Unit 1-Introduction to Medicinal Chemistry.pptx

Sem 4

1. INTRODUCTION TO MEDICINAL CHEMISTRY By Sivabalan Kumar M.Pharm, MRPH.

2. OBJECTIVES Introduction To Medicinal Chemistry 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. Drug Metabolism Principles- Phase I And Phase II. Factors Affecting Drug Metabolism Including Stereo Chemical Aspects.

3. INTRODUCTION TO MEDICINAL CHEMISTRY Medicinal chemistry is about designing and creating compounds for treating diseases. It involves identifying potential drugs, improving their effectiveness and safety, and optimizing the process for making them in large quantities. Medicinal chemistry was defined by International Union of Pure and Applied Chemistry (IUPAC) specified commission as, " it concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level ".

4. INTRODUCTION TO MEDICINAL CHEMISTRY " hit " refers to a chemical compound , that has shown potential biological activity against a specific target . " hit to lead " process involves improving and refining this compound to make it even more effective and safe for potential use as a medicine. “ Lead optimization ” means making a good potential medicine even better .

5. History and development of medicinal chemistry Prehistoric Times (8000 BC): People believed in spirits and practiced primitive surgery like trepanning to treat illnesses. Trepanning- a surgical procedure in which a circular piece of bone is drilled and excised, most commonly from the human skull.

6. History and development of medicinal chemistry Ancient Egypt (2000 BC): Egyptians used compressions on a wound to stop bleeding , had obstetrics and gynecology specialists, and used plant-based substances like opium for treatments . Ancient Greece and Rome (450 BC - 300 AD): Greek philosopher Hippocrates, the father of modern medicine, emphasized a scientific approach to medicine. The Romans realized that there was a link between dirt and disease . To improve public health, they built aqueducts to supply clean drinking water and sewers to remove wastes safely. Middle Ages (500 - 1400 AD): Medicine was heavily influenced by religion ( Sickness was believed to be a punishment from God for sins committed ), and treatment mainly involved prayers, herbal remedies, and surgical procedures.

7. History and development of medicinal chemistry Arabic medicines (700 - 1500 AD): Texts from Greece and Rome were translated into Arabic and studied by Islamic scholars. Islamic physicians began to use the regulation of diet, exercise and the prescription of medicinal herbs in the treatment of their patients. Arabic pharmacists became skilled in the formulation of medicines from plants and minerals . Even though they did not know about microbes, they used alcohol to clean wounds which healed better and did not become infected. 18th - 19th Centuries: Industrial revolution led to crowded, unsanitary living conditions. Medical advances included vaccinations and the understanding of infections caused by bacteria, leading to the birth of the pharmaceutical industry. 20th Century: Significant increase in life expectancy due to the development of antibiotics (like penicillin) and insulin , improving air quality, better hygiene, and continuous discovery of new medicines by pharmaceutical laboratories.

8. PHYSIOCHEMICAL PROPERTIES Physiochemical properties of chemical compounds influence their pharmacological or therapeutic effects. Ionization Solubility Partition Coefficient Hydrogen bonding Protein binding Chelation Bioisosterism Optical and Geometrical isomerism.

9. Ionization Ionization refers to the process where a neutral molecule gains or loses charged particles (ions) like electrons or protons , resulting in a charged molecule. This charge affects the molecule's behavior in chemical and biological environments. Examples: Water, a neutral molecule , can ionize into a positively charged hydrogen ion (H⁺) and a negatively charged hydroxide ion (OH⁻). This ionization process is essential for various chemical reactions and biological processes .

10. Solubility: Solubility influences drug absorption, distribution, and bioavailability . Highly soluble compounds are more likely to be absorbed in the gastrointestinal tract Example: Penicillin G is an antibiotic used to treat various bacterial infections. It has good solubility , allowing it to dissolve readily and be absorbed effectively in the gastrointestinal tract after oral administration, ensuring its therapeutic efficacy.

11. Partition Coefficient The partition coefficient (P) is a measure of how a chemical compound distributes itself between a hydrophilic (water-loving) environment and a hydrophobic (oil-loving) environment. It helps us understand how a substance interacts with both water and oil. Example: molecule X has a concentration of 1000 units in an organic solvent and a concentration of 100 units in water. The partition coefficient (P) for X is ( P = 1000/100 = 10 ). This indicates X has a higher affinity for the organic solvent.

12. Hydrogen bonding Hydrogen bonding is a special connection between atoms. It happens when a hydrogen atom in one molecule forms a bond with another atom, like oxygen or nitrogen. There are two main types: 1. Intermolecular Hydrogen Bonding: 2. Intramolecular Hydrogen Bonding:

13. PROTEIN BINDING Depending upon whether the drug is weak or strong acid or base, or is neutral, it can, bind to a single blood protein, to multiple proteins. The most significant protein involved in the binding of drugs is albumin. Drugs with high protein binding activity values tend to have a greater half life compared to those with lower values.

14. CHELATION The compounds that are obtained by donating electrons to metal ion with the formation of a ring structure are called chelates.

15. BIOISOSTERISM Bioisosterism is a concept in drug design where chemically similar groups or atoms are substituted within a molecule to improve its biological activity or other properties.

16. OPTICAL AND GEOMETRICAL ISOMERISM Molecules' properties depend on how their parts are arranged. There are two types of isomerism: 1. Optical Isomerism: Some molecules look the same but act differently in biological systems . This is due to their shape and reactivity at specific points .

17. 2. Geometric Isomerism: Geometric isomerism is when two molecules have the same atoms but differ in their arrangement around a double bond or in a ring, which can affect their properties and how they interact with other substances.

18. DRUG METABOLISM Drug metabolism is the process which describes biotransformation of drugs in body so that they can be easily eliminated.

19. Phase I Metabolism: This phase typically involves enzymatic reactions, such as oxidation, reduction, and hydrolysis, which modify the drug's structure. This can increase the drug's polarity and prepare it for phase II metabolism. PHASE 1 REACTION: OXIDATION: Oxidation introduces oxygen or removes hydrogen

20. 2. REDUCTION: Reduction adds hydrogen

21. 3. HYDROLYSIS: The chemical breakdown of a compound due to reaction with water.

22. CONJUGATION REACTIONS OR PHASE II REACTIONS In this phase, the drug or its phase I metabolites are conjugated with endogenous, hydrophilic molecules like glucuronic acid, sulfate, or amino acids. These conjugation reactions further increase the drug's water solubility and enhance its elimination from the body.

23. Factors affecting drug metabolism 1. Genetic Factors: Differences in genes among individuals can impact how drugs are metabolized, potentially leading to variations in drug response, including therapeutic effects and the risk of toxicity. 2. Physiological Factors: Various physiological factors, such as age, hormonal changes, sex differences, pregnancy, intestinal microflora changes, liver diseases, and nutritional status, can influence how the body processes drugs. 3. Pharmacodynamic Factors: Drug dosage, frequency of administration, route of delivery, as well as drug distribution in tissues and binding to proteins, all play a role in drug metabolism.

24. Factors affecting drug metabolism 4. Environmental Factors: Factors like competition between drugs and other foreign substances for metabolizing enzymes, as well as enzyme inhibition or poisoning by toxic chemicals, can alter the rate of drug metabolism. 5. Stereochemical factors: Stereochemistry is important in how a drug interacts with its target receptors and can affect how it's metabolized. In some cases, when a drug is given as a mixture of two mirror-image forms (enantiomers), one may be more effective or have different effects than the other . For example, in the case of (+)-alpha-propoxyphene, it's a painkiller , while (-)-alpha-propoxyphene is a cough suppressant . Typically, one enantiomer is more potent than the other in these mixtures.