- C-nitroso can have further bioreduction (debatably important)
11
Q
C-Nitroso
A
- Reacts with thiols like glutathione
- Reacts with cysteine residues on proteins
- Also some nucleobases but NOT just a DNA target
12
Q
Metronidazole Resistance
A
- Several activating systems which would ALL require mutations
- Nonspecific reduction, just grabs electrons from ETC (would need no ETC to be resistant )
13
Q
Metronidazole + Ethanol
A
- Leads to accumulation of acetaldehyde from inhibiting alcohol dehydrogenase and other enzymes
- Leads to disulfiram like side effects including nausea, vomiting, headache, flushing, and cramps
14
Q
Nitroaromatic Activation
A
- Not always nonspecific
- Sometimes its one specific activating enzyme system
- EX: Delamanid, reduced in a 2e- manner and there’s never a midpoint product (works with or without oxygen)
15
Q
Resistance pops up when….
A
-Enzymes involved are NON-essential
