TITLE:

Chemistry of Antibiotics
Active in S-Form

SUBMITTED BY:
Bakhita Maryam

ROLL NO.:
0254-BH-CHEM-17

SUBMITTED TO:
Dr. Gulzar
Contents
CHEMISTRY OF ANTIBIOTICS ACTIVE IN S-FORM.........................................................................................2
Chirality and Drugs:................................................................................................................................2
S-Omeprazole:.........................................................................................................................................4
S-Citalopram............................................................................................................................................6
S-albuterol:..............................................................................................................................................6
Verapamil:...............................................................................................................................................7
Secobarbital:............................................................................................................................................8

CHEMISTRY OF ANTIBIOTICS ACTIVE IN S-FORM

Chirality and Drugs:

Drugs that are chiral have two similar forms, which are similar in structure but behave
differently when placed in biological systems. It is because in space, they have different three-
dimensional shapes. Such two similar forms, which are similar in structure but behave
differently are known as enantiomers. A known chiral drug which has two enantiomers is
thought to be as two drugs rather than one, due to their effective behavior when in biological
systems.
Chirality is formally defined as the geometric property of a rigid object (like a molecule
or drug) of not being superimposable with its mirror image. Those molecules which are not
chiral are achiral. Achiral molecules are obviously superimposable mirror images. They can be
superimposed onto each other as mirror images. Chirality is found all around us- in the
molecules found in our daily life- including carbohydrates, amino acids and lipids. The two
forms of enantiomers, which are mirror images, actually come with the idea of right and left-
handedness. They are termed as S and R isomers. Chemically, both the right and left
enantiomers are same and if drawn in two dimensions, will be completely identical. However, in
the presence of receptors and enzymes in biological systems, their properties are different. A
mixture containing equal amount, i.e. 50% S-form and 50% R-form, of both molecules is known
as racemate.
 In an achiral environment, both R and S forms of a chiral drug will show similar physical
and chemical properties. But a chiral environment makes one enantiomer display characteristics
pharmacologically different from that of the other enantiomer. If a given drug is chiral, the two
enantiomers must be considered two different drugs unless it is proved to be the other way.

In pharmacological context, there are there main groups that the racemic drugs can be
divided into: the drugs having one main biologically active enantiomer, which is called eutomer
and the other inactive or minorly active distomer, the drugs that have both enantiomers as active
as one another, having similar pharmacodynamics and the drugs which have one eutomer (the
active component) but the distomer can easily be inverted to come into its active form.
Omeprazole, Citalopram, Albuterol, Verapamil and Secobarbital are few of the drugs which are
active in their S-form. Even though their other enantiomer, or distomer, the R-form might not
necessarily be toxic, their S-form is therapeutically found to be still more effective.

S-albuterol works as a β2-adrenergic receptor agonist to treat asthma while S-omeprazole treats
gastroesophageal reflux disease by inhibiting a proton pump. In clinical trials, both of their S-
forms are found to work better than their racemic mixtures.

There are other cases where the effectiveness of a drug is contributed by both the enantiomers
instead of a single one. The use of a single enantiomer in such a case would result in less
effective and less safer results than if they were in a racemic mixture.

Citalopram meanwhile has the S-enantiomer bringing out better results. It is mainly responsible
for antagonism of serotonin reuptake while the R-enantiomer is 30-fold less effective. The S-
form of Citalopram marketed as Lexapro was clinically found to be significantly working better
than the mixture of both the R and S, marketed as Celexa Not only was it found to be working
with more efficacy than the mixture at the same doses, but also it produced less side effects.
This appears to show the S-form to have an edge over the R,S mixture and makes it an example
of single-enantiomer drugs but currently, no major evidence exists to suggest that the patients are
actually doing better when switching to S-Citalopram.
Verapamil is a calcium channel antagonist and another diasteroisomer with two pairs of
enantiomers. The pharmacological potency of its S and R enantiomer was studied and compared
and it was found that S-Verapamil works 10-20 times better than its R antipode for negative
chromotrophic effect on AV conduction and vasodilator. Since Verapamil also works as a
modifier of multidrug resistance in cancer chemotherapy. To function in this regard, Verapamil
must be used in high concentrations which leads to cardiotoxicity. The R-Verapamil was found
to have less cardiotoxicity than the S-Verapamil. Thus, R-Verapamil was concluded to be a
better modifier of multidrug resistance while treating cancer while S-Verapamil was found to be
preferable in its action as calcium channel inhibitor in therapy of cardiovascular system.

Secobarbital also exists as R and S which both have different pharmacological properties. The
S-secobarbital is however, found to give a faster anesthetic effect than the R-Secobarbital and
therefore considered as a more potent anesthetic.

S-Omeprazole:
First made in 1979 by AB Hassle in Sweden, Omeprazole was one of the first proton pump
inhibitors. It was launched as the first ulcer medicine with the name Losec. It was sold in
United States for a few years however, US Food and Drug Administration changed the name to
Prilosec.

Omeprazole can exist S or R enantiomer because it contains a tricoordinated sulfinyl surfer and a
pyramidal structure. It exists as a racemate, an equal mixture of both the enantiomers. When
there are greater [H+], i.e. lower pH, the canaliculi of parietal cells, the enantiomers get
converted into their achiral products: sulfenic acid and sulfonamide. These products can react
with a cysteine group in the presence of ATPase and inhibit the ability of parietal cells, which
can now no longer produced gastric acid.

Nexium is a pure S-
enantiomer and an
eutomer which is
developed by
AstraZeneca.
Omeprazole works by
undergoing a chiral shift
in vivo. This shift
converts the inactive
form, the R-enantiomer
to the active S-form.
This doubles the
concentration of the
active form of the drug.
The sifting of the chiral
products is done by the help of CYP2C19 isozyme of cytochrome P450. This isozyme may
not be equally found in all humans. People who are unable to metabolize the drug are called
 "poor metabolizers". This phenotype, which is poor metabolizer, varies widely. It is found to
be 2.0-2.5% in African Americans and in white Americans while up to 20% in Asians.

S-Citalopram

Celexa is a drug which is taken orally and is known as a selective serotonin reuptake
inhibitor (SSRI). The chemical structure of Celexa is quite different and unrelated to other
antidepressants

available like SSRIs of tricycyclic or tetracyclic. Citalopram is effective for depression, anxiety,
eating disorder and obsessive-compulsive disorder and different mood disorders. It works as an
antidepressant and for other disorders by inhibiting CNS, the uptake in the center by serotonin.
It regulates the fluctuation of moods, helps improve aggression, appetite and perception.

The action of Citalopram starts with inhibition of CNS neuronal reuptake of serotonin (5-HT).
Serotonin transporter (SLC6A4) on the other hand, acts as a target. In the synaptic cleft, it lets
Citalopram inhibit the serotonin reuptake. The drug Citalopram is found to have smaller degree
of affinity to histamine, acetlchone and norepinephrine receptors than other tircylc antidepressant
medicines. Other psychotropic drugs that affect a person’s mental state, are known to cause
antagonism of muscarinic, histaminergic, and adrenergic receptors.
S-albuterol:

S-albuterol is also known as Salbutamol. It is a moderately selective beta(2)-receptor agonist. It

is used to treat asthma and esophageal conditions like chronic obstructive airway diseases. The
other R-enantiomer is known as levalbuterol and helps in bronchodilation whereas S helps
bronchial reactivity.
The drug starts is mechanism of action with the activation of beta2-adrenergic receptors in the
smooth muscle of airway. This leads to an increase in intracellular concentration of cyclic-
3’,5’adenosine-monophosphate due to activation of adenyl cyclase. This further results in
activation of protein kinase A. The protein kinase A causes to lower intracellular ionic calcium
concentrations by inhibiting the phosphorylation of the myosin. This results in relaxation. S-
albuterol not only works in relaxing the smooth muscles of of airways, but it also takes care of
all bronchoconstrictor difficulties by functioning as an antagonist, regardless of spasmogen
involved.

Verapamil:

Verapamil is a drug which is used to cure high blood pressure, angina and arrythmias of the
heart. It works as a calcium-channel blocker. It belongs to the class of drugs known as non-
dihydropyridine but is not related to other medicines which are cardioactive. Even though the
drug is administered as a racemate mixture, the S-enantiomer is found to have 20 times more
efficacy than it’s R-enantiomer.

It’s mechanism of action starts with the inhibition of L-type calcium channel, which is present
in the smooth muscle and myocardial tissue. These channels allow calcium influx which starts
the action of potentials responsible to contract muscle tissues and the activity of heart’s electrical
pacemaker. When Verapamil is bound to such channels, the affinity is increased because smooth
muscle potential membrane is now reduced and also there is more stimulus to depolarize.
Similar mechanism of action is followed for the treatment of angina and hypertension.

Secobarbital:

Secobarbital is a barbiturate derivative drug known for its properties of hypnosis, anesthesia and
as a convulsant. It is marketed under the brand names of Seconal and Tuinal and in the United
Kingdom, it is commonly called quinalbarbitone. It is used to anesthetize patients before other
anesthetic agents are used for short surgical procedures, diagnostic or therapeutic ones.

Secobarbital works by binding at a site which is associated with Cl-ionopore at a GABA

receptor. This results in increase in the duration when the Cl-ionopore remains open. This
therefore lengthens the effect of inhibition in the GABA in thalamus.
References:

Nguyen LA, He H, Pham-Huy C. Chiral drugs: an overview. Int J Biomed Sci. 2006 Jun;2(2):85-
100. PMID: 23674971; PMCID: PMC3614593.

McConathy, J., & Owens, M. J. (2003). Stereochemistry in Drug Action. Primary care

companion to the Journal of clinical psychiatry, 5(2), 70–73. doi:10.4088/pcc.v05n0202