Physicochemical properties of a drug Dr. Ahmed Ali Al-Karmalawy Presented by Dr. Ahmed Ali Al-Karmalawy 1 1

Lecture 6

Phosphorylation: The organophosphorus insecticides form covalent bond with acetylcholinesterase enzyme (AChE) through phosphorylation of the hydroxyl group of serine amino acid in the enzyme. Inactivation of the enzyme leads to accumulation of acetylcholine in the body, causing toxic effect. These drugs are nonspecific and attack the acetylcholinesterase enzymes of both mammals and insects.

Acylation: Transpeptidase enzyme is responsible for cell wall formation of the bacterial cell. This enzyme is irreversibly acylated by four membered β-lactam ring of penicillins and cephalosporins antibiotics thereby inhibiting bacterial cell wall formation. Penicillins and cephalosporins are specific drugs, as they react with bacterial transpeptidase enzyme which is not present in human.

2. Stereochemistry of the drug molecule: The spatial arrangement of functional groups in a drug affects the way in which drug molecule interacts with the target site (receptor). The human body is considered as asymmetric environment. Thus, the functional groups should be directed in the proper three-dimensional orientation to produce the exact interaction with the receptor.

Since the drug molecules interact in a three dimensional manner with the receptor site; thus drug molecules exhibiting more than one stereoisomeric forms would interact differently with the receptor site, especially when the chiral center (or centers) is (or are) involved in the binding with the active site of the receptor.

Drugs with one chiral center (levo (-) and dextro (+) rotatory enantiomers): The natural chemical transmitter epinephrine is a classical example for this kind of stereochemistry. Epinephrine molecule contains one chiral carbon to which an OH functional group is attached and this OH if properly oriented is involved in the interaction with adrenergic receptors. Practically, (-)epinephrine, the natural enantiomer, is 15 times more active than the (+)epinephrine.

b) Drugs with geometric isomerism & cis- and trans-isomers (Z and E isomers): Drugs with restricted bond rotation due to carbon-carbon double bonds (alkenes or olefins) can produce stereoisomers referred as geometric isomers. Example: The antihistamine H1-receptor antagonist triprolidine. The E-isomer of triprolidine is more active both in vitro and in vivo than the Z-isomer ((indicating that the distance between the pyridine and pyrrolidine rings is critical for binding to the receptor)).

cis and trans isomers

c) Drugs showing conformational isomerism: Dynamic rotation about one or more single bonds results in a type of isomerism known as conformational isomers. Such bond rotation results in non-identical spatial arrangement of atoms in a molecule. Changes in spatial orientation of atoms due to bond rotation results in different conformations (or rotameters).

Pharmacophores The pharmacophore; is a structural unit in the drug which is essential for the interaction with the receptor. On other words; it is the part of the molecule that contains the functional groups that actually binds to the receptor. For most of drug groups there exist structure features common to all members of the same class of drugs and imparts pharmacological action.

Structure-Activity Relationship (SAR) The aim is to discover which parts of the molecule are important to biological activity and which are not. To improve the pharmacokinetics and pharmaco- dynamics of the drug by changing the duration of action, potency, stability, lipophilic-hydrophilic balance and others properties between different members of the same class of drugs of similar pharmacological activity.

Prodrugs Inactive derivatives of drugs (in vitro) which are converted to active derivatives (in vivo) i.e. after metabolism. Prodrugs are also called carrier prodrugs and labile, reversible, or bioreversible derivatives of drugs. The aim of prodrug development is, in most cases, to solve specific pharmaceutical or pharmacological problems. Drug + Carrier → Drug-Carrier (Prodrug) in vivo→ Drug + Carrier

In the design of prodrugs the following factors should be considered: 1) The linkage between the drug molecule and the carrier moiety is usually covalent bond. 2) The prodrug is inactive or less active than the parent drug. 3) The linkage between the parent drug and the carrier moiety must be cleaved in vivo, by either chemical or enzymatic ways; this means that the prodrug is a reversible or bioreversible derivative of the drug. 4) The released carrier moiety must be nontoxic and, preferably, biologically inactive. 5) The generation of the drug by virtue of its release from the inactive carrier must take place with rapid kinetics to ensure effective drug levels at the site of action and to minimize either direct prodrug metabolization or gradual drug inactivation. 6) The synthesis of the prodrug should not be significally more expensive than that of the drug. (One step synthesis must be preferred and cheap moieties should be utilized).

The main objectives of prodrug formation are as follows: 1- Adjunct to pharmaceutical formulation as the preparation of chloramphenicol ester with palmitic acid to mask the very bitter taste of chloramphenicol to have oral suspension form for infantile use.

2- Increase site specificity as the conversion of the antibacterial drug sulfathiazole to succinylsulfathiazole to act on the large intestine. Succinic or phthalic acid esters of sulfathiazole are poorly absorbed from the intestine and thus, reach the large intestine, where they are subjected to hydrolysis by colon enzymes to sulfathiazole and the acid.

Lead drug “Prototype” The discovery of the antibacterial activity of sulfanilamide opened the way to synthesize other derivatives from sulfanilamide known as sulfa drugs with more potent antibacterial activity and better therapeutic index. Thus, sulfanilamide is described as 'Lead compound' or 'Prototype'.