Fundamentals of Medicinal Chemistry and Drug Metabolism

Book Series: Medicinal Chemistry for Pharmacy Students

Volume 1

by

M.O. Faruk Khan, Ashok Philip

DOI: 10.2174/97816810868731180101
eISBN: 978-1-68108-687-3, 2018
ISBN: 978-1-68108-688-0
ISSN: 2589-6997 (Print)
ISSN: 2589-6989 (Online)



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The primary objective of this 4-volume book series is to educate PharmD students on the subject of medicinal chemistry. The book set s...[view complete introduction]
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Table of Contents

Foreword

- Pp. i
Gayle Brazeau
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Preface

- Pp. ii-iii (3)
M. O. Faruk Khan and Ashok Philip
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List of Contributors

- Pp. iv
M. O. Faruk Khan and Ashok Philip
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Introduction

- Pp. 1-12 (12)
M. O. Faruk Khan and Ashok Philip
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Review of Bioorganic Chemistry

- Pp. 13-75 (63)
M. O. Faruk Khan and Ashim Malhotra
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Acid-base Chemistry and Salt Formation

- Pp. 76-108 (33)
Hardeep Singh Saluja and M. O. Faruk Khan
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Solubility and Lipid-Water Partition Coefficient

- Pp. 109-130 (22)
Hardeep Singh Saluja and M. O. Faruk Khan
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Isosteric and Spatial Considerations of Drugs

- Pp. 131-159 (29)
M. O. Faruk Khan and Timothy J. Hubin
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Fundamentals of Drug Action

- Pp. 160-187 (28)
M. O. Faruk Khan and Taufiq Rahman
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Drug Metabolism

- Pp. 188-280 (93)
Rahmat Talukder, Ashok Philip and M. O. Faruk Khan
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Biosynthetic Pathways Frequently Targeted by Pharmaceutical Intervention

- Pp. 281-323 (43)
Jason L. Johnson and M. O. Faruk Khan
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Subject Index

- Pp. 324-333 (10)
M. O. Faruk Khan and Ashok Philip
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Foreword

For a pharmacist to be a successful member of the health care team, a foundation of medicinal chemistry knowledge is one of the essential elements to developing an adequate knowledge base, and critical thinking and problem solving skills. This e-book provides the fundamental principles of medicinal chemistry including the functional groups occurring in medicinal agents, the acidity and basicity of drugs, and their water and lipid solubility as well as drug-receptor interactions. The physicochemical principles, isosterism and spatial characteristics of drugs are prerequisites to understanding drug pharmacodynamics, pharmacokinetics, biopharmaceutics, formulations and pharmacotherapeutics. Another important aspect crucial to comprehending the mechanism of drug action is the knowledge of important biosynthetic pathways frequently encountered in the pharmaceutical interventions. A comprehensive approach has been taken to explaining the phases of drug metabolism, modifications of drug chemical structures and their effects on drug pharmacokinetics, safety and efficacy.

These authors have carefully integrated the key aspect of Doctor of Pharmacy curriculum in the design and organization of the contents in this eBook series; its novel and innovative layout includes 4 volumes in three distinct areas - the fundamental concepts, detailed structure activity relationships of different drug classes, and recent developments in the area of medicinal chemistry and drug discovery. It offers students the opportunity to learn the principles of drug action in a logical stepwise manner. The case studies, student’s self-study guide and self-assessments at the end of each chapter are unique features of this book that would be beneficial to both students, faculty members and clinicians. Although there are several medicinal chemistry textbooks available in the market, to my understanding, this is the first textbook of its kind focusing on the integration of medicinal chemistry into the foundations for a pharmacy curriculum.

As a pharmacy educator and pharmaceutical scientist, I am pleased to testify and endorse this e-book to the pharmacy educators, and learners as a novel and innovative addition to the available literature. One of the key advantages of this e-book is that it focuses its approach on a student-friendly manner that incorporates the appropriate illustrative diagrams and study guides as well as self-assessments to enable students to enhance their skills as self-learners. The increasing emphasis on clinical and management focuses in our pharmacy curriculum makes it challenging for students with limited time available to learn and internalize concepts in the area of medicinal chemistry. This e-book series brings those memories of my early years as a pharmacy student and the evolution of the pharmacy education, and gives me the confidence that it will pave the way of future medicinal chemistry education for pharmacists and other health professionals.

Gayle Brazeau
Dean School of Pharmacy
Marshall University
Huntington, WV
USA


Preface

This is the first volume of the 4-volume eBook series, “Medicinal Chemistry for Pharmacy Students”. The primary objective of this e-Book series is to educate Pharm-D students in the area of medicinal chemistry and serve as a reference guide to pharmacists on the aspects of chemical basis of drug action. A thorough discussion of key physicochemical parameters of therapeutic agents and how they affect the biochemical, pharmacological, and pharmacokinetic processes and clinical use of these agents is the primary focus of the whole book. The rationale for putting together an e-Book of this nature is to equip Pharm-D students with the scientific basis to competently evaluate, recommend and counsel patients and health care professionals regarding the safe, appropriate, and cost-effective use of medications.

This first volume of the series titled, “Fundamentals of Medicinal Chemistry and Drug Metabolism”, is comprised of 8 chapters focusing on basic background information to build a firm knowledge base of medicinal chemistry. It takes a succinct and conceptual approach to introduce important fundamental chemical concepts, required for a clear understanding of various facets of pharmacotherapeutic agents, drug metabolism and important biosynthetic pathways that are relevant to drug action.

Chapter 1 is designed to ensure that the students learn about the scope and importance of medicinal chemistry, in addition to some important definitions. This chapter is an introduction to the overall role of a pharmacist and to the significance of medicinal chemistry in pharmacy education. It discusses the role of the pharmacist, history of medicinal chemistry and intellectual domains of medicinal chemistry.

Chapter 2 includes a comprehensive discussion of the four major biomolecules: proteins, carbohydrates, lipids, nucleic acids and key heterocyclic ring systems. Organic functional groups present in drugs, and biomolecules are reviewed in this chapter. Additionally, heterocycles present in drugs and biomolecules are reviewed in this chapter.

Chapter 3 focuses on acid base chemistry and salt formation; a brief review of the concepts of acid-base chemistry including the Arrhenius, Brønsted-Lowry, and Lewis concepts of acids and bases. It also highlights the significance of salt formation in pharmaceutical products, factors that determine ionization, and acid-base strengths. The application of acid-conjugate base, base-conjugate acid and Henderson-Hasselbalch equation in pharmacy and drug action and bioavailability are also discussed. The interpretation of pH partition theory, its significance in drug pharmacokinetics, the purpose of salt formation with drug molecules and the acidity or basicity of the salts are illustrated in this chapter.

Chapter 4 covers solubility and lipid-water partition coefficient (LWPC) concepts in detail with specific drug examples. Hydrophilicity, hydrophobicity and lipophilicity of drugs, and their effect on solubility are discussed to enable the readers to predict the water or lipid solubility of drugs based on their chemical composition. Additionally, the chapter includes a discussion of the effects of partition coefficient on drug bioavailability and action.

Chapter 5 reviews the concepts of isosterism, stereochemical principles, and their application. An explanation of drugs’ spatial factors, and their influence on drug action including definitions of important stereochemical parameters are also included.

Chapter 6 is a brief review of the mechanisms of drug action and discusses drug receptor interactions critical for pharmacological responses of drugs. This chapter also discusses the theories of drug action that include: occupancy theory, rate theory, induced-fit theory, macromolecular perturbation theory, and occupation-activation theory of “two-state” model.

Chapter 7 provides a detailed account of drug metabolism, prodrugs and related terminology. It provides a comprehensive account of the fundamental concepts of drug metabolism, describes the significance of drug metabolism, key enzymes involved in the sites of drug metabolism, phase I and phase II metabolic pathways that include oxidation reduction hydrolysis, glucuronic acid conjugation, sulfate conjugation, conjugations with glycine and other amino acids, glutathione or mercapturic acid, acetylation, and methylation. This chapter also defines and differentiates between prodrug, soft drug and antedrugs and discusses their clinical significance.

Chapter 8 provides a brief review of biosynthetic pathways frequently targeted by pharmaceutical interventions. The biosynthetic pathways discussed in this chapter include: eicosanoid biosynthesis (prostaglandins, prostacyclins and leukotrienes), epinephrine and norepinephrine biosynthesis, folic acid biosynthesis, steroid biosynthesis (cholesterol, adrenocorticoids and sex hormones) and nucleic acid biosynthesis (purines and pyrimidines anabolism, catabolism and salvages).

The chapters in this volume are designed to guide the reader to review, integrate and apply medicinal chemistry concepts to the study of therapeutic agents that are the focus of subsequent volumes. All concepts are illustrated with diagrams or figures, with the keywords highlighted, bulleted or numbered. Wherever needed, special boxes and case studies are included. In addition, each chapter is reinforced with practice problems and answer sets. Special notations are highlighted using call-out boxes for visual effect. Tables and figures are used to augment the text as needed.

We would like to express our sincere gratitude to the contributing authors for their time and effort in completing this volume. We would also like to thank Bentham Science Publishers, particularly Ms. Fariya Zulfiqar (Assistant Manager Publications) for their support. We are confident that this volume of the eBook series will guide students and educators of pharmacy and related health professions worldwide.

M. O. Faruk Khan, Ph.D.
Marshall University School of Pharmacy,
Huntington, WV,
USA

&
Ashok Philip, Ph.D.
Union University College of Pharmacy,
Jackson, TN,
USA

List of Contributors

Editor(s):
M.O. Faruk Khan
Marshall University School of Pharmacy
Huntington, WV
USA


Ashok Philip
Union University College of Pharmacy
Jackson, TN
USA




Contributor(s):
M. O. Faruk Khan
Department of Pharmaceutical Sciences and Research
Marshall University School of Pharmacy, Huntington, WV
USA


Ashok Philip
Department of Pharmaceutical Sciences, Union University School of Pharmacy
Jackson, TN
USA


Ashim Malhotra
Department of Pharmaceutical and Biomedical Sciences
College of Pharmacy, California Northstate University
Elk Grove, CA
USA


Hardeep Singh Saluja
Department of Pharmaceutical Sciences
Southwestern Oklahoma State University College of Pharmacy
Weatherford, Oklahoma
USA


Timothy J. Hubin
Department of Chemistry
Southwestern Oklahoma State University
Weatherford, Oklahoma
USA


Taufiq Rahman
Department of Pharmacology
University of Cambridge
Cambridge
UK


Rahmat Talukder
Department of Pharmaceutical Sciences
University of Texas at Tyler College of Pharmacy
Tyler, TX
USA


Jason L. Johnson
Department of Chemistry and Physics
Southwestern Oklahoma State University
Weatherford, Oklahoma
USA




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