1 UNIT I: INTRODUCTION TO MEDICINAL CHEMISTRY

S.Y. B. PHARMACY IV SEMESTER,
UNIT I: INTRODUCTION TO MEDICINAL CHEMISTRY

1. Introduction to Medicinal Chemistry Presented by … Prof. Sonali R. Pawar Assistant Professor, Pharmaceutical Chemistry Department 1

2. History and development of medicinal chemistry 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. 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 .

4. 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 13 th – 20 th 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. 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. History & Development of Medicinal Chemistry:

6. 6 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. History & Development of Medicinal Chemistry:

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8. 8 Structure of Biological Membrane

9. 9 Structure of Biological Membrane

10. 10 Physicochemical Properties in relation to Biological Action DEFINITION: The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical ( physicochemical) properties of the chemical substance on the b io m o l e c ul e th a t it int e r a c t s with. P h y s i c a l P r o p e r t i e s Physical property of drug is responsible for its action 2 ) Ch e m i c a l P r op e r t i e s The drug react extracellularly according to simple c hemical reactions like neutralization, chelation, oxidation etc.

11. Various Physico-Chemical Properties are, Solubility P a r t it i on C o e ffi c i e n t Di ss o c i a t i on c on s t a n t Hy d r o g e n B o n d in g I o n i z a t i on o f D r u g R e d o x P o t e n t i a l Complexation S u r f a c e a c t iv i t y P r o t e in bi nd i n g Isosterism

12. 1 . S o l u b i l i ty: The solubility of a substance at a given temperature is defined as the concentration of the dissolved solute, which is in equillibrium with th e s o l i d s o l u t e . Solubility depends on the nature of solute and solvent as well as t e mp e r a tu r e , pH & p r e s su r e . The solubility of drug may be expressed in terms of its affinity/philicity or repulsion/phobicity for either an aqueous or or g a ni c s o l v e n t. The atoms and molecules of all organic substances are held together by various types of bonds (e.g. hydrogen bond, dipole –dipole, ionic b ond e t c .) These forces are involved in solubility because it is the solvent- solvent, solute-solute, solvent-solute interactions that governs solubility.

13. M e t hod s t o i mp r o v e s o l u bi l i t y o f d r u g s Structural modification (alter the structure of molecules) U s e of C o s o l v e n t s ( E thano l , so r b i to l , P P G , P E G ) E mp l o y i ng su r f a c t ants Complexation I mpo r t a n c e o f s o l u bi l i t y Solubility concept is important to pharmacist because it govern the preparation of liquid dosage form and the drug must be in solution before it is absorbed by the body to produce the b i ol o g i c a l a c t i v i t y . Drug must be in solution form to interact with receptors.

14. 2 . P a r tit i o n Co - e f f i ci e nt Drug (aqueous ) Drug (lipid) Partition co-efficient is one of the Physicochemical parameter which influencing the drug transport & drug distribution., the w a y i n w h i c h th e d r u g r e a c h e s th e s i t e of a c t i o n f r om t h e s i t e of application. Partition co-efficient is defined as equilibrium constant of drug concentration for unionized molecule in two phases. P [ U n i o n i z e d m o l e c u l e ] = [drug] lipid [drug] water

15. F o r i oni ze d (a c i ds, b a s e s a n d sa l t s ) P [ I o n i z e d m o l e c u l e ] = [drug] lipid [ 1 - a ] [ d r u g ] w a t e r a = d e g r ee of i on i z a t i on i n a q u e ous s o l u t i on. Partition coefficient affects the drug transfer characteristics. The contribution of each functional group & structural arrangement help to determine the lipophilic or hydrophilic c h a r a c t e r of d r ug mo l e c u l e s . I t i s w i d e l y u s e d i n Q S A R .

16. F a c t o r s a f f e c t i n g P a r t i t i on C o- e ff i c i e nt pH C o s ol v e n ts Surfactant Complexation Partition Co-efficient are difficult to measure in living system. They are usually determined in vitro 1-octanol as a lipid phase and phosphate b uf f e r of pH 7.4 a s t h e a q ueous p h a s e . 1 - o c t a n o l a s a li p i d p h a s e b e c a u s e , I t h a s pol a r a n d nonp o la r r e g i o n P o /w is e as y t o m e a s u r e Po/w often correlates with many biological properties It can be predicted using computational mode

17. T h e P a r ti t i on c o - e f f i c i e nt, P is dim en si o nle s s a nd i t s l og a r ithm , l og P is w i d e l y u s e d a s t h e m e a s u r e of l i po p hi l i c it y . The log P is measured by the following methods. S h a k e f l a s k m e t h od C h r om a t o g r a p h ic m e t h od ( H P L C ) Phenobarbitone has a high lipid/water partition coefficient of 5.9. Thiopentone sodium has a chloroform/water partition coefficient of a b o ut 1 0, s o it is h i g hl y s ol u b l e in l i pi d . Hence , thiopentone sodium is used as ultra-short acting barbiturates.

18. l o g P Binding to enz y mes /receptor Aqu e o u s solubility Binding to P 450 met a b o lis i ng enzymes Ab s orb a nce through membrane Binging to b l o od/ t i ssue proteins

19. I M P O R T A N C E O F P A R T I C I A N C OEF F I C I ENT: It is generally used in combination with the Pka to predict the distribution of drug in biological system. Th e f a c t or su c h a s ab s o r pti o n, e xc r e t i on & p e n e t r a t i on of the C N S m a y b e r e l a t e d t o th e l og P v a l ue of d r u g . The drug should be designed with the lowest possible Log P , t o r e du c e t o xi c i t y , n on s p e c i f i c b i ndi ng & bioavailability.

20. 3 . H y dr o ge n Bo n d The hydrogen bond is a special dipole-dipole interaction between the hydrogen atom in a polar bond such as N-H, O-H or F-H & e l e c t r o n e ga ti v e a to m O , N , F a to m . Dipoles result from unequal sharing of electrons between atoms w i t h in a c o v a l e nt b o nd. These are weak bonds and denoted as dotted lines. O - H … … . O , H N-H……. O , The compounds that are capable, of forming hydrogen bonding is only s o l u b le in w a te r . h y d r o g e n b on d i n g i s c l as s i f i e d i n t o 2 t y p e s: Intermolecular Intramolecular

21. 1 ) I n t e r m o lec u l a r h y d r o g en b o n d i n g I t i s o c c ur b e t w ee n t w o or m o r e t ha n t w o mo l e c u l e s of th e s a m e or di f f e r e nt c o mpound. D u e t o th i s i nc r e a s e th e b oi l i ng p o i nt o f th e c ompou n d & increase the molecular weight of compound hence more energy i s r e q ui r e d t o d i ss oci a t e t h e mo l e cu l a r f or v apo r i z a t i o n.

22. 2 ) Intr a m o l e c u l a r H y d r o g en b o n d i n g H- bonding occurs within two atoms of the same molecules. This type of bonding is known as chelation and frequently occurs in or g a n i c c o m p o u n d s . S o m e ti m e s h - b ond d e v e l o p s ix o r f i v e m e m b e r r ings Du e t o de c r e a s e the b oil ing p o int s a l i c y li c a c id o-nitrophenol O H C O O H O H N O O

23. Hydrogen Bonding and biological action N N CH 3 H 3 C O Eg. 1) Antipyrin i.e. 1- phenyl 2,3- dimethyl 5- pyrazolone has analgesic activity. C 6 H 5 H N H 3 C O 1-phenyl-3-methyl-5-pyrazolone is inactive. C 6 H 5 H N H N H 3 C O

24. O H O C OH Salicylic acid (O-Hydroxy Benzoic acid) has antebacterial activity O H C O H O H O C O OH Para and meta Hydroxy Benzoic acids are inactive.

25. Eff e c t o f H - b o nd i n g All physical properties affected by H-bonding, B o i l i ng a n d Me l t i n g poi n t W a t e r s ol ub il ity S t r e ng t h of a c ids S pe c t r o s c o p ic p r o p e r tie s On s ur f a c e t en s i on a nd v i s c o s i t y B i o l o g i c a l p r o d u c ts D r u g - r e c ep t o r i n t e r a c ti o n

26. 4 . Ch e l a ti o n / Co m p l e x a ti o n Comp l e x of d r ug mo l e c u l e s c a n ’ t c r o ss th e na t ur a l m e mb r ane barriers, they render the drug biological ineffectivity. Th e r a t e of a b so r pt i on i s p r o po r t i onal t o th e c o n c e n t r a t i on of the free drug molecules i.e. the diffusion of drug. Due to reversibility of the Complexation, equillibrium between f r e e d r ug an d d r ug c o mp l e x D r u g + c omp l exi n g a g en t D r ug c o m p l e x Complexation reduce the rate of absorption of drug but not affect th e a v a i l ab i l i t y of d r ug

27. Importance of chelates in medicine: CH S H 1.Dimercaprol is a chelating agent. CH 2 SH + As ++ CH 2 S CH S CH 2 OH As a)Antidote for metal poisoning CH 3 H C C COOH SH NH 2 CU ++ CH 2 OH 2.Penicillamine CH 3 CH 3 C CH 3 H C C OO H S NH 2 CU 1:1 chelate CH 3 C CH 3 S H C NH 2 C O O H U C NH 2 S H O O C CH 3 CH 3 1:2 chelate

28. 8-Hydroxyquinoline and its analogs acts as antibacterial and anti fungal a ge n t b y c om ple x i ng w ith i r on or c o p pe r . Undesirable side effects caused by drugs, which chelates with metals . A side effect of Hydralazine a antihypertensive agent is formation of a n em i a a nd t h i s i s due t o c h el a t i on of th e d r ug w i t h i r o n. Phenobarbital forms a non-absorbable complex with p o l y e t h y l e ne g l y c o l -400 . Ca l c i um w i t h E D T A f o r m comp l e x w h i c h i s in c r e a s e the p e r me a b i l i t y of m e m b r an e .

29. 5 . Io n iz a ti o n o f d r ug Most of the drugs are either weak acids or base and can exist in either i o ni s e d or u nioni s e d st a t e . = Protonation or deprotonation resulting in charged Ionization mo l e cu l e s . T h e i oni z a t i on of t h e d r u g d e p e nds on i t s p K a & p H . The rate of drug absorption is directly proportional to the concentration of the drug at absorbable form but not the concentration o f th e d r ug a t t h e a b so r p t i on s i t e . Ionization form imparts good water solubility to the drug which is r e q ui r e d of b i ndi n g of d r ug an d r e c e pt o r i n t e r a c t i on Unionized form helps the drug to cross the cell membrane. E g ; B a r b i tu r i c a c i d i s i n a c t i v e b e cau s e i t i s st r ong a c i d. while, 5,5 disubstituted Barbituric acid has CNS depressant action b e cau s e i t i s w e a k a c i d.

30. According to Henderson-Hasselbalch equation pH- p K a = l o g [ io n iz e d/u n i o ni s e d] p H - pK a = l o g [ u nio ni z e d/i o ni s e d] f or a c ids f or b a s e % i o ni s a tion = 1 00 \ [ 1+10 ( p H - p k a ) ] Whe n a n a c id o r b a s e is 5 % i o n is e d : pH = pK a Eg: the solution of weak acid Aspirin 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 on j ug a t e acid A - C onug a t e base BH + H 2 O H 3 O + B C onug a t e base U n i on i z e d Acid i on i s e d C onug a t e acid

31. Eg:Phenytoin injection must be adjusted to pH 12 with Sodium Hydroxide to obtain 99.98% of the drug in ionised form. T r opi ca m i d e e y e d r o p s a n ant i c ho l i n e r g i c d r ug ha s a p k a of 5 . 2 and the drug has to be buffered to pH 4 to obtain more than 90% ionisation . Imp o r t an c e of I o n i z a t i on o f d r u g Weak acid at acid pH: more lipid soluble because it is uncharged, the uncharged form more readily passes through the biological membranes. RCOO - + H + = RCOOH Weak base at alkaline pH: more lipid soluble because it is uncharged, the uncharged form more readily passes through the b i ol o g i c a l m e mb r ane s . RNH + = RNH 2 + H +

32. 6 . R e d o x P o t e n t i a l The oxidation-reduction potential may be defined as a quantitative expression of the tendency that a compound has to g i v e or r e c e i v e e l e c t r o n s . Th e c o r r e l a t i on b e t w e e n r e d o x po t e nt i a l an d b i o l o g i c a l act i v i ty can only be drawn for the compound of very similar structure an d p r op e r t i e s . Th e r e d o x po t e n t i a l of a s y s t e m m a y b e c a l c u l a t e d f r om the f o l l o w i ng e q u a t i o n . E=E +0.0592/n log[conc. of reductant /conc. of oxidant]

33. Examples, 1) R i b o f l a v i n a n a l o g u e s The biological activity of riboflavin is due to E =-0.185 v o l t. N NH O N OH OH O H OH N O r i bo f l a v in Riboflavin E = -0.185 V Riboflavin analogue E = -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 w i t h th e r e d o x po t e n t i a l a t + .03 v o l t, wh e n t e st e d ag a i n s t S t a ph y l o c o c c u s a ur e us.

34. 7 . S u r f a c e A c t i v i ty Surfactant is defined as a material that can reduce the surface t e nsi on of w a t e r a t v e r y l o w c onc e nt r a t i on. Surface active agents affect the drug absorption which depends on: T h e c h emi c a l n a t u r e of s ur f a c ta nt Its concentration 3.Its affect on biological membrane and the micelle formation. In lower conc. of surfactant enhanced the rate of absorption because amphiphilies reduces the surface tension and better absorption. In higher conc. of surfactant reduced the rate of absorption.

35. Applications: T h e a nti h e l m en t i c a c ti v i t y of h e xy l r e s o r c i n ol Bactericidal activity of cationic quaternary ammonium compounds. 3.Bactericidal activity of aliphatic alcohols. D i si n f e c t a n t a c tio n of p h enol a nd c r e s ol . Bile salt solutions of approximately physiological concentration greatly e n h a n c e t h e di s s ol ution r a t e o f p o o r l y w a te r s o l u b le d r u g s l i k e grasiofulvin, hexestrol by micellar solubilization effect.

36. 8 . P r o t e i n b i n d i n g ▶ T h e r e v e r s i b l e b i nd i ng of p r ot e i n w i t h non- s p e c i f i c an d non- f u n c t i onal s i t e on th e b o d y p r o t e i n w i thou t s h o w i ng a n y b i o l o g i c a l e ff e c t i s c a l l e d a s p r ot e i n bi ndi n g . P r o t e i n + d r ug ⇌ P r o t e i n-d r ug comp l e x ▶ D e p e ndi ng on th e wh e th e r th e d r ug i s a w e a k or s t r ong acid,base or is neutral, it can bind to single blood proteins to m u l t i p l e p r o t e i ns ( s e r e um a l b umi n, a c i d - gy cop r o t i e n or lipoproteins).The most significant protein involved in the b i n di ng of d r u g i s a l b u m i n, w h i c h c omp r i s e s m o r e t ha n h a l f of b l o od p r ot e i n s .

37. ▶ protein binding values are normally given as the percentage of total plasma concentration of drug that is bound to all plasma protein. F r e e d r ug (D f ) + F r e e p r o t e i n ( P f ) D r u g / p r o t e i n c o m p l e x ( D p ) T o t a l p l a s m a c o n c e n tr a t i o n ( D t ) = (D f ) + (D p

38. S t e r e o c h e m i s t r y i n v o l v e th e s tu d y o f th r ee d i m e ns i o nal nature of molecules. It is study of the chiral molecules. S t e r e o c h e m i s t r y pl a y s a ma j or r o l e i n th e pha r ma co l o g i c a l properties because; A n y c h a n g e in s te r e o s p e c i f i c i t y of t h e d r u g wi l l a f f e c t its p h a r m a c o l o g i c a l a c tivi t y The isomeric pairs have different physical properties (log p, pKa etc.) and thus differ in pharmacological activity. Th e i s om e r w h i c h h a v e s a m e b ond c onn e c t i v i t y b ut di f f e r e nt a r r ang e me nt of g r o u ps or a t oms i n th e s pace a r e t e r m e d stereoisomer . 9. Stereochemistry of drugs

39. Conformational Isomers D i ff e r e nt a r r ang e me nt of a t o m s t h a t c a n b e c o n v e r t e d i nto one another by rotation about single bonds are called conformations. Rotation about bonds allows inter conversion of conformers.

40. A classical example is of acetylcholine which can exist in different conformations. H H OCOCH3 Staggered H H N + H N + H H H OCOCH3 Eclipsed H 3 COCO H N H H H G A U C H E OCOCH 3 N H H H H Fully Eclipsed N + O 2-Acetoxycyclo propyl trimethyl ammonium iodide O I -

41. O pt i c a l I s o m e r s S te r e o c he m i s t r y , en a ntiom e r s , s y mm e t r y a n d c h ir a lity a r e im pota nt c o n c e pt in the r a pe utic a nd t o x i c e f f e c t o f d r u g . 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. A optical 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 only be able to achieve a two point attachment w i t h the s a m e m o l e c ul e .

42. (-)-Adrenaline (+)-Adrenaline

43. E.g. Ephedrine & Psuedoephedrine MP = 37-39 1 gram/20 mL MP = 118-120 1 gram/200 mL Ep h ed ri n e ( E rythro) CH 3 NHCH 3 OH H H P s e ud o ep h ed ri n e ( T hreo) CH 3 NHCH 3 H H H O

44. The category of drugs where the two isomers have qualitatively similar pharmacological activity but have different quantitative potencies. O O O H O ( s ) - (- ) w arf ar i n O O H O O (R)-(+)warfarin

45. Geomet r i c I s o m e r i s m Geometric isomerism is represented by cis/trans isomerism resulting from restricted rotation due to carbon-carbon double b o nd or i n r i g i d r i ng s y s t e m. OH HO OH HO t r a n s - d i e t h y l s t i b es t e r ol Estrogenic activity c i s - d i e t h y l s t i b es t e r ol Only 7% activity of the trans isomer

46. Lon g m u i r i nt r odu ce d t h e t e r m i s o s t e r i s m i n 191 9 , w h i ch p o s tu l a t e d th a t t w o mo l e c u l e s or mo l e c u l a r f r a g m e nts c o n ta i ni n g a n i d e n t i c a l num b e r an d a r r ang ame nt of el e c t r on s hou l d h a v e s i m i la r p r op e r t i e s a nd t e r m e d a s i so s t e r e s . Isosteres should be isoelectric i.e. they should possess same total charge . B i o i s ost e r is m i s d e f i n e d a s c ompou n ds or g r oups th a t p o ss e ss near or equal molecular shapes and volumes, approximately the same distribution of electron and which exhibit similar physical properties. Th e y a r e c l as s i f i e d i n t o t w o t y p e s ., i ) C l a ss i ca l b i o s o s t e r e s ii ) N o n c l a s s i c a l b i oi s ost e r s .

47. C l a s si c a l B i o i s o s t e r e s They have similarities of shape and electronic configuration of atoms, groups a nd m ole c ul e s w h i c h t h e y r ep l a ce . The classical bioisosteres may be, U n i v a len t a t o m s a nd g r oups C l, B r , I i i ) C H 3, N H 2, - O H , - S H B i v a le n t a tom s a nd g r ou p s R - O - R , R - N H - R , R - S - R , RC H 2 R – C O NH R , - C O O R , - C O S R

48. T r i v a l e nt a t oms an d g r oups i)-CH=, -N= ii) –p=, -AS= T e t r a v a l e nt a t o m s a n d g r o ups = c = , = N = , = P = R i ng e q ui v a l e nt - C H = C H - , - S - , - O - , - N H , - C H 2 -

49. Application of Classical Bioisosteres in in drug design R e p l a c e m e n t o f – N H 2 g r o u p b y –C H 3 g r o u p . Car b u t am i d e Tolbutamide R= NH2 R= CH 3 ii ) R epl a c e m e n t o f –O H & - S H X G u a n i n e = - O H 6 - T h i o g u a n i n e = - S H R SO 2 NH CONH(CH 2 ) 3 CH 3 N H N N H 2 N H N

50. N o n c l a s s ic a l B i o i s o s t e r e s T h e y d o n ot ob e y the ste a r ic a n d e l e c t r on i c de f i n i t i on of c l a s si c a l isosteres. Non-classical biosteres are functional groups with dissimilar valence electron configuration. S pe c i f ic c h a r a c te r i stic s : El e c t r on i c p r ope r t i e s P h y s i c o c h e m i c a l p r ope r t y o f m olec ule S p a t i c a l a r ra n g em ent Fun c t i ona l m o i et y fo r b i ol o g i c a l a c t i v i ty

51. Examples H a l o g e ns C l , F , B r , C N E t h e r - S - , - O - Ca r b o n y l g r oup H y d r o x y l g r o up –O H , - N H S O 2R , C H 2 O H Catechol HO HO Catechol O S O O

52. A classical e.g. of ring Vs. noncycclic structure is Diethylstilbosterol & 17-ß oestradiol. O H H H H H O 1 7 - ß o e st r ad i o l . OH H O trans -diethylstibesterol