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Medicinal & Biological Chemistry > Medicinal Chemistry > Flashcards

Medicinal Chemistry Flashcards

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1
Q

What are the two types of bacteria?

A

gram positive and gram negative

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2
Q

How can we use the gram test to see the 2 diff types of bacteria?

A

the crystal violet dye sticks to the bacteria outer membrane to give colour.
gram negative bacteria are left red, gram positive bacteria are left purple

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3
Q

What is the mode of action of Sulphonamides?
(Prontosil)

A

e.g Prontosil is an example of a prodrug, which is activated by hydride reduction.
Sulfa drugs (reversibly) competitively inhibit dihydropterate synthetase which is involved in the synthesis of Folic acid.
if folic acid cant be produced, the bacteria will die as its essential for DNA synthesis
Sulfanilamide is a reversible, competitive inhibitors

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4
Q

What is DHFR? what makes it important?

A

dihydrofolate reductase
bacterial DHFR has a very different structure to human DHFR so can be used as an anti-cancer target

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5
Q

What is trimethoprim?

A

competitive inhibitor of DHFR so can be used as an anti-bacterial agent

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6
Q

What are anti-metabolite drugs?

A

block enzymes involved in metabolic pathways

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7
Q

what are bacteriostatic drugs?

A

compounds that inhibit growth and replication but do not directly kill

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8
Q

What is a prodrug?

A

inactive compounds that break down into active drugs by metabolism

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9
Q

What is synergistic drugs?

A

mixtures of multiple drugs in the same drug which causes a greater response

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10
Q

What is QSAR

A

quantitative structure-activity relationships.
a method of optimising drug activity

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11
Q

What are Beta Lactams? what do they do?

A

family of compounds containing 4 membered cyclic amide.
they prevent cross linking in peptidoglycan walls which weakens them

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12
Q

What cellular group does B-Lactams mimic?

A

the D-Ala D-Ala group
which is important for forming cross links in peptidoglycan which gives structure of the cell wall.

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13
Q

Give some essential and non-essential examples of SAR of penicillin

A

Cis-stereochemistry of hydrogens on ring is essential
B-Lactam and 5/6 membered fused ring is essential
Free acid also essential
R group can be modified, so can the heteroatom

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14
Q

Give some properties of penicillin G

A

active against some gram positive cocci and many gram negative cocci
Non toxic to humas even at high doses,
not orally effective as acid sensitive
can cause allergies

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15
Q

What is the mechanism of Beta lactams?

A

Beta-Lactam prevents water from entering, stoping the hydrolysis of carbonyl and irreversibly inhibiting the enzyme transpeptidase

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16
Q

What are penicillin’s?

A

suicide substrates (mechanism based inhibitors) irreversibly modifies enzyme by formation of permanent covalent bonds

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17
Q

Why is penicillin acid unstable?

A

carbonyl of lactam ring has more ketone than amide character. makes the carbonyl more electrophilic so easier to hydrolyse

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18
Q

what are the differences between Gram+ve and Gram-ve membranes/cell walls?

A

Gram positive:
thick peptidoglycan at top highly cross linked, made up of peptides and sugars, also has cytoplasmic membrane with transpeptidase within
Gram Negative:
made up of 2 membranes (outer and cytoplasmic) with cell wall between them which is less cross linked. outer membrane has sugars that can trigger allergies

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19
Q

explain Beta-Lactam resistances considering the different bacteria membranes

A

Gram negative bacteria are harder to kill due to:
outer membrane composed of negative phospholipids which repel negative penicillins
beta-lactamases present in periplasmic space which cleaves B lactams

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20
Q

What is Methicillin?

A

1st B-Lactamase resistant penicillins with a large bulky R group to prevent binding

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21
Q

What is MRSA?

A

methicillin resistant bacteria
has to be treated with non-B-Lactam anti biotics

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22
Q

What are sentry drugs? give examples

A

a drug administered with the main drug to protect the main drug from degradation
e.g. sulbactam and clavulanic acid

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23
Q

What is MIC?

A

minimum inhibitory concentration
the lowest concentration that prevents growth of bacteria.
the lower the MIC the better the antibiotic

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24
Q

Why are amoxicillin and clavulanic acid said to be synergistic?

A

their combined activity is greater than the sum of their individual activities

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25
How can semi-synthetic penicillins be made? give examples of them
treatment of penicillin G with penicillin acylase and high pH leads to formation of 6-aminopenicillanic acid. this can then be treated with acid and penicillin acylase at low pH to produce new semi-synthetic penicillins, like amoxicillin and ampicillin
26
What are Cephalosporins?
group of antibiotics with a B-lactam ring they are more stable to B-Lactamases, causes decreased allergic reactions due to slower release of bacterial membrane proteins, active against gram positive and negative, is not toxic
27
What are ionophores?
lipid soluble molecules (drugs)
28
What is Gramacidin A?
modified peptide that forms helices that stack to create pore through bacterial cell membranes is non-selective so can be toxic
29
What are polyene antibiotics?
large and polar molecules that form pores causing leakage of small molecules from cytoplasm often used as anti-fungal agents
30
What are macrolide antibiotics?
ionophores, transport ions across biological membranes wraps around the ion which carries the drug through membrane
31
What is Vancomycin?
antibiotic that prevents D-Ala D-Ala binding to transpeptidase so less peptidoglycan cross linking so cell rupture
32
What are DNA intercalating agents?
describes the bonding between base pairs, flat fused polycyclic compounds that bind between adjacent DNA base pairs interacting with the bases through pi-pi stacking acts as non-covalent glue to stop replication of DNA
33
What are DNA minor groove binders?
crescent shaped molecules that non-covalently bond with DNA to interfere with transcription
34
what are DNA alkylating agents?
chemically modify the DNA they have electrophilic centres so are attacked by nucleophiles
35
What are the effects of DNA crosslinking?
interstrand cross linking prevents replication and transcription intrastrand crosslinking blocks enzyme binding
36
What are the ways of depurination? why do we do i?
ring damages so no purine base causes cell death can be done by DNA cleaving agents like esperamicin and enediynes
37
What is Bergman cyclisation?
when 2 nearby alkynes spontaneously cyclise forming a benzenoid diradical that intercalates between base pairs
38
What are anti-cancer drugs that target DNA biosynthesis? give examples
involves inhibition of formation of T nucleotide from U 5-Fluorouracil inhibits thymidylate synthase by binding to enzyme and forming new covalent bond, irreversible inhibition using F atom methotrexate mimics structure of dihydrofolate reductase so acts as a competitive inhibitor of DHFR
39
what is 5-Fluorouracil?
prodrug, antimetabolite and a suicide substrate mimics U nucleotide structure but with an F, inhibits thymidylate synthase irreversibly from Michael addition of F to the enzyme
40
What is methotrexate?
mimic strcture of DHF so acts as competitive reversible inhibitor of DHFR, has much tighter binding so a high affinity for DHFR
41
What are the two types of cytoskeletal targeting anti-cancer drugs? what do they do?
stabilizing binders and destabilising binders stabilising ones stabilise tubulin subunits to stop formation of microtubules destabilizing ones prompts disassembly of microtubules
42
What is taxol?
microtubule poison (destabilising binders)
43
What are the methods of administration?
orally, nasally, intravenous,
44
What is P?
Partition coefficient compared as logP values hydrophobic compounds have a high logP value (2-5) hydrophilic compounds have a low logP (<2.5) for passive transport across membranes logP 2.5 required
45
what are Lipinski's rules?
for a compound to be orally available and show good absorption it must: -have mr of 500 or less -have clogP of no more than 5 -have no more than 5 hydrogen bond donors (-OH/-NH) -Have no more than 10 hydrogen bond acceptors (O/N) -Have no more than 5 fused rings
46
What are phase 1 reactions in drug metabolism? give examples
introducing/ unmasking of polar groups like oxidation of alkenes to epoxides and then alcohols or hydrolysis of esters to acids and alcohols
47
What are phase 2 reactions of drug metabolism? give examples
takes previous modifications through conjugation to make compound more soluble and ready for excretion sulfatase adds S to alcohols giving stability glutathione transferase adds S-Ar to cystine for stabilisation through conjugation
48
What is the rule of 3? whats it used for?
the rule of three to actively pass the BBB -mr of no more than 30 -clogP value of less than 3 -no more than 3 hydrogen bond donors (OH/NH) -no more than 6 hydrogen bond acceptors (N/O)
49
What is the amino acid shuttle protein system?
way of active transport used to pass through the blood brain barrier used to get dopamine to the brain LevoDOPA binds to alpha-amino acid in the phospholipid membrane and carries it through to brain, can then be turned to dopamine by DOPA decarboxylase
50
What are bipartate drugs?
same drug that can degrade into 2 parts, 1 acting as the main drug and the other part acting as a sentry drug to slow down degradation of main drug e.g. CarbiDOPA bound to levoDOPA
51
describe the structure of an IgG antibody
has a heavy chains, light chains and an antigen binding sites heavy chains bound together with disulphide bond
52
what are antibody drug conjugates? how do they work?
antibodies with linked drug molecules such as Nitrogen mustard, methotrexate or ricin which gives these drugs selectivity. bind to antigen on cell surface and theyre up took by cells in endosomes and broken down in lysosomes leaving release of active drug into cytoplasm.
53
what are antibody enzyme conjugates?
way of antibody based tumour targeting bind to overexpressed proteins/saccharides on tumour cell surface. they have bound enzymes via linkers. typical enzymes are engineered enzymes
54
What are ADEPT prodrugs? Mode of action?
antibody directed enzyme prodrug therapy. antibody enzyme conjugate injected to immobilise on tumour antigen, after 48 hours the prodrug is injected and the enzymes on the antibody activate the drug, letting the drug enter the cell and kill the cell
55
What is a virus? What diseases do they cause? How are they transmitted?
intracellular parasites that require a host cell to replicate. cause of influenza, covid, rabies, herpes, AIDS transmitted via air borne, parasites, physical contact and contaminated food/water
56
describe the basic structure of a virus
has a membranous layer, nucleotides carrying genome, capsids, viral proteins and membrane proteins
57
how do vaccines work?
virus/antigen put in body to trigger an immune response so if the body was to be exposed to antigen naturally, can be fought off easily
58
briefly describe the replication cycle of a virus
firstly the virus adsorbs to receptor on cell surface and membrane fusion occurs leading to penetration of capsid the disassembly of the capsid releases genetic information into nucleus of cell and starts replication on new viral DNA and so formation of new viral proteins, budding occurs releasing new virions
59
how is herpes treated?
to treat herpes we need to inhibit the DNA polymerase so no new viral DNA is made, this is done by using prodrug called acyclovir which has a similar structure to GTP which is activated via phosphorylation.
60
how is covid 19 treated?
dexamethasone used to treat as an anti-inflammatory agent looking to inhibit uncoating process of capsid and inhibit translation of viral proteins via inhibiting RNA polymerase by chain termination
61
what is prophylaxis?
medical care aimed at preventing diseases or stopping them from getting worse
62
what is budding of viruses?
when new virion are made from an infected cell and excreted to carry on infection
63
briefly describe structure of HIV virion
has a phospholipid membrane with gp120 and gp41 that attacks CD4 receptors on host cell, has p18 and p24 capsid layers, contains 2 RNA copies, integrase, reverse transcriptase and HIV protease virial proteins
64
What does HIV integrase do?
inserts viral DNA into the nucleus of the host cell
65
Where does HIV mostly attack?
CD4 helper cells (T helper cells) which weakens the immune response so more severe effects to basic infections
66
What are some key HIV drug targets?
reverse transcriptase as its unique to HIV HIV protease, and at HIV fusion
67
What HIV drugs target reverse transcriptase
NRTIs (nucleoside reverse transcriptase inhibitors) like prodrug azidothymidine (AZT) which acts as a chain termination inhibitor, not good selectivity and NNRTIs (non-nucleoside reverse transcriptase inhibitors) like Nevirapine which blocks ssRNA binding through direct interaction with enzyme, large and greasy compounds bind to hydrophobic DNA groups
68
What does HIV reverse transcriptase do?
a viral HIV enzyme that converts the stored HIV-RNA from capsid into HIV-DNA ready for DNA replication
69
What is RNaseH?
an enzyme used to generate complimentary DNA from viral RNA basically helps reverse transcription
70
What is HIV protease? how does it work?
two polypeptide chains (homodimer) with C2v symmetry which cleaves proteins into smaller, active protein units. uses proteolytic cleavage by using 2x aspartic acid (1 basic, 1 acidic) which cleaved peptide bonds
71
What isosteres? what are bio-isosteres?
atoms, ions and molecules that had identical outer shells of electrons Bio-Isosteres are substituents/groups with similar physical/chemical properties that impact similar biological properties to a chemical compound, but do not obey the electron rules of classical isosteres
72
What are the 1st generation of HIV treatments?
HIV protease inhibitors like Saquinavir and Nelfinavir and Ritonavir
73
what are 2nd gen inhibitors of HIV treatments?
focus on and target integrase strand transfer intermediates which prevents virus from integrating viral DNA into human DNA. they have fewer side effects and higher resistance examples include Dolutegravir and Bictegravir
74
why are symmetrical inhibitors useful?
as HIV protease has C2v symmetry at its active site, its useful for the inhibitors to also have the same symmetry for optimal binding and high specificity
75
how is combination therapy used to overcome resistance in HIV treatment?
HIV will undergo mutations very easily as reverse transcriptase has limited proof reading treating with a single drug leads to resistance over time so multiple drugs used at once: 2NTRIs+1PI or 1NNRTI+2NRTI
76
What is IC50
half-maximal inhibitory concentration which is a measure of potency Lower IC50 means more potent inhibitor
77
What is TI?
therapeutic index TI=LD50/ED50 the higher the ratio, the more tolerance to the drug

Medicinal & Biological Chemistry (2 decks)

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