1 UNIT I: INTRODUCTION TO MEDICINAL CHEMISTRY

INTRODUCTION
TO MEDICINAL
CHEMISTRY
P R E S E N T E D B Y …
P R O F . S O N A L I R . P A W A R
A S S I S T A N T P R O F E S S O R ,
P H A R M A C E U T I C A L C H E M I S T R Y D E P A R T M E N T 1

a) History and development of medicinal
chemistry
b) Physicochemical properties in relation to:
 Biological action Ionization
 Solubility
 Partition Coefficient
 Hydrogen bonding
 Protein binding
 Chelation
 Bioisosterism
 Optical and Geometrical isomerism.
Introduction to Medicinal Chemistry 2
Introduction to Medicinal Chemistry.

3
Introduction
 A branch of chemistry in which the features of biological, and pharmaceutical sciences are studied, is
termed as medicinal chemistry.
 The study of invention discovery, design, and preparation of biologically active compounds.
 Their metabolism, mode of action at the molecular level, and the structure – activity relationships are
also covered under this branch.
 The studies in medicinal chemistry involve a combination organic chemistry with biochemistry,
computational chemistry pharmacology , Pharmacognosy molecular biology , statistics , and physical
chemistry.
 Medicinal chemistry is also used to obtain information on complexities arising due to the presence of
functional moiety and the effect on the physicochemical properties of ‘target-drug molecule’ termed as
Structure Activity Relationship (SAR); and recently it has been given the name of Quantitative –
Structure – Activity Relationship (OSAR).
 Developing a new drugs and determining formulations to deliver bio active compounds.
Introduction to Medicinal Chemistry.

History & Development of Medicinal Chemistry:
History And Development of Medicinal Chemistry:-
> before thousands year ago
-She nung (Chinese emperor) made a Pharmacopoeia
Chaulmoogra fruit -dysentery & diarrhoea
Emetine (ipecacuanha root ) - amoebiasis
Cocaine and tryptamine - hallucination
>The 13th – 20th century
-Chemical :analysis techniques were developed
-Pharmacognosy developed
-Synthesis of chemotherapeutic agent were started
Kolbe (1856) synthesized – Acetic acid
Berthelot (1856) synthesized – Methane
Domagk stated rontosil can cure gram positive bacterial infections in human and animals.
4

5
Medicinal chemistry is a discipline that encloses the design, development, and synthesis of
pharmaceutical drugs. The discipline combines expertise from chemistry, especially synthetic
organic chemistry, pharmacology, and other biological sciences.
Drugs of Antiquity (ancient time)
 The therapeutic plants and minerals are in use since the ancient civilization of the Chinese, the Hindus,
the Mayans of Central America, and the Mediterranean people of bygone days.
 Shen Nung (a Chinese emperor) made a Pharmacopoeia, includind in it ch’ ang shang (an anti –
malarial alkaloid ) and ma huang (from which ephedrind was isolated ).
 The native American Indians used chaulmooger fruit .
 For treating dysentery and diarrhoea, the Brazilians used emetine present in the ipecacuanha root; and
it is still used in amoebiasis ancient explorers discovered that the south American Indians chewed
cocaine containing coca leaves and tryptamine-containing mushoons for hallucination.
 Many of the developments after the 1860s arose from the synthesis of compounds specifically for
their medicinal action.

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 Although the use of willow bark as a pain-killer was known to the herbalists, the analgesic activity of its
constituent salicin 1.1 and of salicylic acid 1.2 were developed in the 1860s and 1870s.
 Exploration in the seventeenth and eighteenth centuries led to the addition of a number of useful
tropical plants to those of European origin. The nineteenth century saw the beginnings of modern
organic chemistry and consequently of medicinal chemistry. Their development is intertwined.

8
Structure of Biological Membrane

9
Structure of Biological Membrane

10
Physicochemical Properties in relation to Biological Action
DEFINITION:
●The ability of a chemical compoundto elicit a pharmacological/ therapeutic
effect is related to the influence of various physical and chemical (physicochemical)
properties of the chemical substance on the biomolecule that it interactswith.
1)Physical Properties
Physicalproperty ofdrug isresponsibleforitsaction
2)Chemical Properties
Thedrug react extracellularly according to simple chemical
reactionslikeneutralization,chelation,oxidationetc.

VARIOUS PHYSICO-CHEMICAL PROPERTIES ARE,
✓ Solubility
✓ PartitionCoefficient
✓ Dissociationconstant
✓ HydrogenBonding
✓ IonizationofDrug
✓ RedoxPotential
✓ Complexation
✓ Surfaceactivity
✓ Proteinbinding
✓ Isosterism

1.SOLUBILITY:
• The solubility of a substance at a given temperature is defined as the concentration of the
dissolvedsolute, whichisinequillibriumwith the solidsolute.
• Solubilitydependsonthe natureofsoluteandsolventaswellas temperature , pH&pressure.
• The solubility of drug may be expressed in terms of its affinity/philicity or
repulsion/phobicity foreither anaqueousor organicsolvent.
● The atoms and molecules ofall organic substances are held together byvarious types ofbonds
(e.g.hydrogenbond,dipole–dipole, ionic bondetc.)
● These forces are involved in solubility because it is the solvent- solvent, solute-solute, solvent-
soluteinteractionsthat governs solubility.

● Methodstoimprove solubilityofdrugs
1) Structuralmodification(alter the structure ofmolecules)
2) UseofCosolvents(Ethanol, sorbitol,PPG,PEG)
3) Employingsurfactants
4) Complexation
● Importance ofsolubility
1. Solubility concept is important to pharmacist because it govern the preparation of
liquiddosageform andthe drug mustbein solutionbeforeit isabsorbedbythe bodyto
producethe biologicalactivity
.
2. Drugmustbeinsolutionformto interact withreceptors.

2.PARTITIONCO-EFFICIENT
●Drug (
a
q
u
e
o
u
s
) Drug(lipid)
●Partition co-efficient is one of the Physicochemical parameter which influencing the
drug transport & drug distribution., the way in which the drug reaches the site of
action from the site of application.
●Partition co-efficient is defined as equilibrium constant of drug concentration for
unionized molecule in two phases.
●P[U
n
io
n
iz
e
d
m
o
le
c
u
le
]
= [drug]lipid
[drug]water

For ionized (acids, basesand salts)
P[Io
n
iz
e
dm
o
le
c
u
le
] = [drug]lipid
[1-a][drug]w
a
te
r
a= degree of ionization in aqueous solution.
●Partition coefficient affects the drug transfer characteristics.
●The contribution of each functional group & structural
arrangement help to determine the lipophilic or hydrophilic
character of drug molecules.
●It iswidelyused in QSAR.

●FactorsaffectingPartition Co-efficient
➢ pH
➢ Co solvents
➢ Surfactant
➢ Complexation
● Partition Co-efficientare difficult to measurein livingsystem.
● Theyareusuallydetermined invitro 1-octanolasalipidphaseandphosphatebuffer ofpH
7.4 asthe aqueousphase.
● 1-octanol asalipid phase because,
●It haspolar andnonpolarregion
●Po/w iseasytomeasure
●Po/w oftencorrelateswith manybiologicalproperties
●It canbe predicted usingcomputationalmode

THEPARTITIONCO-EFFICIENT,PISDIMENSIONLESSANDITSLOGARITHM, LOGP ISWIDELYUSEDAS
THEMEASUREOFLIPOPHILICITY
.
• The log Pis measured bythe followingmethods.
1) Shake flaskmethod
2) Chromatographic method (HPLC)
 Phenobarbitone hasahigh lipid/water partition coefficient of 5.9.
 Thiopentone sodium has achloroform/water partition coefficient ofabout 100, so it is
highlysoluble in lipid.
 Hence, thiopentone sodium is used as ultra-short acting barbiturates.

logP Binding
to
enzymes
/recepto
r
Aqueous
solubility
Binding to
P450
metabolising
enzymes
Absorbance
through
membrane
Binging to
blood/tissu
e proteins

● IMPORTANCEOFPARTICIANCOEFFICIENT:
●It is generally used in combination with the Pka to
predict the distribution ofdrug inbiologicalsystem.
●The factor such as absorption, excretion &penetration of the
CNSmaybe relatedto the logPvalue ofdrug.
●Thedrug shouldbe designedwith the lowestpossible
●Log P
, to reduce toxicity
, nonspecific binding &
bioavailability.

3.HYDROGENBOND
●The hydrogen bond is a special dipole-dipole interaction between the hydrogen atom
inapolarbondsuchasN-H, O-H or F-H&electronegativeatom O, N, Fatom.
●Dipoles result from unequal sharing of electrons between atoms within a covalent
bond.
These are weak bonds and denoted asdotted lines. O-H…….O, HN-
H…….O,
●The compounds that are capable,of forming hydrogen bonding isonlysoluble inwater.
● hydrogenbondingisclassified into 2 types:
1. Intermolecular
2. Intramolecular

1)INTERMOLECULAR HYDROGENBONDING
●It is occur between two or more than two moleculesof the same or different
compound.
●Due to thisincrease the boiling point ofthe compound & increase the molecular
weight of compound hence more energyisrequired to dissociate the molecular for
vaporization.

2)INTRAMOLECULARHYDROGENBONDING
●H- bondingoccurswithin twoatomsofthe samemolecules.
●This type of bonding is known as chelation and frequently occurs
inorganiccompounds.
●Sometimesh-bond develop sixor fivemember rings
●Due to decrease the boilingpoint
salicylicacid o-nitrophenol
O H
C
O
OH
O H
N
O
O

HYDROGEN BONDING AND BIOLOGICAL ACTION
N
N
CH3
H3C
O
Eg. 1) Antipyrin i.e. 1- phenyl 2,3- dimethyl 5- pyrazolone has analgesic
activity.
C6H5
HN
H3 C
O
1-phenyl-3-methyl-5-pyrazolone is inactive.
C6 H5
H N
H
N
H3 C
O

O
H
O
C
OH
SALICYLIC ACID (O-HYDROXY BENZOIC ACID) HAS ANTEBACTERIAL ACTIVITY
OH C
OH
O
HO C
O
OH
Para and meta Hydroxy Benzoic acids are inactive.

EFFECT OFH-BONDING
All physical properties affected byH-bonding,
1. Boilingand Meltingpoint
2. W
ater solubility
3. Strength of acids
4. Spectroscopic properties
5. On surface tension and viscosity
6. Biological products
7. Drug-receptor interaction

4.CHELATION/COM
PLEXATION
● Complexofdrugmoleculescan’t crossthe naturalmembrane barriers, theyrender the drug
biological ineffectivity.
● The rate of absorption is proportional to the concentration of the free drug molecules i.e. the
diffusionofdrug.
● Dueto reversibilityofthe Complexation,equillibriumbetweenfree druganddrugcomplex
Drug+ complexingagent Drugcomplex
● Complexationreducethe rate ofabsorption ofdrug but not affectthe availabilityofdrug

IMPORTANCE OF CHELATES IN MEDICINE:
CHSH
1.Dimercaprol is a chelating
agent.
CH2SH
+ As++
CH2S
CHS
CH2OH
As
a)Antidote for metal poisoning
CH3
H
C C COOH
SH NH2
CU++
CH2OH
2.Penicillamine
CH3
CH3 C
CH3
H
C COOH
S NH2
CU
1:1 chelate
CH3 C
CH3
S
H
C
NH2
COOH
UC
NH2 S
HOOC
CH3
CH3
1:2 chelate

●8-Hydroxyquinoline and its analogs acts as antibacterial and anti fungal agent by
complexingwith ironor copper.
●Undesirablesideeffectscaused bydrugs,whichchelateswith metals.
●Aside effect of Hydralazine a antihypertensive agent is formation of anemia and this is
due to chelation ofthe drugwith iron.
● Phenobarbital forms anon-absorbable complex with polyethylene glycol-
4000.
● Calcium with EDT
A form complex which is increase the permeability of
membrane.

5.IONIZATION OFDRUG
●Mostofthe drugs are either weakacidsor baseandcanexist in either
ionised or unionised state.
= Protonation or deprotonation resulting in charged
●Ionization
molecules.
●The ionization of the drugdepends on its pKa&pH.
●The rate of drug absorption is directly proportional to the
concentration of the drug at absorbable form but not the concentration
ofthe drug at the absorption site.
●Ionization form imparts good water solubility to the drug which is
required of bindingof drug and receptor interaction
●Unionized form helps the drug to cross the cell membrane.
●Eg; Barbituric acid is inactive because it is strong acid.
while, 5,5 disubstituted Barbituric acid has CNS depressant action
because it is weakacid.

According to Henderson-Hasselbalch equation
pH-pKa = log[ionized/unionised]
pH-pKa = log[unionized/ionised]
for acids
for base
%ionisation = 100[1+10 (p
H
-p
k
a
) ]
When an acid or base is 50%ionised: pH = pKa
Eg: the solution of weak acidAspirin in stomach (pH-1.0) will get
readily absorbed because it is in the un-ionosed form(99%).
H A H 2 O H 3 O +
C o n j u g a t e
a c i d
A -
C o n u g a t e
b a s e
B H + H 2 O H 3 O +
B
C o n u g a t e
b a s e
U n i o n i z e d
A c i d
i o n i s e d C o n u g a t e
a c i d

● Eg:Phenytoin injection must be adjusted to pH 12 with Sodium Hydroxide to obtain 99.98%
ofthe druginionisedform.
● Tropicamide eye dropsananti cholinergic drughas apkaof 5.2 and the drug hasto be buffered
to pH4to obtainmore than90%ionisation.
● ImportanceofIonizationofdrug
● Weak acid at acid pH: more lipid soluble because it is uncharged, the uncharged form more
readily passesthroughthe biological membranes.
RCOO- + H+ = RCOOH
● Weak base at alkaline pH: more lipid soluble because it is uncharged, the uncharged form
more readily passesthroughthe biologicalmembranes.
RNH+ = RNH2+ H+

6.REDOX P
OTENTIAL
●The oxidation-reduction potential may be defined as a quantitative
expression of the tendency that a compound has to give or receive
electrons.
●The correlation between redox potential and biological activity can only
bedrawnfor the compoundofverysimilarstructure andproperties.
●The redox potential of a system maybe calculated from the following
equation.
● E=E0+0.0592/nlog[conc. of reductant /conc. of oxidant]

EXAMPLES,
1) Riboflavin analogues
The biological activity of riboflavin is due to E=-0.185
volt.
N
NH
O
N
OH
OH
OH
OH
N O
riboflavin
0
Riboflavin E = -0.185 V
Riboflavin analogue E0 = -0.095V
N
N H
N
O H
O H
O H
O H
N O
O
Dichloro riboflavin
C l
C l
2).The optimum bacteriostatic activity in quinones is associated
with the redox potential at +0.03 volt, when tested against
Staphylococcusaureus.

7. SURFACE ACTIVITY
● Surfactantisdefinedasamaterial that canreduce the surfacetensionofwater at very
lowconcentration.
● Surfaceactive agents affectthe drug absorption whichdepends on:
1.The chemical nature ofsurfactant
2.Its concentration
3.Its affect on biological membrane andthe micelle formation.
● In lower conc. of surfactant enhanced the rate of absorption because amphiphilies
reducesthe surfacetensionandbetter absorption.
● Inhigherconc.ofsurfactantreduced the rate ofabsorption.

Applications:
1.The antihelmenticactivityofhexylresorcinol
2.Bactericidalactivityofcationicquaternary ammonium compounds.
3.Bactericidalactivityofaliphaticalcohols.
4.Disinfectant action ofphenolandcresol.
5.Bilesalt solutionsofapproximatelyphysiological concentration greatly
enhance the dissolution rateofpoorly water soluble drugslike
grasiofulvin,hexestrol bymicellarsolubilizationeffect.

8. PROTEIN BINDING
• ▶ The reversible binding of protein with non-specific and non- functional site on the body
proteinwithout showingany biologicaleffect is calledasprotein binding
.
• Protein+ drug⇌ Protein-drugcomplex
• ▶ Dependingon the whether the drugisaweakor strong acid,base or isneutral, it canbind
to single blood proteins to multiple proteins (sereum albumin, acid-gycoprotien or
lipoproteins).The most significant protein involved in the binding of drugisalbumin, which
comprisesmore thanhalfof bloodproteins.

▶ protein binding values are normally given as the percentage of total
plasmaconcentration ofdrug that isboundto allplasma protein.
Freedrug(Df) + Freeprotein(Pf) Drug/proteincomplex(Dp)
Total plasma concentration (Dt) = (Df) + (Dp

● Stereochemistryinvolve the studyofthree dimensional natureof
molecules.It isstudyofthe chiralmolecules.
● Stereochemistryplaysamajor role inthe pharmacological properties
because;
1. Anychange instereo specificityofthe drugwillaffect its
pharmacological activity
2. Theisomeric pairs havedifferent physicalproperties (logp, pKaetc.)
andthus differinpharmacologicalactivity.
● Theisomer whichhave same bondconnectivitybut different arrangement of
groupsor atomsinthe spaceare termed stereoisomer.
9. STEREOCHEMISTRY OF DRUGS

CONFORMATIONAL ISOMERS
●Different arrangement of atoms that can be converted into one
another byrotation aboutsinglebondsare calledconformations.
●Rotation aboutbondsallowsinter conversionofconformers.

●Aclassical example is of acetylcholine which can exist in different
conformations.
H H
OCOCH3
Staggered
H H
N+ H N+
H
H
H
OCOCH3
Eclipsed
H3COCO H
N
H
H
H
GAUCHE
OCOCH3
N
H
H H
H
Fully Eclipsed
N +
O
2-Acetoxycyclo propyl trimethyl ammonium iodide
O
I -

● OpticalIsomers
●Stereochemistry
, enantiomers, symmetry and chirality are impotant concept in
therapeutic and toxiceffect ofdrug.
●A chiral compound containing one asymmetric centre has two enantiomers.
Although each enantiomer has identical chemical & physical properties, they may
have different physiological activity like interaction with receptor, metabolism &
protein binding.
●Aoptical isomers in biological action is due to one isomer being able to achieve a
three point attachment with its receptor molecule while its enantiomer would
onlybeableto achieveatwopoint attachment withthe same molecule.

(-)-Adrenaline (+)-
ADRENALINE

E.G. EPHEDRINE & PSUEDOEPHEDRINE
MP = 37-39
1 gram/20 mL
MP = 118-120
1 gram/200 mL
Ephedrine
(Erythro)
CH3
NHCH3
OH
H
H
Pseudoephedrine
(Threo)
CH3
NHCH3
H
H
HO

●The category of drugs where the two isomers havequalitatively
similar pharmacologicalactivitybut havedifferent quantitative
potencies.
O
O
OH
O
(s)-(-)warfarin
O
O
H
O O
(R)-(+)warfarin

• Geometric Isomerism
Geometric isomerismisrepresented bycis/trans isomerism
resulting from restricted rotation due to carbon-carbon double
bond or in rigid ring system.
OH
HO OH
HO
trans-diethylstibesterol
Estrogenic activity
cis-diethylstibesterol
Only 7% activity
of the trans isomer

● Longmuir introduced the term isosterism in 1919, which postulated that two
moleculesor molecular fragments containing anidenticalnumber andarrangament
ofelectronshould have similar propertiesandtermedasisosteres.
● Isosteresshould beisoelectrici.e.theyshouldpossesssametotal charge.
● Bioisosterism is defined as compounds or groups that possess near or equal
molecular shapesandvolumes, approximately the samedistribution ofelectron and
whichexhibitsimilarphysicalproperties.
●Theyare classifiedintotwotypes.,
i)Classical biososteres
ii)Nonclassicalbioisosters.

●Classical Bioisosteres
● They havesimilarities of shape and electronic configuration of atoms, groups
and moleculeswhich theyreplace.
● The classical bioisosteres maybe,
Univalent atoms and groups
i) Cl, Br, I ii) CH3, NH2, -OH, -SH
Bivalent atoms and groups
i) R-O-R,R-NH-R, R-S-R, RCH2
R
ii)–CONHR, -COOR, -COSR

●Trivalent atoms and groups
i)-CH=, -N= ii) –p=, -AS=
●T
etravalent atoms and groups
=c=, =N=, =P=
●Ring equivalent
-CH=CH-, -S-, -O-, -NH, -CH2
-

●Application of Classical Bioisosteres in in drug design
i) Replacement of–NH 2 group by–CH3 group.
Carbutamide
Tolbutamide
R= NH2
R= CH3
ii)Replacement of –OH &-SH
X
Guanine= -OH
6-Thioguanine = -SH
R SO2 NH CONH(CH2)3CH3
N H
N
N
H 2 N
H N

● NonclassicalB
ioisosteres
➢ Theydonot obeythe stearicand electronicdefinition ofclassical
isosteres.
➢Non-classicalbiosteres are functionalgroups with dissimilarvalence
electron configuration.
➢Specificcharacteristics:
➢Electronicproperties
➢Physicochemical propertyofmolecule
➢Spatical arrangement
➢Functional moiety for biological activity

●Examples
●Halogens Cl, F
, Br, CN
●Ether -S-, -O-
●Carbonyl group
●Hydroxyl group –OH, -NHSO2R, CH2OH
●Catechol
HO
HO
Catechol
O
S
O O

●Aclassical e.g.of ringVs.noncycclic structure is
Diethylstilbosterol &17-ß oestradiol.
O
H
H
H H
H
O
17-ß oestradiol.
OH
HO
trans-diethylstibesterol

1 UNIT I: INTRODUCTION TO MEDICINAL CHEMISTRY

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1 UNIT I: INTRODUCTION TO MEDICINAL CHEMISTRY