CHEM 1: Anthelmintics Flashcards
What are the structure-activity relationships (SARS) that retain anthelmintic activity?
C5 + C6 modifications
Heterocyclic modifications
C2 modifications
Show how Imidazole undergoes tautomerism
Which tautomers are/not identical?
Show how benzimidazoles undergo tautomerism
Heterocyclic tautomers are usually difficult to detect spectroscopically or otherwise.
Why is that?
Tautomers end up having nearly identical energies
Which benzimidazole cannot undergo tautomerism?
N-substituted benzimidazoles
Benzimidazoles = amphoteric (both an acid + base)
At what pHs does the neutral, positively-charged + negatively-charged form predominate?
Neutral = 7.4
Positive = < 5.8
Negative = > 12.3
Why does pKa matter
For drugs to be bioavailable = water-soluble @ level comensurate with their target affinity
Drugs whose molecular targets are within cells + drugs administered enterally, need to be membrane-permeable
Membrane permeability + water solubility depend on the charge status + polarity of a drug
pKa = deciding factor if a drug is bioavailable or not
How do we make a drug water-soluble?
Polar/charged
For a drug to be membrane-permeable?
Uncharged + apolar
How to measure solubility?
Turbidity
Excess solid
How can permeability be measured?
Involves monolayers of a cell line called Caco-2
Cells cultured onto semi-permeable plastic supports
Buffer on opposite side of support sampled for drug
Can we predict solubility + permeability?
Polar surface area (PSA) - measured in square angstroms
LogP + LogDpH
(However solubility = difficult to predict)
What should logP, logD7.4 + PSA be for our drug molecules?
logP < 5
logD7.4 < 4
However, compounds with logP or logD7.4 > 2 often have poor aqueous solubility.
PSA < 120 Å2
Nitrogen-containing heterocyclic compounds found in natural products + drugs.
Why do they feature as scaffolds + substructures in drugs?
- they possess balanced charge, lipophilicity, and solubility properties (pKa, logP, logD),
- they have chemical features for both hydrophilic and lipophilic interactions with drug targets,
- they are comparatively rigid, reducing the entropic penalty upon drug–target engagement, and
- they generally have favourable metabolic properties (can be processed and eliminated at a suitable rate without undue accumulation leading to toxicity).
What are microtubules?
Components of the cytoskeleton that determine position of cellular components + involved in intracellular transport
Role in cells esp. cell division
- Mitotic spindle is formed of microtubules*
- Sister chromatids are separated using microtubules*
- Microtubules are both structural and functional.*
What are microtubules made from?
Tubulin
Dimer made up of 2 kDa subunits, α-tubulin and β-tubulin, bound by noncovalent bonds
Each subunit has a GTP-binding site. The α site is buried and never hydrolysed, but the β site is active during polymerisation
Microtubules reach a dynamic equilibrium with tubulin.
How?
Presence of GTP-bound tubulin encourages polymerisation
Hydrolysis of the GTP encourages depolymerisation
Addition of inhibitors causes ‘capping’ and halts polymerisation, allowing only depolymerisation with the loss of microtubule structure.
Anthelmintic benzimidazoles promote microtubule depolymerisation.
How?
Anthelmintic benzimidazoles promote microtubule depolymerisation by binding to a single high-affinity site on the β-tubulin subunit near the monomer-monomer interface in the unpolymerised α/β-tubulin dimer
What compounds interfere with tubulin polymerisation?
Vinca Alkaloids, Taxanes + Colchicine
Toxic to all proliferating eukaryotic cells
e.g. Colchicine side-effects include gastrointestinal upset, neutropoenia, bone marrow damage, anaemia, and hair loss.
All of these side-effects result from hyper-inhibition of mitosis
What affects selectivity of benzimidazoles?
Different pharmacokinetics
