PHRD 521 Medicinal Chemistry Lecture 1 (Functional Groups and Stereochemistry) PDF

PHRD 521 Medicinal Chemistry Fall 2024 Dr.Radhika V. Kumar Office: PSC –612B Email: [email protected] 1  Drug Discovery Medicinal Chemistry...

PHRD 521 Medicinal Chemistry Fall 2024 Dr.Radhika V. Kumar Office: PSC –612B Email: [email protected] 1  Drug Discovery Medicinal Chemistry Stages in Drug Discovery Process Reference : Lombardino, J., Lowe, J. The role of the medicinal chemist in drug discovery — then and now. Nat Rev Drug Discov 3, 853–862 (2004). 2 Importance of Medicinal Chemistry in PharmD Curriculum Reference : Khan MO, Deimling MJ, Philip A. Medicinal chemistry and the pharmacy curriculum. Am J Pharm Educ. 2011;75, 8, 161 3  Topics of Importance Functional Groups (Lecture 1) Stereochemistry (Lecture 1) Structure Activity Relationships (Lecture 2) Drug Targets (Lecture 3) Drug Target Interactions (Lecture 3) 4  Functional Groups Key Objectives Identify the individual functional groups in the structure of a given drug molecule. Importance of functional group in a given drug molecule (electronic, solubility, and steric effects) Influence of functional groups in contributing to activity (Pharmacology and Toxicological outcomes) on a given target Identify the nature of the chemical properties of the functional groups present in amino acids and proteins ( drug targets/receptors ) 5  Functional Groups Functional groups provide specific properties and behaviors that allow drug molecules to exert their desired pharmacodynamic and pharmacokinetic effects. Functional groups on drug molecules play a significant role in: Water/ Lipid solubility Route of administration Interaction with targets Mechanism of action (Pharmacodynamics) Fate of the drug : ADME (Pharmacokinetics) Adverse effects / drug interactions (Toxicology) 6  Review : List of Common Functional Groups in Drug Molecules (Posted on Brightspace) Note: “The document is a general list, not a comprehensive or all inclusive one” 7 Lets Practice !! 8 Identify all possible functional groups in the structure below ! 4 2 1 Answers!! 3 1. Carboxylic Acid 5 2. Pyrrolidine Ketorolac 3. Pyrrole Use : Non-Steroidal Anti-inflammatory Drug (NSAID) 4. Ketone 5. Aromatic Ring/ Benzene 9 Identify all possible functional groups in the structure below ! Answers !! 4 1. Phenol 2. Amine (primary) 5 3 1 3. Amide 4. Carboxylic Acid 6 5. 𝛽-lactam ring (cyclic amide) 2 6. Thioether Amoxicillin Use: Antibiotic 10 Identify all possible functional groups in the structure/s below ! 4 2 3 2 1 1 Acetylcholine 1 4 Use : Neurotransmitter, parasympathomimetic Anastrozole (Arimidex) Use : Anti-neoplastic, Breast Cancer, Aromatase Inhibitor Answers!! Answers!! 1. Ester 1. Nitrile/ Cyano 2. Quaternary Amine 2. Triazole 3. Phenyl 4. Isopropyl 11  Effects of Functional Groups Steric Effects Functional group/s have a finite size or steric dimension. Contributes to the conformation or three-dimensional shape of a given drug molecule. May provide therapeutic benefits for a drug molecule : Increased selectivity for its biological target Enhanced binding interactions with its biological target Alteration of pharmacokinetics Methyl group Non-selective Cholinergic Agonist Selective Cholinergic Agonist (binds and acts on both nicotinic and (binds and acts only on muscarinic muscarinic receptors) receptors) Relatively shorter duration of action Relatively longer duration of action 12  Effects of Functional Groups Electronic Effects Electronegative atoms that tend to inductively attract electrons from usually adjacent carbon atoms in drug molecule contributing to a dipole (partial charge separation between the atoms in a functional group) Ex: Halogens (-F,-Cl,-Br,-I), oxygen (-O-) , and nitrogen (-N=) These dipoles play an important role in enhancing water solubility of a drug molecule to interact with its biological target. Penicillin V- Stable in Acidic Stomach Environment – Penicillin G- Inactivated in Acidic Stomach due to the ether oxygen taking the electrons away from Environment – due to the electron shift from carbonyl oxygen preventing the attack on the beta- carbonyl oxygen attacking the beta- lactam ring lactam ring 13  Effects of Functional Groups Solubility Effects Refers to both water and/or lipid solubility of a drug molecule It is the sum of contributions of each functional group present within the drug structure. Overall solubility contribution of a specific functional group varies depending on adjacent groups ( needs to be a balance ) Lipid-Soluble Functional Groups Often referred to as Hydrophobic or Lipophilic functional groups Enhance lipid solubility of a drug molecule Does not tend to ionize or form hydrogen bonds. Water-Soluble Functional Groups Often referred to as hydrophilic functional groups. Enhance the water solubility of a drug molecule through ionization and/or its ability to form hydrogen bonds Acidic and basic functional groups are capable of ionization (negatively or positively charged) enhancing the water solubility of a drug molecule. Ex: Acidic Functional Groups and Basic Functional Groups 14  Water Solubility Effect Role of Hydrogen bonding (H-bonds) in Functional Groups A hydrogen bond is a specialized type of interaction. H-atom serves as a bridge between two electronegative atoms. Functional groups fall into 2 categories for H- bonding Hydrogen Bond Donor (HBD) wherein the hydrogen atom is covalently bound to one atom. Hydrogen Bond Acceptor (HBA) wherein the hydrogen atom is non-covalently bound to one atom. “Lipinski rule” states that biologically active drug molecules generally tend to adhere to: No more than 5 hydrogen bond donors (HBD) No more than 10 hydrogen bond acceptors (HBA) Oxygen and Nitrogen are the most common hydrogen bond donors and acceptors. Water molecule can act as both a hydrogen bond donor and an acceptor Functional groups that can form H-bonds with water, contribute to increased solubility. 15  Example Identify potential # of HBA and HBD interactions of Benazepril (Lotensin) with water HBD (unionized) HBA HBA (unionized) HBA HBA HBA H-Bonding Notes : Amines Could be both HBD and HBA depending on the pH Tertiary amines are mainly HBA’s (lack of H) Count the # of O’s and N’s for Hydrogen bonding ( Lipinski Rule ) 16  Acidic and Basic Functional Groups Sulfonamide Celecoxib (Celebrex) (pKa-10.7) Levothyroxine (pKa-6.7) Tetrazole Ibuprofen (Motrin) Imide (pKa- 5.2) Valsartan (Diovan) Phenytoin (Dilantin) (pKa-4.9) (pKa-8.33) 17 NOTE: Adjacent functional groups may have an influence on the acidity or basicity of the drug molecule  Acidic and Basic Functional Groups Gabapentin (Neurontin) pKa’s 3.8 and 10.7 Imine Guanidine/ Diazepam (Valium) pKa 3.4 Guanidino Phenazopyridine (Pyridium) pKa 5.2 Imidazole Cimetidine (Tagamet) pKa 6.8 Atenolol (Tenormin) pKa 9.6 18 NOTE: Adjacent functional groups may have an influence on the acidity or basicity of the drug molecule 19 Lets Practice !! 20  Diphenhydramine 1. Identify the hydrophilic functional group indicated in the drug molecule. Amine (tertiary) 2. What is the nature ( acidic/ basic / neutral ) of the functional group indicated in the structure of diphenhydramine ? Basic 3. Identify the potential hydrophobic functional group in the drug molecule. Aromatic ring/Benzene/Phenyl 4. Identify functional group/s that are capable of H-bonding with water/ drug target ? Amine, Ether 5. Which of the functional groups identified in 4 is HBA or HBA ? Both are HBA’s 21  The functional group indicated in the structure of Acetylcholine is a) Hydrophilic Acetylcholine b) Hydrophobic v The functional group indicated in the structure of Ciprofloxacin is a) Hydrophilic Ciprofloxacin b) Hydrophobic The nitrogen in the piperazine ring in the structure v of Ciprofloxacin is a) HBA only b) HBD only Ciprofloxacin c) Both HBA and HBD Lipinski Rule d) Neither HBA or HBD 22  The nature of the functional group indicated in the structure of Estrone is Estrone a) Acidic b) Basic c) Neutral d) Both Acidic and Basic The nature of the functional group indicated in the structure of Amitriptyline is a) Basic b) Acidic Atenolol c) Neutral d) Both Acidic and Basic The nature of the functional group indicated in the structure of Loperamide is a) Acidic (None) b) Basic ( Piperidine ) Loperamide c) Neutral ( tertiary alcohol and tertiary amide ) d) Both Acidic and Basic 23  Stereochemistry Refers to spatial (3D) arrangement of atoms Also referred to as Stereoisomers Asymmetric center or chiral center * Could be none, 1 or more in drug molecules Example Configurational isomers Enantiomers : 1 or more chiral center, non- * superimposable mirror images 2 isomers Similar physical and chemical properties (enantiomers) Diastereoisomers : More than 1 chiral center, non- Ibuprofen 3 4 superimposable non-mirror images Different physical and chemical properties 1 2 Designations for Enantiomers and Chiral Centers Clockwise - R 4 stereochemical designations that can be used to describe enantiomers: (+)/(−), d/l, D/L, and R/S. R-(-)-ibuprofen The (+)/(−) same as d/l - identifies the direction in which 3 4 Hydrogen –forward the enantiomer rotates plane polarized light. (+ = d, -=l ). A 50: 50 mixture of both enantiomers is called a racemic 1 v mixture 2 Counterclockwise - S d/l (drugs) should not be confused with D/L (sugars and amino acids) S-(+)-ibuprofen 24 Assignment of R and S  Diastereomers 2 * * * 1 * * * * * Geometric Isomers Also Called Cis/Trans or E/Z isomers 25 Conformational Isomers Non-superimposable orientations Result of free rotation around single bonds Not distinct molecules, but different orientations of the same molecule. Drug conformations have a significant role to play in the energy (enthalpy and entropy) changes involved in the binding of a drug molecule to its biological target. Fentanyl Opioid Analgesic Conformational flexibility/restriction can provide beneficial pharmacological/therapeutic benefits Identify the conformers/rotatable bonds ? depending on the specific drug or drug class. 26  Importance of Stereochemistry Helps to understand the orientation, steric influence of the drug structure in establishing/optimizing binding at the target site. Pharmacological /Toxicological activity of the drug Pharmacokinetics of the drug ( Metabolism ) 27 Lets Practice !! 28 Identify the # of chiral centers and assign stereochemistry (R/S) as indicated in the drug molecule/s below 1 chiral center S * 0 or no chiral centers Gabapentin Levothyroxine Tramadol 2 chiral centers 29  References 1. Lombardino, J., Lowe, J. The role of the medicinal chemist in drug discovery — then and now. Nat Rev Drug Discov 2004, 3, 853–862. 2. Khan MO, Deimling MJ, Philip A. Medicinal chemistry and the pharmacy curriculum. Am J Pharm Educ. 2011, 75, 8, 161 3. Harrold, M. & Zavod, R. (2018). Basic Concepts in Medicinal Chemistry (2nd ed.). American Society of Health-System Pharmacists. 4. https://go.drugbank.com 5. https://pubchem.ncbi.nlm.nih.gov 6. Hancu, G.; Modroiu, A. Chiral Switch: Between Therapeutical Benefit and Marketing Strategy. Pharmaceuticals 2022, 15, 240. 30