PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 23 (vi)Biological products.The three dimensional structures of proteins and nucleic acids is due to In a-helices,hydrogen bon exten from the hydroger atoms of polar N I units in peptide group to oxygen atoms of polar carbonyl units N-H…p…0=C Hydrogen bonding code.The dou honds The hydrogen bonds which selectively connect specific base the genetic message determines the specific order of amino acids in a protein. ralstepsbywhiC (Drug-Receptor interactions.Hydrogen bonding is also a secondary binding force in drug-receptor interactions. MOLAR REFRACTIVITY (MR) The molar refractivity is the molar volume connected by the refractive index.It represents size and polarizab ility of a fragment or molecule.Originally proposed oy Pauling and Pressmal as a parameter for the correlation of dispersion forces involved the binding of haptens to It is oftmthe rractived%山e molccular"cei，adh金 MR=(n2-1 MW n2+1 Since refractive index doesn't change much for organic molecules,the term is domi- nated by the MW and density.Larger MW,larger the steric effect and greater the density.A smaller MR for the same MW indicates stronger interactions in the crystal (larger density indicates that the packing is better due to stronger interactions) IONIZATION OF DRUGS The accumulation of an ionized drug in a compartment of the body is known as"ion trapping". The ionization of a drug is dependent on its pK and the pH.The pK is the negative Loga rithm of K.The K is the acidity constant of a compound,its tendency to release a proton.The ratio of ionized/non ionized drug may be determined by the Henderson-Hasselbalch relation ship, pH -pK,log ([A-VIHAJ) =log (fionizedl/[non ionized]) for acids pH-pK,log ([BV/[HB*]) =log([non ionized/[ionized]) for bases Fraction non-ionized=[HA]/([HA]+[A-]) =1/1+([A-/HA]))=1/1 +antilog(pH -pK )
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 23 C-8—N-CHEMI\CHE3-1.PM5 (vi) Biological products. The three dimensional structures of proteins and nucleic acids is due to hydrogen bonding. In α-helices, hydrogen bonds extend from the hydrogen atoms of polar N—H units in peptide group to oxygen atoms of polar carbonyl units. —N— ················ H ·O=C Hydrogen bonding Hydrogen bonds are extremely important in the chemistry of the genetic code. The double strands of DNA are held together by hydrogen bonds. The replication of DNA depends on hydrogen bonds which selectively connect specific base pairs, as do the several steps by which the genetic message determines the specific order of amino acids in a protein. (vii) Drug-Receptor interactions. Hydrogen bonding is also a secondary binding force in drug-receptor interactions. The molar refractivity is the molar volume connected by the refractive index. It represents size and polarizability of a fragment or molecule. Originally proposed by Pauling and Pressman as a parameter for the correlation of dispersion forces involved the binding of haptens to antibodies. It is determined from the refractive index, n, the molecular weight, and the density of a crystal, d. MR = ( MW 2 n n d − + 1 1 2 ) ( ) . Since refractive index doesn’t change much for organic molecules, the term is dominated by the MW and density. Larger MW, larger the steric effect and greater the density. A smaller MR for the same MW indicates stronger interactions in the crystal (larger density indicates that the packing is better due to stronger interactions). The accumulation of an ionized drug in a compartment of the body is known as”ion trapping”. The ionization of a drug is dependent on its pKa and the pH. The pKa is the negative Logarithm of Ka. The Ka is the acidity constant of a compound, its tendency to release a proton. The ratio of ionized/ non ionized drug may be determined by the Henderson- Hasselbalch relationship, pH – pKa = log ([A–]/[HA]) = log ([ionized]/[non ionized]) for acids pH – pKa = log ([B]/[HB+]) = log([non ionized]/[ionized]) for bases Fraction non-ionized = [HA]/ ([HA]+[A–]) = 1/1 + ([A–]/[HA])) = 1/(1 + antilog(pH – pKa))
24 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY This may be used to derive an Effective partition coefficient: would be predominantly in the sed form in Importance of ionisation of drugs 1.The lower the pH relative to the pK,greater is the fraction of protonated drug (protonated drug may be charged or uncharged) 2.weak acid at acidic pH:more lipid-soluble,becauses it is uncharged-the uncharged form more readily passes through biological membranes. Note that a weak acid at acidic pH will pick up a proton and become uncharged RCOO+H-RCOOH 3.ueahbaseatalhal line pH:more lipi because it is uncharged-the uncharged form more readily passes through biological membranes. Note that a weak base at more alkaline pH will lose a proton,becoming uncharged RNH→RNH2+Hr DRUG SHAPE the drug is an important factor in defining the nature of the drug-receptor inter shape of a co mentar ing reg ptor,typi lly a prote spec the which blocks biolo n or as For exa mple,consider acetylcholine or a synthetic analogue bethanechol (Urecholine). Interaction of these molecules with receptor (nicotinic or muscarinic cholinergic receptor)causes a physiol gica Iresponse i.e a decre ase in heart rate for instance.In st,a muscarin su asa山 nd even more tight than ac response may be .However,follow ng adr ogi as a result of receptor blo COMPLEXATION Complexes n compounds result from a donor-acceptor mecha ism (donating accepting e on or,rathe pair or Le is acid-b on(do mting-nccen ing pro ons Any non-m c ato whe cont in ar th ca the ceptor,o 05 the formation m fo also Complexes may be divided broadly into two classes depending on whether the acceptor compound is a metal ion or an organic molecule
24 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE3-1.PM5 This may be used to derive an Effective partition coefficient : Ex: Phenobarbital pKa is 7.4. It is evident that phenobarbital would be predominantly in the unionised form in acidic environment. Importance of ionisation of drugs 1. The lower the pH relative to the pKa greater is the fraction of protonated drug (protonated drug may be charged or uncharged) 2. weak acid at acidic pH : more lipid-soluble, becauses it is uncharged—the uncharged form more readily passes through biological membranes. Note that a weak acid at acidic pH will pick up a proton and become uncharged RCOO– + H+ → RCOOH 3. weak base at alkaline pH : more lipid-soluble, because it is uncharged—the uncharged form more readily passes through biological membranes. Note that a weak base at more alkaline pH will lose a proton, becoming uncharged RNH3 + → RNH2 + H+ The shape of the drug is an important factor in defining the nature of the drug-receptor interaction. The three-dimensional shape of the drug is thought to interact with a complementary structural binding region of the receptor, typically a protein. The specific nature of the interaction defines whether the drug acts as an agonist promoting a change in cellular function or as an antagonist, which blocks the receptor usually resulting in no direct biological effect. For example, consider acetylcholine or a synthetic analogue bethanechol (Urecholine). Interaction of these molecules with receptor (nicotinic or muscarinic cholinergic receptor) causes a physiological response i.e a decrease in heart rate for instance. Incontrast, a muscarinic antagonist such as atropine may bind even more tightly than acetylcholine to muscarinic receptor but causes no direct effect. However, following administration of antagonist a biological response may be observed as a result of receptor blockade. Complexes or coordination compounds result from a donor-acceptor mechanism (donatingaccepting electron or, rather, an electron pair) or Lewis acid-base reaction (donating-accepting protons). Any non-metallic atom or ion, whether free or contained in a neutral molecule or in an ionic compound, that can donate an electron pair, may serve as the donor. The acceptor, or constituent that accept the pair of electrons, can be a metallic ion or sometimes also a neutral molecule. In addition to “coordinate covalence” (i.e., bonds formed by the classical electron donor-acceptor mechanism), intramolecular forces can also be involved in the formation of complexes. Complexes may be divided broadly into two classes depending on whether the acceptor compound is a metal ion or an organic molecule.
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 25 COOH 0= COOH Heme a(found in cytochrome oxidase) ON Benzene-1.2.3-Trinitrobenzene complex A third class,the inclusion complexes,involve the entrapment of one compound in the molecular framework of another. Ho- O OH Inclusion Complex of B-Cyclodextrin (Host)and Toluene(Guest)
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 25 C-8—N-CHEMI\CHE3-1.PM5 A third class, the inclusion complexes, involve the entrapment of one compound in the molecular framework of another
26 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY The compounds that are obtained by donating electrons to metal ion with the formation of a ring structure are called"chelates".The compounds capable of forming a ring structure with a metal atom are termed as ligands.Most of the metals are capable of forming chelates or complexes (if the metal is not in a ring,the compound is called a metal complex),but the chelating property is restricted to atoms like N,O and S,which are electron donating. Applications of chelation The phenomenon of chelation is significantly involved in biological system and to some extent in explaining drug action. 1.Dimer rolisa chelating agent.Itis an effective antidote for o be used of poisoning due toa organic ars imony,gold and mercury 2.Penicillamine is an effective antidote for the treatment of copper poisioning because it forms water-soluble chelate with copper and other metal ions. 3.8-Hydroxyquinoline and its analogs act as antibacterial and antifungal agents by complexing with iron or copper. SURFACE ACTIVITY A surfactant is briefly defined as a material that can greatly reduce the surface tension of water when used in very low concentrations.This molecule is made up of water soluble (hydrophilic)and a water insoluble (hydrophobic)component. Hydrophobe Hydrophile and can be e tural fate ely high molecular weight synthetic alcohols.The hyd ups may be anionic,cationic or non-ionic in nature.The anionic hydrophiles are the carboxylates(soaps),sulphates,sulphonates and phos- phates.The cationic hydrophiles are some form of an amine product.The non-ionic hydrophiles associate with water at the ether oxygens of a polyethylene glycol chain.In each case,the hydrophilic end of the surfactant is strongly attracted to the water molecules and the force of attraction between the hydrophobe and water is only slight.As a result,the surfactant mol ecules align themselves at the surface and internally so that the hydropl hile end is toward the molecules is treferred to s micelleer aer e Because of this characteristic behaviour of surfactants to orient at surfaces and to form micelles,all surfactants perform certain basic functions
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 27 1.The bacterieidal activity of cationie quaternary ammonium com pounds such as cetrimide,cetylpyridinium chloride.ete,is explained through their surface activity property. 2.The anthelmentic activity ofhexylresorcinols is explained by its surface activity prop erty. 3.Steroidal hormones and barbiturates have surface activity properties. 4.Phenol and cresol act as disinfectants by denaturing the proteins of biological mem. 5.Foamin or a solid ,and dispersants are surfactants,which suspend,an liquid in water or some other liquid. PROTEIN BINDING hether the ak or strong acid or bas ote n, ipoprot pro in the in the pro n s.AGP inte te with as li Lind with both basic and neutral drugs.Protein binding values(%fraction bound)are nor mally given as the percentage of the total plasma concentration of a drug that is bound to all plasma proteins.In most cases,binding to plasma proteins is reversible,and the concentration of the free and bound species of the drug at equilibrium may be expressed as: Free drug[D,]+Free protein [P Drug/Protein complex D The total plasma concentration of the drug is expressed as the sum of the percent of free drug and the percent bound. Total plasma concentration [D,]=[D,]+[Dp] Binding me nents are made in ritro.at multiple drug plasma c centration levels in the clinically achiovable range A sinele (ave a relatively constant bound-to-free ratio over the range of plasma concentrations examined. In situations where drug binding is concentration dependant,two values are given,representing the percent bound values for the upper and lower limits of the range of concentrations examined Only single activity values,indicating an average,were used in the generation of this model. The protein samples used in binding studies are taken from healthy individuals because there is several disease states that can affect the protein binding of drugs.Examples include hepatic diseases that alter the concentration of albumin in the plasma and uremia that can cause changes in the binding affinity of some drugs. The extent to which a drug is bound to plasma proteins can affect the distribution of the drug in several ways