Download Bioisosteres

Medicinal Chemistry 1
lecture 5
Lana Hammad
Last time we talked about isosteric replacement, which is changing a functional group in a structure to
modify certain properties
How do I know that a certain functional group is isosteric with another?
Both molecules (that are being compared) should have almost identical size\volume(3D shape), and
electronic properties.
Why do we make isosteric replacement?
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To make sure that the drug reaches the target without being degraded ( modifying
pharmacokinetics of the drug)
*Pharmacokinetics describes how the body affects a specific drug after administration through
the mechanisms of absorption and distribution, as well as the chemical changes of the substance
in the body, and the effects and routes of excretion of the metabolites of the drug*
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To improve the solubility
To increase selectivity (less side effects)
To gain potency and make it more active  more active means we need a lower dose, which
means less toxicity
To decrease side effects and toxicity
To increase or decrease metabolism  balance (biodegradable + stable)  biodegradable so
that we get an effect, but stable and resistant to metabolism at the same time so that it reaches
the target #BALANCE
Ease of administration (oral instead of IV)
Chemical stability (shelf life, transport,pH –stomach acidity)
Cost of production
Intellectual properties
As medicinal chemists our role is to start with a lead molecule that might have low activity and many
side effects, and its kinetics might not be as good as needed, this lead molecule is chemically modified
to form a drug suitable for using.
There are several methods that we could use to modify the properties of the molecule (to increase
properties needed, and decrease unwanted properties, and control kinetics, specificity, site of action ,
side effects)
Isosteric replacement is used without changing the pharmacological activity of the molecule (except
increasing the pharmacological activity and decreasing side effects)
How do we decide which molecule should be isosterically replaced?
Depending on the “pharmacophore”
What is a pharmcophore? Functional groups responsible for biological activity and their 3D shape
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Medicinal Chemistry 1
lecture 5
Lana Hammad
*its not the functional group itself that gives us a biological activity, its actually the position where this
group is*
When we consider the type of interactions the molecule does, and the 3D position of these interactions
(without considering the exact chemical structure)  pharmacophore
What is the importance of pharmacophores?
it makes the concept of isosteric replacement valid  by changing functional groups without changing
the resulting interaction
(example: replacing a functional group that is capable of forming a Hydrogen bond, with another
functional group that is chemically different but can also form a Hydrogen bond)
We must know the features of the structure which enable it to have a certain biological action, so that
when we change functional groups we keep the same biological activity
# it is all by trial & error method #
isosteres:
molecules having the same size, shape and electron properties
Not necessarily all properties are the same : - same size  isosteres
- same shape  isosteres
- same electron properties  isosteres
If we change a certain functional group and the biological activity doesn’t change  we call them
bioisosteres (bioisosteres are receptor\target specific but the most important thing is giving the same
activity even if they don’t bind to the same receptor)
To increase oral absorptivity for an example  we can should replace (remove) a charged group,
because the more charged  the more hydrophilic  less absorption
(amino glycosides-charged- : injected because if taken orally they won’t be absorbed
#note:
the part “ster” (“stereo”)  is used when we talk about atoms or functional groups
the part “mer” (iso”mer”)  is used when we talk about a molecule
#note : replacement in medicine, and creating new drugs are always subjected to “trial and error”
but it is always more probable that a patient will be cured when we use a certain drug
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Medicinal Chemistry 1
lecture 5
Lana Hammad
Bioisosteres:
1- classical  bioisosteres : same biological activity & the same chemical structure , they agree with
the definition of chemical isosteres
Example 1:
fluoride replacement with hydrogen  the size of fluoride is very small (smallest halogen) therefore it is
comparable with hydrogen  many drugs substitute with fluoride to affect the biological properties.
-- both hydrogen and fluoride have almost identical sizes, but differ in the electronic properties;
F is electronegative and can form H-bond (F is the most electronegative atom in the periodic table)
properties are slightly changed but the compatibility of the drug with the binding pocket doesn’t
change, which means it can bind to the same receptor, but it will form additional hydrogen bonds
(while hydrogen might not form an H-bond if it was on a carbon)
Example 2:
NH2 with OH (comparable size not the exact same size)
 both are hydrogen donors & acceptors (both form hydrogen bonds)
- oxygen is more electronegative  forms stronger H-bond
- the amine is ionizable (hydroxyl is not)
so if I put NH2 instead of OH, the size & hydrogen bonding will be the same, but it will be charged
Example 3:
Thiol with alcohol (comparable
- both form hydrogen bonds, but O is more electronegative, because sulphur is a big molecule and it is
more lipophilic (and is preferably used if we want the drug to reach the brain)
Example 4:
“bivalent groups”
C=C with C=N (alkene with emine )  N is a hydrogen bond acceptor (when it is in a double bond) with
is the difference between N & C
Example 5:
“ring equivalent replacement”  replacing a ring with another ring
(pyridine with benzene)
(six-memberd ring with five-membered ring *without changing the biological activity*)
cyclopentadiene with furan  O forms H-bond, which means it increases its polarity
or with pyrrole  polarity increases & solubility (due to the presence of N)
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Medicinal Chemistry 1
lecture 5
Lana Hammad
more examples:
C=O with C=S  O is more polar, C=S used for drugs that must reach the brain
CH2 with NH2  N increases polarity (H-bond & ionization “acid base properties”)
2- non-classical  size , or shape, or electronic properties might differ but still they have similar
biological activities
Both have estrogenic effect but they are not structurally the same (the second one doesn’t have an
estrogenic ring)
“nonclassical “  because we replaced a cyclic structure with an acyclic one
or using exchangeable groups
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Medicinal Chemistry 1
lecture 5
Lana Hammad
#‫حفظ‬:
Notice that the shape,
size & electronic
properties differ,
but biological activity
are usually the same
COOH (carboxyl group) 
affects acidity = ionization
 so replacing it is usually
effective in modifying the
drug properties
especially when ionization
is considered a problem

carboxylic acid with
tetrazole
(heteroaromatic cycle –
ionizable – N- & H+ )

Phenol with endole
Nonclassical isosteric replacement can be used when we are trying to restrict a structure and make it
more rigid
#Q: replacing cyanide group with a halogen is a classical or a nonclassical replacement?
 nonclassical because they differ in size
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Medicinal Chemistry 1
lecture 5
Lana Hammad
#Q: what types of interactions does carboxylic acid form?
- ionic (ionization  affects absorption)
- H-bond
#Q :how are nitro & NH2 different?
- nitro is not chargeable
- amine is positively charged
## why do we replace H with F?
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Improve metabolic stability (because our body is cannot metabolise halogens, so when we use F;
we reduce metabolism and increase stability )
Modify acidity and basicity (F is the most
electronegative atom)
Conformational bias via intramolecular interactions (because F is highly electronegative and very
small, it can form H-bond and intramolecular interactions  conformational bias , which means
that the structure will prefer a certain conformation even if it has higher energy )
## Carboxyl isosteres:
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Enhance potency
Reduce polarity
Increase lipophilicity (improve membrane
permeability)  to cross BBB  replace it with a functional group with similar biological activity
but not ionizable
Enhance pharmacokinetic properties (absorption, distribution)  when it is ionizable it is
directed to the urinary tract, so if I want it to reach the urinary tract, this property is considered
an advantage, but I few want the drug to reach the brain, we replace it with a nonionizable
group.
Reduce the potential for toxicity
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Medicinal Chemistry 1
lecture 5
Lana Hammad
IC50  the concentration needed to inhibit 50% of the enzyme
the lower the value of IC50 the better it means we need less of the compound to inhibit a certain
enzyme (better inhibition at lower concentration)
Captoprill is an ACE-inhibitor : replacement of carboxyl group with SH (although they have different size
& properties)  100-fold improvement
*biological activity was significantly improved*
When the R group was a carboxyl group IC50 was 275, when replaced with a sulphonamide group there
was an improvement (lower IC50) m and more improvement when replaced with a lactone, and the best
substituent is tetrazole
# replacing amides with esters:
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Modulate polarity
Improve bioavailability
Stability of peptide‐based molecules (amides resemble peptide bond, and are used in peptidic
drugs such as hormones
Ester isosteres used mainly to address metabolism issues since esters can be rapidly cleaved
in vivo.
esters are highly degradable because our bodies have esterases (so replacing the ester group
will increase the molecule’s stability against metabolism)
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Medicinal Chemistry 1
lecture 5
# Phenyl ring isosteres:
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Heteroaromatic ring or saturated ring
To improve efficacy
Improve lipophilicity
Modify specificity.
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Lana Hammad