Harrold MW, Zavod RM. Basic Concepts in Medicinal Chemistry. American Society of Health-System Pharmacists; 2013, 440pp, $49 (softcover), ISBN 978-1-58528-266-1.

This new medicinal chemistry textbook by Drs. Harrold and Zavod is unlike any other on the market. The text is succinct and well suited for an introductory or “principles” course in medicinal chemistry, with 9 chapters. The intention behind this book is the establishment of a deep understanding of fundamental principles of medicinal chemistry that could then be applied to specific drug classes, either through a subsequent course or as part of a curriculum where medicinal chemistry is integrated with other areas, such as pharmacology and pharmacotherapy. The text possesses several strong features that help students self-asses their understanding of the concepts, including review questions at the end of each chapter and clear learning objectives at each chapter introduction. The review questions that conclude each chapter are particularly useful because they stick to the concepts of the chapter, and do not try to branch out into counseling points or therapeutics. This drives home the point that these questions are for learning medicinal chemistry, and this content will serve as building blocks for future pharmacy knowledge. The learning objectives that start each chapter are easily assessable and the summary points throughout the chapters provide useful recaps of the content, so the “take home” points are not missed. The book’s Introduction clearly explains the organization of the book and its intention. While this may not be particularly useful for students, it clarifies for faculty members how this text can be used. It will especially be helpful for faculty members who have taught from other texts in the past, but wish to adopt this one because of its unique approach of focusing heavily on fundamentals. The second chapter presents functional groups, sticking with the philosophy that each drug molecule is a sum of several parts (functional groups), and that in understanding the parts, one can understand the whole. This chapter also offers great coverage of organic chemistry topics such as resonance, electronegativity, water/lipid solubility, hydrogen bonding, and steric hindrance in a context that applies them to drug molecules. An especially strong feature of Chapter 2 is the coverage of the R-groups in the amino acids. This is a key topic in understanding drug-target binding, and will help in equipping those students who have a superficial understanding of amino acid chemistry. Chapters 3 and 4 are related by their coverage of acid/base chemistry. Chapter 3 goes into depth about acidic and basic functional groups, how to recognize them, and how they contribute to the overall acidic or basic character of a drug molecule. Especially useful is a tabular summary of acidic and basic functional groups and their respective pKa ranges. Chapter 4 then builds on this to teach both quantitative and qualitative approaches for solving Henderson-Hasselbach problems. From an instructor’s perspective, this chapter offers several approaches to solving these problems; however, students may find this confusing if they do not carefully read the text that accompanies each approach. Chapter 5 transitions the student into applying understanding of functional groups and pKa to the topic of salts and solubility. There is a thorough coverage of both organic and inorganic salts, the former of which is not always discussed extensively in other textbooks. The authors use a presentation of solubility coefficient and partition coefficient to transition into covering water and lipid solubility, and the therapeutic implications behind these chemical properties. The focus of Chapter 6 is drug-target binding, which is a logical next step in applying fundamental principles from previous chapters. The tendency for drugs to interact with amino acids, or other biomolecules, within a target site is reliant upon chemical properties such as pKa, solubility, and partition coefficient, so these concepts are reiterated throughout Chapter 6. The strength of Chapter 6 lies in the extensive presentation of example drugs from each type of covalent and non-covalent drug-target interaction. Chapter 7 presents concepts of stereochemistry, a significant aspect of drug chemistry that is often not covered in depth in medicinal chemistry textbooks. Students do not always recall the distinction between different isomer types from their pre-requisite courses, and this chapter helps to “even the playing field” with regards to prepharmacy preparation. As stereochemistry is a key aspect to drug binding, this chapter may be best covered before Chapter 6. Chapter 8 follows with a presentation of drug metabolism through a thorough overview of all Phase I and Phase II reactions. There are multiple examples of drugs that are affected by each metabolic reaction, which is better than a generic molecule that is used in some books for the less common pathways. This chapter includes an interesting discussion of the chemical basis of the cytochrome P450 names as they relate to the structure of cholesterol. Finally, the discussion of hydrolysis reactions transitions seamlessly into teaching about pro-drugs and the use of metabolic activation of drug compounds. The final chapter, entitled “Structure Activity Relationships and Basic Concepts in Drug Design,” represents a capstone for the text where students are expected to pull together concepts from the previous chapters and apply them to looking at drug structures within a class. The second learning objective of this chapter really summarizes the intent of the entire book, where the student is expected to compare drug structures and explain how their differences “could affect their pharmacological, physicochemical, or therapeutic activity.” This chapter begins with examples of how structure-activity relationships affect drug binding, ADME (absorption, distribution, metabolism, and excretion), and pharmacology, and then transitions into specific structural modifications, including isosteric replacements. This chapter would benefit from a longer set of review questions at the end, where the integrated nature of the textbook’s content is emphasized and students are given the opportunity to tie together the concepts from previous chapters. In conclusion, this textbook provides a refreshing and unique approach to teaching introductory medicinal chemistry. There is no impetus whatsoever for the student to be able to memorize drug structures, but instead the student is taught to critically evaluate the different parts of the drug molecule and predict how it fits into a class with regards to pKa, solubility, etc. Instructors who are accustomed to a more traditional approach to teaching medicinal chemistry may find this text challenging to work with, as they may disagree with the “depth over breadth” approach presented by this book. However, the flow of the material in the text is intentional, and the content builds upon itself to end in a chapter that introduces the concept of structure-activity relationships. Using the end-of-chapter review questions as a guide, faculty members could develop ancillary active-learning or on-line modules to accompany the implementation of this textbook in the medicinal chemistry classroom. If the content is indeed mastered by the student as a result of using this book, he or she should have the confidence and competence to apply these fundamental concepts to the study of any drug class moving forward.