- The substitution on nitrogen can be referred to as a primary, secondary or tertiary, depending on the number of carbons attached.
- are formally derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group (these may respectively be called alkylamines and arylamines; amines in which both types of substituent are attached to one nitrogen atom may be called alkylarylamines).
Physical and Chemical Properties
- Amines from intermolecular hydrogen bonds
- Common to ammonia and amines. The nitrogen is at the apex of a pyramid and the other groups are at each apex of a triangular base.
Preparation of Amines
- Nucleophilic substitution on alkyl halides by ammonia
- The reaction of ammonia with an alkyl halide leads to the formation of a primary amine. The primary amine that is formed can also react with the alkyl halide, which leads to a disubstituted amine that can further react to form a trisubstituted amine. Therefore, the alkylation of ammonia leads to a mixture of products.
Reactivity of Amines
- The chemical behavior of amines is due to the tendency of N to share its lone pair of electrons
Basicity of Amines
- Amines in water solution exist as ammonium ions. In water, the ammonium salts of primary and secondary amines undergo solvation effects (due to hydrogen bonding) to a much greater degree than ammonium salts of tertiary amines.
- a simple organic compound containing both a carboxyl (—COOH) and an amino (—NH2) group.
- Amino acids are organic compounds that combine to form proteins.
- Amino Acids are the building block of peptides and proteins. Proteins play crucial roles in practically every biological process
- Amino acids which can’t be synthesized in the body are required in the diet
Amino Acids, Peptides and Proteins
- Many amino acids joined by peptide bonds form a polypeptide chain. An amino acid unit in a polypeptide is called a residue.
- A polypeptide chain has direction because its building blocks have different ends; the a-amino and the a-carboxylic group. By convention, the amino end (N terminal) is taken as the beginning of a polypeptide chain.
- Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs.
- Longer chain peptides are called proteins.
- Proteins can be formed of thousands of amino acids residues.
Sites of Drug Action
- When researchers first began to isolate active ingredients from plants it was not known how they would affect the body
- Gradually, chemical structure started to be linked to biological activity (structure activity relationship)
- A receptor is a site where a drug binds and then the receptor brings about a physical response
- Receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems
- It is described as an agonist
- In the case of a muscle relaxants the receptor was identified as being in a family called the cholinergic receptors
- A ligand is a protein that attaches (binds) to another protein called a receptor; receptor proteins have specific sites into which the ligands fit like keys into locks.
- Drugs which block active sites without giving rise to a response are called antagonists
- Other active sites where drugs can bind include enzymes
- Both receptors and enzymes are made up of proteins
- Proteins contain a variety of functional groups including acidic, neutral, basic, polar, non-polar and ionized
- Drugs will form interactions with the functional groups lining the active site of the receptor or enzyme
- Drugs are recognized by their targets by a number of types of interaction
- Drugs binding at the same time but in a different way can give rise to different effects
- Knowledge of interactions allows us to work out how a drug binds
Types of Interaction-Biological Interactions
Van der Waals Bonding
- Exists between all atoms
- They arise because the electron cloud associated with an atom or molecule is constantly moving so that the electrons are never evenly distributed.
- Small, local, instantaneous dipoles occur
- Dipoles behave like small magnets will attract one another
- Van der Waal’s forces are weak
- The larger the surface area and the larger the number of electrons in the molecules the larger the interactions will be
Dipole- Dipole Interactions
- In many molecules there are permanent dipoles due to the difference in electronegativity of atoms sharing chemical bonds
- Dipole-Dipole interactions result when two dipolar molecules interact with each other through space. When this occurs, the partially negative portion of one of the polar molecules is attracted to the partially positive portion of the second polar molecule.
- Hydrogen bonds are special types of dipole interactions
- They are formed when there are functional groups present which contain N, O or S and there is H linked to one of these atoms
Hydrogen Bond donor and acceptor
- The H is effectively shared between the donor and acceptor
- Hydrogen bonds are directional
- Hydrogen bonds are important not only in drug-target interactions but also in holding the structure of proteins and DNA
- Many drug molecules will have ionized functional groups
- The charges on these groups will bind with permanent dipoles
- This type of bonding plays a key role in the water solubility of a drug
- Ionic bonds formed between species with opposite charges are strong and can act across long distances
- Drugs are often ionized and the active sites in receptors contain charged groups (carboxylic acids and amines)
- The majority of the bonds within drugs and their targets will be covalent
- A small number of drugs can also make covalent bonds with their targets.
- Covalent bonds are strong and hence drugs forming them will usually be permanently bound to their target
- Some anti-cancer drugs alkylate DNA in tumor cells.
- The alkylated DNA cannot function and hence the cell dies
Role of water
- Any system will adopt the lowest energy configuration
- In chemical systems this will mean that the participant will form as many bonds as possible of the strongest type
- Water will dissolve and solvate other polar molecules
- A shell of water is formed around polar molecules which prevents them from interacting with each other
- Life on earth uses water as a solvent
- deals with the relations between heat and other forms of energy (such as mechanical, electrical, or chemical energy), and, by extension, of the relationships between all forms of energy.
- The energy can be decreased by merging the drops into one larger one
- The water squeezes the non-polar molecules together- they do not have a strong affinity for each other but water does for itself
Shape and Isomerism
- In order for drugs to fit an active site they must first have the correct shape
- Usually one isomer of a drug will have the required activity
- Most natural molecules have stereocentres and occur in single optical isomers
- Drugs should be administered as single entantiomers as the mirror images may have other effects
Importance of correct stereochemistry
- Thalidomide was developed in the 1950’s as a sedative and found use being prescribed to counter nausea in pregnancy
- It was found that the drug caused devastating abnormalities to the children of mother’s taking thalidomide- the most common being limb malformation
- Further investigation showed that the S isomer causes the sedation whereas the R isomer causes birth defects
- Reactions occurring in the body
- Enzymes are macromolecular biological catalysts that accelerate chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products.
- In order for biological chemistry to work, there are complex catalysts called enzymes which control the reactions
- The reaction of carbon dioxide with water is necessary to help remove carbon dioxide from tissues into the blood stream to be returned to the lungs.
- This reaction would be too slow to sustain life if uncatalyzed
- Carbonic Anhydrase enzyme speeds the reaction rate up by over 1 million times
- An enzyme will only catalyze a certain type of reaction using certain substrates
Enzymes work by means of
- Binding the substrate
- Binding the molecules which help with the reaction
- Doing the reaction
- Releasing the product
Roles of Enzymes
- The recognition and catalytic abilities of enzymes come about through specific interactions with the functional groups in the active site
- Aby drug containing an ester which enters the bloodstream is normally hydrolyzed by esterase
- Esterases have the ability to bind a wide range of substrates
- Pro-drugs are often activated by esterases
- The enzyme works by binding the substrate and a molecule of water
- Acidic and basic groups in the active site catalyze the reaction
Metal Containing Enzymes
- Metal-activated enzymes associate loosely with ions to adopt structural shapes
- Metalloenzymes contain tightly bound metals which can do the following:
- Bind substrates in specific orientations
- Carry out RedOx reactions
- Stabilize negative charges
Enzymes and Drugs
- Not only are enzymes important in maintaining the reactions in the body, they are also important in regulating drug actions
- Enzymes bring about drug metabolism
- Enzymes activate pro-drugs
- Enzymes can themselves be drug targets
- Some diseases states arise through the malfunctioning of an enzyme
- If the body is attacked by foreign invaders, these can be halted by interference with their enzymes
- Enzymes are generally targeted by inhibitors which prevent them from working
- These are molecules which can bind in the enzyme and prevent substrates or cofactors from binding
- The reaction which the enzyme would normally catalyze cannot then take place
- It is found that some enzyme inhibitors block the active site by binding a similar way to substrate
- Some inhibitors will bind to the enzyme permanently by making covalent bonds to it
- Reversible inhibition comes on quickly, as soon as the concentration of inhibitor near the enzyme rises
- Irreversible inhibition may take time to come on as it may take time for the covalent bonds to form
- Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change involving protein dynamics.
- The binding is an equilibrium
- Aspirin is a pro-drug for salicylic acid
- Salicylic acid inhibits the enzyme cyclooxygenase (COX)
- COX is important in the body for the biosynthesis of prostaglandins- these are responsible for pain and inflammation
- By inhibiting the production of prostaglandins, pain can be alleviated
Pharmacokinetics and Pharmacodynamics
- In pharmacokinetics phase the compound with the best binding affinity for a target in vitro is not necessarily the best drug
- For the drug to be useful, it must be observed in sufficient quantity, must reach its target site, must be distribute into target tissue and should not be metabolized too quickly or extensively
- The higher the lipophilicity of a drug, the higher its membrane permeability and the higher its metabolic clearance
- refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene.
- It is important to balance lipophilicity with metabolic susceptibility
- Benzyl penicillin is prone to acid hydrolysis due to influence of acyl side chain
- because of the high reactivity of the β-lactam ring, a penicillin can react with water under acidic conditions
- The blood-brain barrier (BBB) is composed of tightly packed endothelial cells that restrict the ability of substances carried in the bloodstream from passing through.
- While protecting the bodies central nervous system (CNS), this presents significant difficulties for the development of drugs specifically designed to target problems within the CNS. Conversely, it should be remembered that researchers developing drugs targeting non-CNS targets will want to ensure that these drugs do not cross the BBB otherwise there will be an elevated risk of side-effects.
- A prodrug is a compound which is inactive when administered but gets converted in the body to the active form through biotransformation
- a biologically inactive compound which can be metabolized in the body to produce a drug.
- Usually produced by attachment of the active drug to a promoiety through a metabolically labile linkage
- The prodrug must really be converted in the body to the active form and the promoiety used must not itself be toxic
- Prodrugs depend on endogenous enzymes to transform them to the active species
Creation of a Prodrug
- Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body. … A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target.
- If a drug needs to cross the blood brain barrier, it needs to be lipophilic or to be able to utilize the carrier proteins in the cell membrane which exists to transport amino acids into the cells
- It is used for Parkinson’s Disease as a prodrug of the natural neurotransmitter dopamine
- Dopamine is too polar to cross the BBB and is therefore not useful as a therapeutic agent
- However, levodopa is an amino acid and crosses BBB
Prolong Duration of Action
- Prodrugs can be used to prolong the duration of action
- Prodrugs can be used to make drug more acceptable to take
- Prodrugs can also be used to prevent unpleasant side effects produced by the parent drug
Beta Lactam Antibiotics
- Antibiotics are one of the most frequently prescribed medications
- A medicine (such as penicillin or its derivatives) that inhibits the growth of or destroys microorganisms.
- Selective toxicity to the pathogen is the key concept in antibiotic therapy
- Approximately half of worldwide sales of antibiotics are due to B-lactams
- An antibiotic is a type of antimicrobial substance active against bacteria and is the most important type of antibacterial agent for fighting bacterial infections. Antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria.
- β-lactam antibiotics are a class of antibiotic consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures. This includes penicillin derivatives, cephalosporins, monobactams, carbapenems and carbacephems.
- Discovered in 1929 by Fleming
- Consist of a b-lactam ring = cyclic amide
- Fused with a substituted thiazolidine ring
- Produced by fermentation of Penicillium Chrysogenum
- Benzylpenicillin (penicillin G) obtained when phenylacetic acid in medium
- Phenoxymethylpenicillin could be obtained if phenoxyacetic acid is added to medium
- Peptidoglycan is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of most bacteria, forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid.
Action of Transamidase
- Transamidase is an enzyme that in humans is encoded by the PIGK gene. This gene encodes a member of the cysteine protease family C13 that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis.
Problems with Penicillin
- Benzylpenicillin is acid-sensitive, not active over wide spectrum of bacteria and sensitive to b-lactamases
- Medicinal chemists have set out to try to overcome these disadvantages through making penicillin analogues
- Activity against Gram-Ve bacteria is related to the ability of the penicillin to cross the cell wall
- Polar groups on the side chain increase penetration across the outer membrane of Gram-ve bacteria, especially if group is on the alpha carbon to the carbonyl
Problems with Beta Lactamases
- Penicillin-resistant bacteria produce b-lactamases which catalyze the hydrolysis of the b-lactam bond, causing inactivation of the penicillin
- Methicillin is not orally-active due to the absence of EWG in side-chain ‘
- An isoxazolyl ring system provides bulky group plus acid stable
Other Approaches to Beta Lactamase Issue
- Clavulanic acid can be given with penicillin to treat penicillin-resistant bacteria
- Cephalosporins has a resistance to acid and hydrolysis and lactamase
- Carbapenems are a class of beta-lactam antibiotic that are active against many aerobic and anaerobic gram-positive and gram-negative organisms. Thienamycin was the first carbapenem to be discovered in 1976.
- Carbapenems are a class of highly effective antibiotic agents commonly used for the treatment of severe or high-risk bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant bacterial infections.