It has been recognized that while pharmacy students need a solid foundation in medicinal chemistry knowledge the extent cannot be the same as chemistry students may need. The pharmacy profession and the role of pharmacists in the modern healthcare systems have evolved quite rapidly in the world. The services that pharmacists provide the introduction of supplementary prescribing, provision of health checks, patient counselling and many others role. The impact of these recent changes is more innocuous in the area of pharmaceutical medicinal chemistry. As all drugs are chemicals, and pharmacy is mainly about the study of various aspects of medicinal drugs, including manufacture, storage, actions and toxicities, metabolisms and managements, chemistry still plays a vital role in pharmacy education. However, the extent at which chemistry used to be taught a couple of decades ago has certainly changed significantly. In this issue by compiling a medicinal chemistry book for Pharmacy students, which will cover general, medicinal chemistry and their synthesis in relation to drug molecules which cover the specific area.. Thus, the aims of our book are to provide the knowledge and overview of all core topics related to medicinal chemistry. We recognize that learning styles and levels vary from student to student, we can still try to strike the balance in terms of the level and standard at a point, which is not too difficult or not too easy for any students, but will certainly be student friendly. This book is dedicated to my parents and Family.
(Raj K. Prasad)
- Drug action results from the interaction of drug molecules with either normal or abnormal physiological processes. Drugs normally interact with targets (which they are proteins, enzymes, cell lipids, or pieces of DNA or RNA). The ability of a chemical compound to elicit a pharmacologic /therapeutic effect is related to the influence of its various physical and chemical (physicochemical) properties. Objective of Physicochemical s t u d y a r e -
- Functional group contributions to the physicochemical propertie
Physicochemical parameter affecting Drug Action
The influence of the organic functional groups within a drug molecule on:
- Water solubility.
- Lipid solubility.
- Steric factors.
1. Water solubility
- Majority of drugs’ molecules possess balanced solubility (have some degree of solubility in both aqueous and lipid media). Because there is a need for drugs’ molecules to move through both aqueous (plasma, extracellular fluid, cytoplasm, etc.) and lipid media (biologic membranes) in the biological system.
- Most Important Intermolecular Attractive forces Involved in Solubilization Van der Waals Attraction, Weakest intermolecular force (0.5-1.0 kcal/mole), Electrostatic, Occurs between nonpolar groups (e.g. hydrocarbons), highly distance and temperature dependent.
- Stronger (1.0 to 10 kcal/mole), Occurs electrostatically between electron deficient and electron excessive/rich atoms (dipoles)., Hydrogen bonding is a specific example of this bonding and serves as a prime contributor to hydrophilicity.
- Electrostatic between a cation/anion and a dipole, Relatively strong (1-5 kcal/mole), Low temperature and distance dependence, Important attraction between drugs’ molecule and H2O.
- Highly dissociable salts are more water soluble than less dissociable ones. Because the cation and anion must be able to separate and interact with water molecule
- Highly dissociable salts are formed from: strong acids with strong bases, weak acids with strong bases, and strong acids with weak base.
- Less dissociable salts are formed from: weak acids with weak base.
Prediction of Relative Solubility
- The relative solubility of a drug molecule is a function of the presence of both lipophilic and hydrophilic features within its structure, which serve to determine the extent of interaction of the drug molecule with lipid and/or aqueous phase
- Therefore, the relative solubility of a drug molecule is the sum of the contributions of each group and substituent to overall solubility.
Laboratory Estimation of Relative Solubility
- The relative solubility of a drug molecule can be determined in the laboratory.
- The ratio of the solubility of the compound in an organic solvent to the solubility of the same compound in an aqueous is called partition coefficient (P).
- Partition coefficient (P) is a measure of the solubility of a drug in aqueous and lipid phase.
Mathematical Estimation of Relative Solubility
- Solubility contributions (groups and substituents) are expressed as hydrophilic (negative value) or lipophilic (positive value) fragment constant.
Log Pcalc = Σπ
Where; Log Pcalc = log of partition coefficient and Σπ = sum of hydrophilic-lipophilic constants.
- Compounds with log Pcalc values greater than +0.5 are considered water insoluble (lipophilic, solubility is less than 3.3% in water) and those with log Pcalc values less than +5 are considered water soluble (hydrophilic).
Hydrophilic-Lipophilic Fragment Constants (π)
- Measures the hydrophobicity of a specific region on the drug. Log P is measured experimentally for a standard compound with and without a substituent (X).
- The following equation is used:
πx = log Px — log PH, Positive π = X more hydrophobic than H. Negative π = X less hydrophobic than H.).
- The relative solubility of a drug molecule greatly affects: Routes of administration, Absorption, Distribution, Elimination.
- Higher or smaller values of (Log P): Affect the Solubility in plasma (distribution), Lipid barriers (brain and neuronal tissues), Trapping (first site of loss).
- Contrary to propranolol, practolol has no CNS side effect.
- Drugs with Log P values close to 2 should be able to enter the CNS efficiently.
- Acid base properties of drug affect the Absorption (Un-ionized form (lipid soluble)), Distribution: (Ionized form (soluble in plasma)), Excretion, Drug-Receptor interaction, Drug- Drug incompatibility.
Acidic functional group
Basic functional group
- Any compound that undergoes biotransformation prior to exhibiting its pharmacological effects. That is chemical modification of a biologically active compound to form a new compound that, upon in vivo enzymatic attack will liberate the parent compound.
Classification of prodrugs
- Depending upon constitution of the constitution lipophilicity method of bio-activation and catalyst Involved; they are classified in two groups.
- Carrier – linked prodrugs
- Bio precursor prodrug
A. Carrier linked prodrug
- They are one where the active drug is covalently linked to an inert carrier. They are generally ester or amide.
- Such prodrugs have greatly modified lipophilicity due to the attached carrier. The active drug is released by hydrolytic cleavage either chemically or enzymatically. E.g. Ditrimethylethanoate groups of dipivaloyladrenaline hydrolyze to original-OH groups on adrenalin in presence of esterase enzyme.
- The carrier – linked prodrug consists of the attachment of a carrier group to the active drug to alter its physicochemical properties and then subsequent Enzymatic or nonenzymatic mechanism to release the active drug moiety. Depending upon the nature of carriers used the Classification: carrier- linked prodrug may further be classified into-
- Double prodrugs pro-prodrugs or cascade-latentiated prodrug-where a prodrug is further derivatized in a fashion such that only enzymatic conversion to prodrug is possible before the latter can cleave to release the active drug.
- Macromolecular prodrugs-where macromolecules like polysaccharides, dextrans, cyclodextrins, proteins, peptides and polymers are used as carrier
- Site- specific prodrugs-where a carrier acts as a transporter of the active drug to a specific targeted site.
- Mutual prodrug-where the carrier used is another biologically active drug instead of some inert molecule. A mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a promoiety for the other agent and vice versa. The carrier selected may have the same biological action as that of the parent drug and thus might give synergistic action.
The carrier drug may be used to overcome some side effects of the parents drugs as well.
- I Increased absorption
- I Injection site pain relief
- I Elimination of unpleasant taste
- I Decreased toxicity
- I Decreased metabolic inactivation
- I Increased chemical stability
B. Bioprecursor/Metabolic precursor
- This prodrug does not contain carriers but ready up on metabolism to induce the necessary functionally active species.
- Bioprecursor prodrugs rely on oxidative or reductive activation reactions unlike the hydrolytic activation of carrier-linked prodrug.
- They metabolized into a new compound that may itself be active or further metabolized to an active metabolite (e.g. amine to aldehyde to carboxylic acid). Examples-
- APPLICATION OF PRODRUG
- Pharmaceutical Application
- Change of physical form for preparation of solid dosage for
- Reduction of pain on injec
- Enhancement of drug solubility and dissolution rate.
2. Pharmacokinetic application
- Enhancement of bioavailability (lipophilicity),
- Prevention of presystemic metabolism,
- Prolongation of duration of action,
3. Pharmaceutical Applications
- Site-specific drug delivery
- Improvement of taste
- Reduction of the drug solubility in saliva.
- To lower the affinity of drug towards taste receptor Prodrug with improved taste
- Improvement of odour
- The odor of the compound depends upon the pressure of vapour’s liquid with high vapour pressure (& low B.P.) will have strong odour. E.g. ethylmercapto is one such drug which is foul smelling liquid at B.P.
- The drug useful in treatment of leprosy is converted into its phthalate ester.
- Diethyldithio-isopthalate which has high B.P. &odorle The prodrug is administered by rubbing on skin after absorption the esters are metabolized to parent drug by thioesterase.
Change of physical form of drug
- Some drugs which are in liquid form are unsuitable for formulation as a tablet especially if their dose is high.
- The method of converting such liquid drug in solid prodrug involves formation of symmetrical molecule having higher tendency to crystallize.
Example: - ester of ethyl mercapto & trichloro –ethanol.
Reduction in GIT irritation
- Several drug cause irritation & damage to the gastric mucosa through direct contact increased stimulation of acid secretion or through interference with protective mucosal layer.
- The NSAID’s especially salicylates have such a tendency. They lower gastric PH & induce ulcera
- Examples of prodrug design to overcome such problems of gastric distress are given below.
Reduction of pain on injection
Enhancement of chemical stability
- Intramuscular injections are particularly painful when the drugs precipitate in to the surrounding cell or when the solution is strongly acidic, alkaline or alcoholic.
- For example: the low aqueous solubility of clindomycin hydrochloride & alkaline solution of the phenytoin are responsible for the pain on injec
- This can be overcome by use of more water soluble prodrug of such agent like the 2-phosphate ester of clindomycine.
- A drug may stabilize either during its self-life or in the GIT when used orally.
- The prodrug design of such agent is also a good alternative to improve stability. An example of anti-neoplastic drug azacytidine.
- The aqueous solution of this drug is readily hydrolyzed but the bisulfite prodrug is stable to such as degradation at acidic PH & is more water soluble than the parent drug.
- The prodrug converts to the active drug at the physiological PH of 4.
- Enhancement of bio-availability (lipophilicity)
2. Prevention of presystemic metabolism
- A big advantage of increased bioavailability through increased lipophilicity is the reduction in new dosage. For example: Bacampicillin is as effective as ampicillin in just one-third of the dose of latter.
3. Reduction of toxicity
- Several corticosteroids undergo extensive first-pass hepatic metabolism which can be prevent by use of their esters or either prodrug For example: Triamcin
- Frequent dosing is required for drug having short biological half-live This can be overcome by use of both controlled release & prodrug approaches.
- An important objective of a drug design is to develop one which high active & low toxicity. Example of drug for systemic use with local
Publisher: BookRix GmbH & Co. KG
Publication Date: 07-06-2017
All Rights Reserved
Authors Raj K. Prasad (Gold Medallist), Ph. D. (P), working as Assot. Prof. at department of pharmaceutical chemistry, SIP, ALD, U. P.-India (AKTU Lucknow). He is also awardees of fellowships granted by AICTE Govt. of India and working in various pharmaceutical scientific research and development.