Textbook on the Bases of Pharmaceutical and Medicinal Chemistry of Antibiotics

By Naeem Hasan Khan and Nabila Perveen

The use of antibiotics is the major medicinal fragment in therapy. With the development of latest modern academic and research sector, it has become of vital importance to let the professionals be informed with the modern trends by which they can be in a drastic position to understand and deliver to other places of their interest. Pharmacists and Pharmacologists will surely avail this opportunity to grasp knowledge about the medicinal chemistry of antibiotics. This resource book is invaluable, essential for learning and covers uniquely almost all core materials of the subject in a versatile manner which is necessary to provide a greater understanding of the antibiotics. One should always cultivate a devotion to science, the scientific methodology as well as emerging technology to achieve meaningful goals with humanistic consequences. Consequently, this book is of particular interest who might be considering future carrier in academics, research and product development.

• Language: English
• Publisher: Partridge Publishing Singapore
• Release date: Jun 3, 2021
• ISBN: 9781543764727

Naeem Hasan Khan

NAEEM HASAN KHAN Professor, Department of Pharmaceutical Chemistry, AIMST University, Malaysia. He holds Ph.D. from Katholieke Universiteit Leuven, Belgium in the grade of GREAT DISTINCTION. He enjoys about 53 years of his academic, research and professional carrier around globe. He has 50 original research publications in The U.S.A., The U.K., France, Belgium, The Netherlands, Singapore, India and Malaysia. As a key-note speaker, he has participated in many conferences in The U.K., Spain, France, Philippines, Belgium, Malaysia and Singapore. NABILA PERVEEN As a co-author, she holds a Ph.D. degree from U.S.M, Malaysia. Presently she is serving as lecturer at Faculty of Pharmacy, AIMST University, Malaysia. She has about 12 years of professional experience with numerous research publications of International repute.

Book preview

Copyright © 2021 by Nabila Perveen.

All rights reserved. No part of this book may be used or reproduced by any means, graphic, electronic, or mechanical, including photocopying, recording, taping or by any information storage retrieval system without the written permission of the author except in the case of brief quotations embodied in critical articles and reviews.

Because of the dynamic nature of the Internet, any web addresses or links contained in this book may have changed since publication and may no longer be valid. The views expressed in this work are solely those of the author and do not necessarily reflect the views of the publisher, and the publisher hereby disclaims any responsibility for them.

www.partridgepublishing.com/singapore

"In the Name of Almighty ALLAH (ALMIGHTY GOD),

the Most Gracious, the Most Merciful"

DEDICATED TO OUR CHILDREN

LAILA NAEEM HASAN

AAMNA NAEEM HASAN

MAHNOOR FATIMA HASAN

FAYSAL RAIHAN HASAN

FOREWORD

I am delighted to write a foreword for the book Textbook on the bases of Pharmaceutical and Medicinal Chemistry of antibiotics by Prof. Dr. Naeem Hasan Khan and his wife Nabila Perveen, both the authors are known to me for more than a decade, since Prof. Dr. Khan and myself were contemporaries in the two Malaysian universities, AIMST, (Kedah), and QUIP, (IPOH). During these years, I had long academic discussions with the two authors on our mutual interest, that is antibiotics.

Prof. Dr. Naeem Hasan Khan has a brilliant and enviable tract record in academics. He obtained Ph. D. Degree from Katholieke Universiteit Leuven (KUL), Belgium in the grade of Great Distinction. His research work during his stay over Belgium was recognized world- wide. The new methods developed by him has been officially adopted as an official method for quantitative analysis of Oxytetracycline, Tetracycline, Chlortetracycline and their related substances in the U.S. Pharmacopeia (USP) 23, Official National Formulary Supplement 9, pages 4588-4590, November 15, 1998, in The European Pharmacopoeia (Euro. Pharm.) and in The British Pharmacopoeia (B.P.). Throughout his academic carrier, Prof. Dr. Naeem has been pursuing research and has published the number of original research articles in prestigious International journals of The U.K., The U.S.A., The Netherlands, France, Spain, Belgium, Bulgaria, Singapore and some others. He has also been invited as a keynote speaker at various International scientific conferences abroad.

Since the discovery of penicillin in early 1940, it is difficult to imagine practice of medicine without antibiotics. The problem with antibiotics is the development of drug-resistance by the microorganisms. That is why there is continuous search for newer antibiotics to bypass mechanisms of drug-resistance. Better understanding of the physicochemical properties of antibiotic chemical space is required to form new antibiotic discovery. Innovations such as the development of antibiotic adjuvants to preserve efficacy of existing drugs together with expanding antibiotic chemical diversity through synthetic biology or new techniques to develop antibiotic- producing organisms, are required to bridge the growing gap between the need for new drugs and their discovery. The book is bound to be of immense value to those involved in this field of research. Prof. Dr. Khan and Dr. Nabila deserve gratitude of the fraternity of pharmacists and pharmacologists for their singular service to the profession. I hope this book would be as popular as Prof. Dr. Khan’s earlier book New HPLC methods for quality control of tetracycline antibiotics which was published by VDM Verlag Publishers, Germany (in English language), and printed in The U.S.A. and The U.K. in 2010.

Prof. R. K. Marya

MBBS; MD; PhD

January 2021

Former:

Professor and Head, Unit of Physiology, Faculty of Medicine, AIMST University, BEDONG

Kedah Darul Aman, Malaysia.

Professor and Head, Department of Physiology, Quest International University of Perak, IPOH, Perak, Malaysia.

Professor and Head, Department of Physiology, Postgraduate Institute of Medical Sciences, ROHTAK, India.

PREFACE

MEDICINAL CHEMISTRY is a science whose fundamental roots lie in all branches of chemistry and biology. The term Pharmaceutical Chemistry is been used for Medicinal Chemistry. The purposes of the medicinal chemistry are the isolation, characterization, elucidation of the structure and the synthesis of the compounds which can be used in medicine for the cure/treatment of disease or a pharmaceutical agent which will benefit humanity. Moreover, medicinal chemistry is concerned with the understanding of the chemical and biological mechanisms by which the action of drugs can be explained. It also establishes the relation between chemical structure and biological activity and to link the later to the physical properties of the drugs.

The medicinal chemist is necessarily a member of a research team which usually consists the medicinal chemist, the biochemist who determine the fate of the drug in the body as an explanation of its mode of action, pharmacologist who test the drugs on animals, transposing animal experiments into clinical trials and chemical engineers/pharmacists who manufacture the tested and proved drug for general therapeutic use.

Indeed, the research area of the antibiotics has become the most important in the whole field of pharmaceutical research. Almost incredible amount of new knowledge on antibiotics involving their Chemistry, Biochemistry, Cell biology, Pharmacology is still under extensive research all over the globe.

This book is basically aimed to design for undergraduate postgraduate students of pharmacy, medical and other science disciplines, in a very simple language, as well as who might be considering a future career in academics or in the pharmaceutical industry.

The book is divided into portions. The first part deals with the antibiotics in general. Second portion covers the basic principles and techniques of medicinal chemistry. The third part is related in dealing with the chemotherapeutic properties of antibiotics while the fourth portion is composed of specific topics, within medicinal chemistry, of clinically important individual antibiotics in divided chapters.

A comprehensive description of nowadays clinically useful antibiotics is described in the book, as regards the medicinal chemistry point of view is concerned. They are the basic principles of antibiotic development, various classes of chemical compounds, difference in origin, mechanism of pharmacological actions and spectrum of activity and their structural activity relationship.

The secretarial assistance from Miss MAHNOOR FATIMA HASAN cannot be forgotten in the completion of this manuscript.

6996.png

CONTENTS

Foreword

Preface

CHAPTER 1    GENERAL MEDICINAL CHEMISTRY

1.1    The nature and sources of drugs in general

1.2    Pharmaceutically / pharmacologically active ingredients from plants, microbes and marine origins

1.3    Briefing on important alkaloids

1.4    Marine medicinal chemistry

1.5    Isolates of important plant extracts

1.6    Nomenclature of various organic / inorganic groups

1.7    Heterocyclic nuclei

1.8    Nomenclature of various heterocyclic ring systems

1.9    Nomenclature of various fused heterocyclic ring system

1.10     Diazanaphthalene

1.11     Medicinally important heterocyclic compounds

1.12     Arrangement of heterocyclic ring systems

1.13     Functional groups

1.14     Carbocyclic or homocyclic chemistry / carbocyclic or homocyclic compounds

1.15     Classification of drugs

1.16     Pharmacologically influential physicochemical properties of organic medicinal agents:

1.17     Principles of drug design

1.18     Antibiotics

1.19     Natural occurrence of antibiotics

CHAPTER 2   BASIC PRINCIPLES AND TECHNIQUES OF MEDICINAL CHEMISTRY FOR ANTIBIOTICS / ANTIBACTERIALS

2.1    The bacterial / human cell

2.2    Screening, isolation, development and production of antibiotics

2.3    Mechanisms of biological activity of antibiotics

2.4    Combination and resistance of antibiotics

2.5    Biogenesis of some basic antibiotics

CHAPTER 3   CHEMOTHERAPEUTIC PROPERTIES OF ANTIBIOTICS

3.1    Clinical uses and antibacterial spectrum

3.2    Frequently occurring pathogens, typical diseases caused and their therapy with basic antibiotics / chemotherapeutic agents commonly used

3.3    Route of administration and major indications of important basic antibiotics / chemotherapeutic agents.

3.4    Pharmacokinetics of antibiotics in general

CHAPTER 4   CLINICALLY IMPORTANT ANTIBIOTICS

4.1    Pharmaceutical And Medicinal Chemistry Of Clinically Important Antibiotics / Structure Determination

4.2    Classification of antibiotics

CHAPTER 5   STRUCTURAL FORMULAE, CHEMISTRY, CHEMICAL CLASSIFICATION AND STRUCTURE ACTIVITY RELATIONSHIP (SAR) OF ANTIBIOTICS

5.1    List of chemical groups of antibiotics

5.2    Antibiotics derived from respective chemical groups

5.3    Chemistry of β-lactam

5.4    Penicillin and its derivatives

5.5    Chemical synthesis of penicillin, ampicillin and amoxicillin

5.6    Broad spectrum and powerful combination

5.7    Antibiotic derived from one amino acid (individual compounds).

5.8    Properties of individual important beta-lactam penicillin antibiotics

5.9    Antibiotics derived from two amino acids (penams)

5.10     Second Generation

5.11     Third Generation (Aminopenicillin)

5.12     Fourth Generation

5.13     Fourth Generation

5.14     Fourth Generation

5.15     Penems

5.16     β-Lactamase Inhibitor

5.17     General list of compounds from Cephalosporin group of antibiotics

5.18     First Generation

5.19     Second Generation

5.20     Third Generation

5.21     Fourth Generation

5.22     Fifth Generation

5.23     Miscellaneous Others

5.24     Antibiotics derived from two amino acids.

5.25     Second Generation

5.26     Third Generation

5.27     Fourth Generation

5.28     Fifth Generation

CHAPTER 6 TETRACYCLINES

6.1    General characters of Tetracyclines

6.2    Acid–base equilibria for tetracycline

6.3    Biosynthesis of Tetracyclines

6.4    Chemical synthesis of Tetracyclines in general

6.5    Bioavailability of Tetracyclines in general

6.6    Formation of metal chelates

6.7    Permissible changes in the structure

6.8    Structure activity relationship

6.9    Pharmacological uses

6.10     Mechanism of action of Tetracyclines in general

6.11     Properties of individual important compounds of tetracycline group of antibiotics

CHAPTER 7 POLYPEPTIDE ANTIBIOTICS

7.1    Polypeptide antibiotics in general

7.2    Active Against Gram-Positive Bacteria

7.3    Active Against Gram-Negative Bacteria

CHAPTER 8 ANTIBIOTICS DERIVED FROM SUGARS

8.1    General list of antibiotics derived from sugars.

8.2    Pharmacological uses and adverse effects of streptomycin in general

8.3    Properties of individual important compounds of antibiotics derived from sugars

CHAPTER 9 ANTIBIOTICS DERIVED FROM ACETATES AND PROPIONATE

9.1    Properties of individual important compounds of antibiotics derived from acetates or propionates

CHAPTER 10 MACROLIDE ANTIBIOTICS

10.1     List of macrolide antibiotics (old)

10.2     Chemistry of macrolides antibiotics

10.3     Properties of individual important compounds of macrolide antibiotics

CHAPTER 11 POLYENE ANTIBIOTICS

11.1     List of polyene antibiotics

11.2     Properties of individual important compounds of polyene antibiotics

CHAPTER 12 MACROCYCLIC ANTIBIOTICS

12.1     List of macrocyclic antibiotics

12.2     Properties of individual important macrocyclic antibiotics

CHAPTER 13 ANTIBIOTICS FROM VARIOUS OTHER STRUCTURES

13.1     List of antibiotics with other various structures

13.2     Properties of individual important antibiotics with various structures

CHAPTER 14 SYNTHETIC QUINOLONE GROUP OF ANTIBIOTICS (MACROCYCLIC)

14.1     General chemistry of Quinolone antibiotics (macrocyclic)

14.2     List of quinolone antibiotics

14.3     General chemistry of quinolone antibiotics

14.4     Properties of individual important compound from quinolone group of antibiotics

CHAPTER 15 ANTINEOPLASIC ANTIBIOTICS

15.1     Etiological factors responsible that may develop cancer cell

15.2     Classification of chemically heterogenous group of antitumor antibiotics

15.3     List of important antitumor antibiotics

15.4     Properties of individual antitumor antibiotics with various structures

CHAPTER 16 ANTI-TUBERCLOSTATIC ANTIBIOTICS

16.1     List of anti-tuberclostatics

16.2     Chemistry of important anti-TB antibiotic drug

16.3     Active against gram-positive bacteria

References

About the Author

CHAPTER 1

GENERAL MEDICINAL CHEMISTRY

1.1 The nature and sources of drugs in general

1.2 Pharmaceutically / pharmacologically active ingredients from plants, microbes and marine origins

1.3 Briefing on important alkaloids

Alkaloids may be defined as chemical group having heterocyclic natural products containing heterocyclic Nitrogen. The alkaloids are considered to be alkaline in nature because they possess:

• Primary amine

• Secondary amine

• Tertiary amines

Some of the alkaloids are neutral in action and some of them possess phenolic activity which actually contributes the acidic nature of the molecule. The alkaloids display an exceptionally wide array of biological activities, being present in plants, fungi, bacteria, amphibia, insects, marine animals and humans. Alkaloids may also naturally exist as salts which are the product of a reaction of acid and base.

The alkaloids are classified based upon

their chemical nucleus, as under:

Some important alkaloids are briefed below:

A. OPIUM

Opium is the sun-dried gummy exudate of the unripe capsule of the opium poppy (papaver somniferum) and contains 20 % of 30 different alkaloids. Opium contains isoquinoline type of alkaloids. It is cultivated in China, Persia, India, Pakistan, Afghanistan, Egypt, Southeren Eastern Europe and Golden Triangle. Some major alkaloids are mentioned below.

Apart from alkaloids, it also contains gums, sugars, organic acids, resins, proteins. It is used as supreme pain- relieving action, C.N.S. stimulant, smooth muscle relaxant, veterinary sedative, male impotence and cough depressant / expectorant.

B. RAUWOLFIA

The plant rauwolfia serpentina is also called as snake root (apocynaceace) and is cultivated in China, Indian sub-continent, South America, Middle East, Western African countries. In 1931, two Indian research brothers (Siddiqui and Siddiqui brothers) were awarded the Noble Prize for the isolation of very important alkaloid "AJMALINE’ from rauwolfia serpentina. Major alkaloids are mentioned below.