Handbook of Research on Medicinal

Chemistry Innovations and

Methodologies 1st Edition Debarshi Kar
Mahapatra
Visit to download the full and correct content document:
https://textbookfull.com/product/handbook-of-research-on-medicinal-chemistry-innova
tions-and-methodologies-1st-edition-debarshi-kar-mahapatra/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Medicinal Chemistry with Pharmaceutical Product

Development 1st Edition Debarshi Kar Mahapatra

https://textbookfull.com/product/medicinal-chemistry-with-
pharmaceutical-product-development-1st-edition-debarshi-kar-
mahapatra/

Research Methodologies and Practical Applications of

Chemistry 1st Edition Lionello Pogliani (Editor)

https://textbookfull.com/product/research-methodologies-and-
practical-applications-of-chemistry-1st-edition-lionello-
pogliani-editor/

Medicinal plant research in Africa pharmacology and

chemistry Kuete

https://textbookfull.com/product/medicinal-plant-research-in-
africa-pharmacology-and-chemistry-kuete/

Handbook of Research on Food Science and Technology:

Volume 1: Food Technology and Chemistry 1st Edition
Monica Chavez-Gonzalez (Editor)

https://textbookfull.com/product/handbook-of-research-on-food-
science-and-technology-volume-1-food-technology-and-
chemistry-1st-edition-monica-chavez-gonzalez-editor/
Medicinal Chemistry and Drug Design 1st Edition Deniz
Ekinci

https://textbookfull.com/product/medicinal-chemistry-and-drug-
design-1st-edition-deniz-ekinci/

Annual Reports in Medicinal Chemistry 1st Edition Desai

https://textbookfull.com/product/annual-reports-in-medicinal-
chemistry-1st-edition-desai/

Progress in medicinal chemistry 1st Edition G. Lawton

https://textbookfull.com/product/progress-in-medicinal-
chemistry-1st-edition-g-lawton/

Foye s Principles of Medicinal Chemistry Thomas Lemke

https://textbookfull.com/product/foye-s-principles-of-medicinal-
chemistry-thomas-lemke/

Natural Products in Medicinal Chemistry 1st Edition

Stephen Hanessian

https://textbookfull.com/product/natural-products-in-medicinal-
chemistry-1st-edition-stephen-hanessian/
HANDBOOK OF RESEARCH
ON MEDICINAL CHEMISTRY
Innovations and Methodologies
HANDBOOK OF RESEARCH
ON MEDICINAL CHEMISTRY
Innovations and Methodologies

Edited by
Debarshi Kar Mahapatra, PhD
Assistant Professor, Department of Pharmaceutical Chemistry,
Dadasaheb Balpande College of Pharmacy, Rashtrasant Tukadoji
Maharaj Nagpur University, Nagpur, Maharashtra, India

Sanjay Kumar Bharti, PhD

Assistant Professor, Division of Pharmaceutical Chemistry,
Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya
(A Central University), Bilaspur – 495009, Chhattisgarh, India
Apple Academic Press Inc. Apple Academic Press Inc.
3333 Mistwell Crescent 9 Spinnaker Way
Oakville, ON L6L 0A2 Canada Waretown, NJ 08758 USA
© 2018 by Apple Academic Press, Inc.
Exclusive worldwide distribution by CRC Press, a member of Taylor & Francis Group
No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
International Standard Book Number-13: 978-1-77188-544-7 (Hardcover)
International Standard Book Number-13: 978-1-315-20741-4 (eBook)
All rights reserved. No part of this work may be reprinted or reproduced or utilized in any form or by any
electric, mechanical or other means, now known or hereafter invented, including photocopying and record-
ing, or in any information storage or retrieval system, without permission in writing from the publisher or its
distributor, except in the case of brief excerpts or quotations for use in reviews or critical articles.
This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission and sources are indicated. Copyright for individual articles remains with the authors
as indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable
data and information, but the authors, editors, and the publisher cannot assume responsibility for the validity
of all materials or the consequences of their use. The authors, editors, and the publisher have attempted to
trace the copyright holders of all material reproduced in this publication and apologize to copyright holders
if permission to publish in this form has not been obtained. If any copyright material has not been acknowl-
edged, please write and let us know so we may rectify in any future reprint.
Trademark Notice: Registered trademark of products or corporate names are used only for explanation
and identification without intent to infringe.

Library and Archives Canada Cataloguing in Publication

Handbook of research on medicinal chemistry : innovations and methodologies / edited by Debarshi Kar
Mahapatra, PhD (Assistant Professor, Department of Pharmaceutical Chemistry, Kamla Nehru College of
Pharmacy, RTM Nagpur University, Nagpur, India), Sanjay Kumar Bharti, PhD (Assistant Professor, Divi-
sion of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A
Central University), Bilaspur – 495009, Chhattisgarh, India).
Includes bibliographical references and index.
Issued in print and electronic formats.
ISBN 978-1-77188-544-7 (hardcover).--ISBN 978-1-315-20741-4 (PDF)
1. Pharmaceutical chemistry. 2. Drugs--Research--Methodology. I. Mahapatra, Debarshi Kar, editor II.
Bharti, Sanjay Kumar, editor
RS403.H36 2017 615'.19 C2017-904170-3 C2017-904171-1

Library of Congress Cataloging-in-Publication Data

Names: Mahapatra, Debarshi Kar, editor. | Bharti, Sanjay Kumar, editor.

Title: Handbook of research on medicinal chemistry : innovations and methodologies / editors, Debarshi
Kar Mahapatra, PhD Sanjay Kumar Bharti, PhD.
Description: Toronto ; New Jersey : Apple Academic Press, 2017. | Includes bibliographical references and
index.
Identifiers: LCCN 2017026981 (print) | LCCN 2017027643 (ebook) | ISBN 9781315207414 (ebook) |
ISBN 9781771885447 (hardcover : alk. paper)
Subjects: LCSH: Pharmaceutical chemistry. | Drugs--Research--Methodology. Classification: LCC RS403
(ebook) | LCC RS403 .H34 2017 (print) | DDC 615.1/9--dc23
LC record available at https://lccn.loc.gov/2017026981

Apple Academic Press also publishes its books in a variety of electronic formats. Some content that appears
in print may not be available in electronic format. For information about Apple Academic Press products, visit
our website at www.appleacademicpress.com and the CRC Press website at www.crcpress.com
CONTENTS

List of Contributors ....................................................................................... vii

List of Abbreviations ...................................................................................... ix
Foreword ....................................................................................................... xv
Preface ........................................................................................................ xvii
Acknowledgments ......................................................................................... xix
About the Editors.......................................................................................... xxi

PART I: TECHNIQUES IN DRUG DISCOVERY............................................. 1

1. Combinatorial Chemistry: Role in Lead Discovery...................................3
Premlata K. Ambre, Anish N. Gomatam, Santosh Nandan,
and Evans C. Coutinho
2. Advanced Techniques in Biomolecular Simulations ................................ 71
Anirudh V. Belubbi and Elvis A. F. Martis
3. Retrometabolic Drug Design .................................................................... 105
Nirzari Gupta

PART II: PHARMACOLOGICAL ASPECTS

OF NATURAL PRODUCTS ....................................................................125
4. Insight into the Pharmacological Potentials
of Camellia sinensis Linn. ......................................................................... 127
Prabodh Chander Sharma, Amit Yadav, Archana Sharma,
and Aakash Deep
5. Pharmaceutical Importance of Natural Aphrodisiac Drugs .................163
Ram Kumar Sahu and Amit Roy

PART III: CHEMICAL MEDIATORS: DRUGGABLE TARGETS ............ 199

6. Serotonin: Chemical, Biological and Therapeutic Aspects.................... 201
Bibhudatta Mishra and Gunjan Joshi
7. Eicosanoids: Constitution and Pathophysiological Functions .............. 239
Gunjan Joshi
vi Contents

PART IV: ADVANCES IN MEDICINAL CHEMISTRY ............................... 291

8. Development of Antimalarial Drug Analogs
to Combat Plasmodium Resistance .......................................................... 293
Aakash Deep, Shivani Sharma, and Manav Malhotra
9. Chemistry and Pharmacology of β-Lactam Analogs ............................. 339
Ankur Vaidya and Shweta Jain
10. General Anesthetics...................................................................................413
T. N. V. Ganesh Kumar
11. Stereochemical Aspects in Medicinal Chemistry ................................... 435
Sidhartha S. Kar
12. Pharmaceutical Interactions in Drug Practices ..................................... 459
Sachinkumar Patil, Shitalkumar Patil, Sudha Kharade,
and Dipali Kamble
Index ............................................................................................................ 597
LIST OF CONTRIBUTORS

Premlata K. Ambre
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E),
Mumbai – 400098, India

Anirudh V. Belubbi
Molecular Simulations Groups, Department of Pharmaceutical Chemistry, Bombay College
of Pharmacy, Kalina, Santacruz (E), 400098, India

Evans C. Coutinho
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E),
Mumbai – 400098, India

Aakash Deep
Department of Pharmaceutical Sciences, Ch. Bansi Lal University, Bhiwani – 127021, India

Anish N. Gomatam
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E),
Mumbai – 400098, India

Nirzari Gupta
Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Shweta Jain
ADINA College of Pharmacy, Sagar, M.P., 470003, India

Gunjan Joshi
Center for Biomedical Engineering and Technology, School of Medicine, University of Maryland,
Baltimore, USA

Dipali Kamble
Ashokrao Mane College of Pharmacy, Peth-Vadagaon, District Kolhapur, Maharashtra, India

Sidhartha S. Kar
Department of Pharmaceutical Chemistry, IGIPS, Bhuabneswar – 751015, India

Sudha Kharade
Ashokrao Mane College of Pharmacy, Peth-Vadagaon, District Kolhapur, Maharashtra, India

T. N. V. Ganesh Kumar
Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Chandramoulipuram, Chowdavaram,
Guntur, Andhra Pradesh – 522019, India
Manav Malhotra
M. K. Drugs, F-10 Industrial Focal Point, Derabassi – 140507, India

Elvis A. F. Martis
Molecular Simulations Groups, Department of Pharmaceutical Chemistry, Bombay College of
Pharmacy, Kalina, Santacruz (E), 400098, India

Bibhudatta Mishra
Wilmer Eye Institute, John Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD
20287, USA
viii List of Contributors

Santosh Nandan
Chemworx Pvt. Ltd., Kalina, Santacruz (E), Mumbai – 400098, India

Sachinkumar Patil
Ashokrao Mane College of Pharmacy, Peth-Vadagaon, District Kolhapur, Maharashtra, India

Shitalkumar Patil
Ashokrao Mane College of Pharmacy, Peth-Vadagaon, District Kolhapur, Maharashtra, India
Amit Roy
Department of Pharmaceutics, Columbia College of Pharmacy, Raipur, Chhattisgarh, India

Ram Kumar Sahu

Department of Pharmaceutics, Columbia College of Pharmacy, Raipur, Chhattisgarh, India

Archana Sharma
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra – 136119, India

Prabodh Chander Sharma

Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra – 136119, India

Shivani Sharma
Department of Pharmaceutical Chemistry, Indo-Soviet Friendship (ISF) College of Pharmacy,
Ferozepur Road, Moga – 142001, India

Ankur Vaidya
Pharmacy College, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, 206130, Uttar
Pradesh, India

Amit Yadav
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra – 136119, India
LIST OF ABBREVIATIONS

API active pharmaceutical ingredients

ACTH adrenocorticotrophic hormone
ADH alcohol dehydrogenase
AP alkaline phosphatase
APP amyloid precursor protein
BPH benign prostatic hyperplasia
BZF benzoflavone moiety
BBB blood brain barrier
BP blood pressure
BHA butylated hydroxyanisole
CIP Cahn-Ingold-Perlog
CEA carboxyethyl-L-argininesynthase
CVD cardiovascular disease
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CNS central nervous system
CDS chemical delivery systems
CI chemical ionization
CRTH2 chemoattractant receptor-homologous molecule
CG coarse-grained
CV collective variables
CBPA competitive binding protein technique
CUDA compute unified device architecture
CG conjugate gradient
DP D-prostanoid receptor
DOR delta opioid receptor
DCC dicyclohexylcarbodiimide
DPPH diphenyl-1-picrylhydrazyl
DUR drug utilization review
EPA eicosapentaenoic acid
ESI electrospray ionization
EBT embryonic bovine tracheal
EAE encephalomyelitis
x List of Abbreviations

ELS endosomes and lysosomes

EE energy expenditure
EC enterochromaffin cells
ELISA enzyme linked immunosorbent assay
EC epicatechin
EGC epigallocatechin
EGCG epigallocatechin gallate
EET epoxyeicosatrienoic acid
ENL erythema nodosum leprosum
EMDT ethyl-5-methoxy-N,N-dimethyltryptamine
EI eudismic index
ER eudismic ratio
ES extended-spectrum
ESBLs extended-spectrum β-lactamases
ERK extracellular signal-regulated kinases
FAERS FDA adverse event reporting system
FRAP ferric reducing-antioxidant power
FRET fluorescence resonance energy transfer
FSH follicle-stimulating hormone
FDA Food and Drug Administration
GPCR G-protein-coupled receptor
GC gallocatechin
GI gastrointestinal tract
GA general anesthetics
GTE green tea extract
GTP green tea powder
GH growth hormone
HF Hartree-Fock
HCC hepatocellular carcinoma
HDL high density lipoprotein-cholesterol
HPLC high performance liquid chromatography
HTRF homogeneous time resolved fluorescence
HLE human lens epithelial
HMBA hydroxy methyl benzoic acid
HETE hydroxyeicosatetraenoic acid
IBD inflammatory bowel disease
IR infrared
IMDH inosine monophosphate dehydrogenase
List of Abbreviations xi

IRS-1 insulin receptor substrate-1

IL-6 interleukin 6
IPAT intraperitoneal adipose tissues
IBS irritable bowel syndrome
KE kinetic energy
LOSCs laser optical synthesis chips
LTB4 leukotriene B4
LTs leukotrienes
LCAO linear combination of atomic orbitals
LE loteprednol etabonate
LDL low density lipoprotein
LH luteinizing hormone
LSD lyzergic acid diethylamide
MHT malignant hyperthermia
MBHA Marshall benzhydryl amine linker
MS mass spectrometry
MALDI matrix assisted laser desorption/ionization
MTD maximum tolerated dose
MPI message parsing interfaces
MRSA methicillin-resistant Staphylococcus aureus
MSSA methicillin-susceptible Staphylococcus aureus
MMC migrating motor complex
MED minimal erythema dose
MAC minimum alveolar concentration
MICs minimum inhibitory concentrations
MAPK mitogen activated protein kinase
MD molecular dynamics
MO molecular orbital
MAO monoamine oxidase
MAOA monoamine oxidase A
MAOI monoamine oxidase inhibitors
OMe-PEG monomethyl polyethylene glycol
MCs mononuclear cells
MPA mycophenolic acid
NMTT N-methylthiotetrazole
TCP N‐tetrachlorophthaloyl
NDDO neglect of diatomic differential overlap
NCEs new chemical moieties
xii List of Abbreviations

NO nitric oxide
NVOC nitro veratryl oxycarbonyl
NBH nitrobenzhydryl linker
NBHA nitrobenzhydrylamine linker
NSAID nonsteroidal antiinflammatory drugs
NA noradrenaline
NET noradrenaline transporter
NMR nuclear magnetic resonance
ODV O-desmethylvenlafaxine
OR odds ratio
PT parallel tempering
PBP penicillin binding proteins
PFOS perfluorooctane sulfonate
PFOA perfluorooctanoic acid
PBC periodic boundary conditions
PAS peripheral anionic site
PAM phenyl acetamido methyl
PDE-5 phosphodiesterase-5
PRA plasma renin activity
PDGF platelet-derived growth factor
PARP poly-adenosine diphosphate ribose polymerase
PEG polyethylene glycol
PE potential energy
PES potential energy surface
PI propidium iodide
PGI prostacyclin
PGHS-1 prostaglandin endoperoxide H synthase-1
PG prostaglandins
PSA prostate-specific antigen
PKA protein kinase A
PKC protein kinase C
PPI proton pump inhibitor
PPTS pryidinium p-toluenesulfonate
QSAR quantitative structure-activity relationship
QSMR quantitative structure–metabolism relationship
QM quantum mechanics
RIA radioimmunoassay
RF ranking factors
List of Abbreviations xiii

RBL-1 rat basophilic leukemia

ROS reactive oxygen species
RTK receptor tyrosine kinase
REM replica exchange method
REMD replica exchange molecular dynamics
RPE retinal pigment epithelial
RMDD retrometabolic drug design
RMSD root mean squared deviation
RMSF root mean squared fluctuation
SEVI semen-derived enhancer of virus infection
SERT serotonin reuptake transporter
SMC smooth muscle cell
SD soft drugs
PBP penicillin-binding proteins
SRS spontaneous reporting systems
SD steepest descent
STZ streptozotocin
SHRSP stroke-prone spontaneously hypertensive rats
SAR structure activity relationship
SBP systolic blood pressure
TBAF tetrabutyl ammonium fluoride
TCP tetrachlorophthaloyl
TMA tetramethyl ammonium
TF theaflavins
TD thiamine diphosphate
TX thromboxanes
TSH thyroid-stimulating hormone
TRH thyrotropin-releasing hormone
TC total cholesterol
TBI traumatic brain injury
TFMSA trifluoromethane sulfonic acid
TG triglycerides
TMSE trimethylsilylethyl
TPH tryptophan hydroxylase
TNF tumor necrosis factor a
IV intravenous
XIAP X-linked inhibitor of apoptosis protein
FOREWORD

It is my pleasure to provide this foreword and to recommend this valuable

book to all who have been involved in research in medicinal chemistry. I
am absolutely delighted to learn that Debarshi Kar Mahapatra and Sanjay
Kumar Bharti, both distinguished researchers in the area of medicinal chem-
istry, have presented a very useful reference book that encompasses vari-
ous principles and applications associated with medicinal chemistry. As the
title implies, Handbook of Research on Medicinal Chemistry: Innovations
and Methodologies, this book integrates insights regarding drug discovery,
pharmacological aspects of natural products, druggable targets of chemical
mediators, and several classes of medicinal agents. The book is comprised
of 12 well-written chapters by various reputed authors across the globe.
The insightfulness of this book relies on the verity that the authors have
made use of their own knowledge in this area of research, and also cap-
tures contemporary relevant literature. From Chapter 1 to 12, a good skillful
blend of medicinal chemistry, chemical biology, chemical synthesis, phar-
macology, formulation, and miscellaneous subjects has been achieved. The
book demonstrates a prime focus toward drug discovery and development
using conventional or unconventional approaches. This book is illustrated
with several examples, diagrams, and figures, and is authored in a students
friendly manner. Although the book mainly focuses on medicinal chemistry,
it also incorporates an interesting chapter on pharmaceutical interactions,
which is a part of pharmacy practice. This book is meant to serve as a refer-
ence for students, chemists, biochemists, and pharmacologists interested in
learning about various interdisciplinary techniques of pharmaceutical rel-
evance. I am very confident that this book will deliver newer aspects and
applications in the field of medicinal chemistry.
—Vivekananda Mandal, PhD
Former WERC Researcher, Government of Japan;
Institute of Pharmaceutical Sciences
Guru Ghasidas University (Central University)
Bilaspur, Chhattisgarh, India
PREFACE

The unprecedented pace over recent years in the field of drugs has empha-
sized the relevance of pharmaceutical chemistry. With the development of
scientific thought and practices, this subject is no longer restricted to any
boundaries. This book is prepared with the objective to deliver the latest
advancements in the various fields of combinatorial chemistry, drug discov-
ery, biochemical aspects, pharmacology of medicinal agents, current practi-
cal problems, and nutraceuticals. The book aims to keep the drug molecule
as the central component and to explain the associated features essential to
exhibit pharmacological activity. Adopting a user-friendly format, like intro-
duction, prototype, mechanisms, techniques, procedures, kinetics, formula-
tions, toxicology, illustrations, etc., makes this book unique. It is a unique
combination of biology, clinical aspects, biochemistry, synthetic chemistry,
medicine and technology. The sole motive of the text is to provide a broad
exposure to the essential aspect of pharmaceuticals. Figures, pictures, flow-
charts, and illustrations make for an easy understanding of contents.
All the chapters are up to date, complete, and compiled in easy to repro-
duce format and availability of worthy content in only few pages. The book
includes the base of USP along with all the latest therapeutic guidelines put
forward by WHO & USFDA. Drug discovery remains an important part
of medicinal chemistry. In Chapter 1, accelerating the drug discovery pro-
cess by finding new chemical moieties (NCEs) faster using combinatorial
chemistry approach is discussed. In Chapter 2, molecular dynamics simula-
tion and methods to improve the sampling to overcome the convergence
problems of classical molecular dynamics have been discussed. The chapter
also focuses on ligand-protein interaction and protein folding carried out of
using molecular dynamics based methods. In Chapter 3, a retrometabolic
drug design approach is discussed with a focus on developing compounds
by predicting the metabolic pathways of the current lead compound and to
design novel analogs having predicted metabolic route, better therapeutic
index, and fewer side effects.
Natural products have been popular among the growing population due
to their varied advantages, and belief of being free from any side effects and
are a part of many traditions across the globe. Since the awareness among the
xviii Preface

population has increased, nutraceuticals have gained adequate importance

in daily life. Tea and its products are the most popular of them. Chapter 4
has focused on pharmacological targets, pharmacotherapeutics approaches,
and clinical aspects of Camellia sinensis. This chapter focuses on the ratio-
nal and science behind the use of natural supplements (or nutraceuticals) in
daily routine.
Men and women have since ages been curious to improve, revive and
maintain their sexual efficiency, and aphrodisiacs substances are employed
for this purpose. Sexual dysfunction among any of the sexes often results
in psychological stress, and affects quality of life. Chapter 5 describes vari-
ous aphrodisiac molecules obtained from both plant and animal sources for
treating sexual dysfunction. These molecules, in the form of whole plant,
are used in many nations and are considered safe for long-term use. The aim
of Chapter 6 is to describe the biosynthesis, metabolism, pathophysiologi-
cal roles, agonists and antagonists of serotonin. Chapter 7 deals with the
biochemistry, synthesis, pathophysiological functions, biochemical aspects,
and mechanism of action(s) of eicosanoids.
Chapter 8 highlights the emergence of drug resistance parasites that have
led to evolution of new approaches, such as modification of existing agents,
discovery of new natural compounds, and identification of new targets. This
chapter reviews the potential of newly synthesized compounds against plas-
modial resistance for the prevention and treatment of malaria. Chapter 9
describes the chemistry, essential structural features, pharmacology, synthe-
sis, structure activity relationships and applications of recently discovered
and newer generations of β-lactam analogs.
A research note on anesthetics has been presented in Chapter 10, where
pharmacodynamics, pharmacokinetic, drugs, their synthesis, mechanism of
action, toxicity aspects are described exhaustively. Chapter 11 describes a
detailed note on stereochemical aspects in medicinal chemistry. This chapter
comprehensively describes fundamentals, importance, influence, role and
advantages of stereochemistry in drug chemistry and pharmacology. Chapter
12 depicted the common drug interactions in daily practices.
ACKNOWLEDGMENTS

The editors would like to thank all the authors across the globe for their
generous contributions. Without their support the book would not have been
compiled. We respect their interest and sincere commitment for contributing
and working with us even they are have such busy schedules. Thanks are
also due to Apple Academic Press for their priceless support of this book.
—Debarshi Kar Mahapatra
Sanjay Kumar Bharti
ABOUT THE EDITORS

Debarshi Kar Mahapatra, PhD

Assistant Professor, Department of Pharmaceutical Chemistry, Dadasaheb
Balpande College of Pharmacy, RTM Nagpur University, Nagpur, India

Debarshi Kar Mahapatra, PhD, is currently Assistant Professor in the

Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of
Pharmacy, RTM Nagpur University, Nagpur, India. He taught medicinal and
computational chemistry at both the undergraduate and postgraduate levels
and has mentored students in their various research projects. His area of
interest includes computer-assisted rational designing and synthesis of low
molecular weight ligands against druggable targets, drug delivery systems,
and optimization of unconventional formulations. He has published research,
book chapters, reviews, and case studies in various reputed journals and has
presented his works at several international platforms, for which he received
several awards from a number of bodies. He has also authored a book titled
Drug Design. Presently, he is serving as a reviewer and editorial board mem-
ber for several journals of international repute. He is a member of a number
of professional and scientific societies, such as the International Society for
Infectious Diseases (ISID), the International Science Congress Association
(ISCA), and ISEI.

Sanjay Kumar Bharti, PhD

Assistant Professor, Institute of Pharmaceutical Sciences, Guru Ghasidas
Vishwavidyalaya (A Central University), Bilaspur, India

Sanjay Kumar Bharti, PhD, is Assistant Professor at the Institute of

Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central
University), Bilaspur, India. He has working experience in several organi-
zations, such as Win-Medicare Pvt. Ltd, Meerut, India (as a chemist) and
the National Institute of Pharmaceutical Education and Research (NIPER),
Hajipur (as a lecturer). He has published several research papers, one book,
several book chapters and review articles in various reputed journals. His
xxii About the Editors

research interests include synthesis of Schiff’s base, heterocyclic com-

pounds, and metallopharmaceuticals for therapeutics. He is an active
member of various scientific and pharmaceutical organizations, including
IPA, IPGA, ISCA, etc. Dr. Bharti has completed a BPharm from IT-BHU,
Varanasi, India, in 2003, an MPharm from RGPV, Bhopal, India, in 2004,
and a PhD from IIT-BHU, Varanasi, India, in 2011.
 PART I

TECHNIQUES IN DRUG DISCOVERY

CHAPTER 1

COMBINATORIAL CHEMISTRY:
ROLE IN LEAD DISCOVERY
PREMLATA K. AMBRE,1 ANISH N. GOMATAM,1
SANTOSH NANDAN,2 and EVANS C. COUTINHO1
1
Department of Pharmaceutical Chemistry, Bombay College of
Pharmacy, Kalina, Santacruz (E), Mumbai – 400098, India,
Tel: +91-22-26671871; E-mail: Premlata.ambre@gmail.com
2
Chemworx Pvt. Ltd., Kalina, Santacruz (E), Mumbai – 400098, India

CONTENTS

1.1
Introduction to Combinatorial Chemistry ..........................................4
1.2
Principles of Combinatorial Chemistry .............................................4
1.3
Combinatorial Libraries .....................................................................5
1.4
Characterization of Libraries Obtained from
Combinatorial Synthesis ..................................................................13
1.5 General Methods of Combinatorial Synthesis .................................15
1.6 Applicability of Combinatorial Technology ....................................23
1.7 Split and Mix Synthesis ...................................................................51
1.8 Screening..........................................................................................53
1.9 Strategies for Synthesis of Small Molecule Libraries......................54
1.10 Deconvolution/Identifying the HIT
from the Screening ...........................................................................55
1.11 Role in Drug Discovery ...................................................................57
Acknowledgement ......................................................................................60
Keywords ....................................................................................................60
References ...................................................................................................61
4 Handbook of Research on Medicinal Chemistry

1.1 INTRODUCTION TO COMBINATORIAL CHEMISTRY

Accelerating the drug discovery process by finding new chemical moieties

(NCEs) faster is a major objective in the field of medical research. Hunting
for a drug among the vast numbers of chemotypes, is a daunting task as is
evidenced by the small number of molecules that are approved as drugs even
though significant resources are expended on this activity. The drug discov-
ery process generally involves identification of a validated biological target
(enzyme, receptor, DNA & RNA) and developing a biological assay to hunt
for novel chemotypes as a starting point for drug design. After finding a novel
chemotype with the required biological activity multiple rounds of optimiza-
tion with respect to pharmacokinetics and drug metabolism lead to clinical
candidates. Drug hunters have evolved various strategies in order to perform
this task efficiently, among these combinatorial chemistry is a strategy that
has been used to efficiently sample the large chemical space that is available
to them. The starting point or the initial discovery of a novel chemotype with
the required biological activity is often called a “lead compound” and this
phase of drug discovery is often called the “lead discovery” phase. A suit-
able lead compound is a small molecule with measurable and reproducible
activity in the primary assay(s). In case the target is unknown then random
screening may be need to test many thousands or millions of compounds in
order to discover a lead. Combinatorial chemistry is designed to support the
lead discovery process. It is a technique by which a large number of structur-
ally distinct molecules can be synthesized together at a time and submitted
for focused or varied pharmacological assay. Combinatorial chemistry has
enabled the identification of many leads in drug discovery programs.

1.2 PRINCIPLES OF COMBINATORIAL CHEMISTRY

“Combinatorial synthesis involves synthesis of diverse analogs under the

same reaction conditions, in the same reaction vessel followed by identifica-
tion of the biologically most active compound for further development using
high-throughput screening” (Furka, 2007; Jung, 2008).
The main principle behind this combinatorial chemistry is the synthesis
of products all at a time from all possible combinations of a given set of
building blocks (starting material). The collection of these synthesized com-
pounds is referred to as a combinatorial library. This title is normally used
Combinatorial Chemistry: Role in Lead Discovery 5

when synthesis is done producing compound mixtures; however, if the step-

wise synthesis of individual compounds is made then they are designated as
‘arrays’. The combinatorial libraries are generally structurally related by a
central core structure, a common backbone, termed the scaffold. The total
number of compounds within the combinatorial library is determined by the
number of building blocks used per reaction, and the number of reaction
steps, in which a new building block is incorporated. The number of all
synthesized compounds (N) is given by the equation N = bn, where b is an
equal number of building blocks used in each reaction (1, 2, 3, ...) and n is
the number of reaction steps, in which a new building block is introduced
(Gallop, 1994; Houghten, 1991; Swartz, 2000).

1.3 COMBINATORIAL LIBRARIES

The creation of libraries composed of hundreds or thousands or millions

of molecules by combining and mixing solid supports and various building
blocks or by parallel addition of substrates at a time during the organic reac-
tion is the main goal of combinatorial chemistry. A library of compounds
is an ensemble of compounds that have originated from the same assembly
strategy and building blocks. The members of a library exhibit a common
core structure with different appended substituents. This assembly strategy
defines the position and sequence of addition of the building blocks. The
assembly strategy can be illustrated by the examples shown in Figure 1.1.

Assembly of compounds

Different building blocks

a;tb ;tc

One linear assembly One /multiple directed

One core structure
al -3

1\
b
33 = 27 compounds 3x3x3 = 27 (a-b-c) 1\
a-c b- e
a--c - b
1>-a- c 3x3x3x6 = 162 3x3x3x2 =54
b-e-e
c-a-b
c-b-a

FIGURE 1.1 Strategy for preparation of assembly of compounds or libraries.

6 Handbook of Research on Medicinal Chemistry

If a, b, and c are the three different building blocks assembled in a linear

fashion, then the expected library would have either 27 products or in a
nonlinear fashion the library would have 162 products with the basic core
structure. If the building blocks are assembled in a cyclic fashion then the
same building block assembly gives rise to 54 products in a library. In addi-
tion to this assembly strategy of reactive building blocks, the focus remains
on the solid-phase chemistry that uses suitable resins and linkers on which
the synthesis of the structurally diverse set of small-molecular weight com-
pound libraries is achieved (Obrecht, 1998).
A library made by the process described above, suffers from low hit rates
(low actives), partly because the library members possess poor structural
diversity and have poor physicochemical properties, and partly because they
are produced with the aim for quantity rather than quality. The key to synthe-
sizing a diverse combinatorial library is a thorough knowledge about the rela-
tionship between the structure of a molecule and its physiological function.
An ideal combinatorial library should be relatively small and should con-
tain chemically and functionally diverse compounds; each having a distinct
biological activity, oral bioavailability and less toxicity (Welsch et al., 2010).
A good library, thus, has to take into account the requirements of both the
products that will be made and the reagents that will be used to synthesize
them. A general scheme for the design of a combinatorial library is demon-
strated in Figures 1.2 and 1.3.
Following are the general considerations while designing a combinato-
rial library:
a. overall similarity or diversity to a target;
b. drug-like properties;
c. predicted activity;
d. deconvolution/decoding strategy;
e. availability of reagents;
f. cost of reagents;
g. combinatorial constraints (Brown et al., 2000).
To achieve good success while synthesizing such a library, careful thought
must be given in the following five steps:
i) use of computational techniques to enumerate all possible com-
pounds, creating a so called ‘virtual library’, keeping in mind factors
such as reagent availability and synthetic feasibility;
ii) choosing a subset out of these compounds which is representative of
the virtual library;
Another random document with
no related content on Scribd:
water, whether in one of those dismal swamps swarming with
loathsome reptiles, or by the margin of the clear blue waters that
bathe the Keys of Florida, is large, flat, and composed of sticks,
often so loosely put together as to make you wonder how it can hold,
besides itself, the three young ones which this species and all the
larger Herons have at a brood. In a few instances only have I found it
compactly built, it being the first nest formed by its owners. It almost
always overhangs the water, and is resorted to and repaired year
after year by the same pair. The eggs, which are never more than
three, measure two inches and a quarter in length, an inch and five-
eighths in breadth, and when newly laid are smooth, and of a pale
blue colour, but afterwards become roughish and faded. When the
nest is placed on a tall tree, the young remain in it, or on its borders,
until they are able to fly; but when on a low tree or bush, they leave it
much sooner, being capable of moving along the branches without
fear of being injured by falling, and knowing that should they slip into
the water they can easily extricate themselves by striking with their
legs until they reach either the shore or the nearest bush, by clinging
to the stem, of which they soon ascend to the top.
This Egret is shy and vigilant at all times, seldom allowing a person
to come near unless during the breeding season. If in a rice-field of
some extent, and at some distance from its margins, where cover
can be obtained, you need not attempt to approach it; but if you are
intent on procuring it, make for some tree, and desire your friend to
start the bird. If you are well concealed, you may almost depend on
obtaining one in a few minutes, for the Egrets will perhaps alight
within twenty yards or less of you. Once, when I was very desirous of
making a new drawing of this bird, my friend John Bachman
followed this method, and between us we carried home several
superb specimens.
The long plumes of this bird being in request for ornamental
purposes, they are shot in great numbers while sitting on their eggs,
or soon after the appearance of the young. I know a person who, on
offering a double-barrelled gun to a gentlemen near Charleston, for
one hundred White Herons fresh killed, received that number and
more the next day.
The Great Egret breeds in company with the Anhinga, the Great
Blue Heron, and other birds of this family. The Turkey Buzzards and
the Crows commit dreadful havoc among its young, as well as those
of the other species. My friend John Bachman gives me the
following account of his visit to one of its breeding places, at the
“Round O,” a plantation about forty miles from Charleston: “Our
company was composed of Benjamin Logan, S. Lee, and Dr
Martin. We were desirous of obtaining some of the Herons as
specimens for stuffing, and the ladies were anxious to procure many
of their primary feathers for the purpose of making fans. The trees
were high, from a hundred to a hundred and thirty feet, and our shot
was not of the right size; but we commenced firing at the birds, and
soon discovered that we had a prospect of success. Each man took
his tree, and loaded and fired as fast as he could. Many of the birds
lodged on the highest branches of the cypresses, others fell into the
nest, and, in most cases, when shot from a limb, where they had
been sitting, they clung to it for some time before they would let go.
One thing surprised me: it was the length of time it took for a bird to
fall from the place where it was shot, and it fell with a loud noise into
the water. Many wounded birds fell some distance off, and we could
not conveniently follow them on account of the heavy wading
through the place. We brought home with us forty-six of the large
White Herons, and three of the great Blues. Many more might have
been killed, but we became tired of shooting them.”

Ardea Egretta, Gmel. Syst. Nat. vol. i. p. 629.—Lath. Ind. Ornith. vol. ii. p.
694.
Ardea alba, Ch. Bonaparte, Synopsis of Birds of United States, p. 304.
 Great White Heron, Ardea Egretta, Wils. Amer. Ornith. vol. vii. p. 106, pl.
61, fig. 1.
Ardea Egretta, Wagler, Syst. Avium,—Great White Heron, Nuttall,
Manual, vol. ii. p. 47.
Ardea Leuce, Illiger, Lichtenstein.

Adult Male in Summer. Plate CCCLXXXVI.

Bill much longer than the head, straight, compressed, tapering to a
point, the mandibles nearly equal. Upper mandible with the dorsal
line nearly straight, the ridge broad and slightly convex at the base,
narrowed and becoming rather acute towards the end, a groove from
the base to two-thirds of the length, beneath which the sides are
convex, the edges thin and sharp, with a notch close to the acute tip.
Nostrils basal, linear, longitudinal, with a membrane above and
behind. Lower mandible with the angle extremely narrow and
elongated, the dorsal line beyond it ascending and almost straight,
the edges sharp and direct, the tip acuminate.
Head small, oblong, compressed. Neck very long and slender. Body
slender and compressed. Feet very long, tibia elongated, its lower
half bare, slender, covered anteriorly and laterally with hexagonal
scales, posteriorly with scutella; tarsus elongated, compressed,
covered anteriorly with numerous scutella, some of which are divided
laterally and posteriorly with angular scales. Toes of moderate
length, rather slender, scutellate above, granulate beneath; third toe
considerably longer than the fourth, which exceeds the second; the
first large; the claws of moderate length, rather strong, arched,
compressed, rather acute, that of the hind toe much larger, the inner
edge of that of the third regularly pectinated.
Space between the bill and eye, and around the latter, bare.
Plumage soft, blended; the feathers oblong, with their filaments
generally disunited, unless on the wings and tail. There is no crest
on the head, but the feathers on its upper and hind part are slightly
elongated; those on the lower part of the neck anteriorly are
elongated; and from between the scapulæ arises a tuft of extremely
long, slightly decurved feathers, which extend about ten inches
beyond the end of the tail, and have the shaft slightly undulated, the
filaments long and distant. The wing is of moderate length; the
primaries tapering but rounded, the second and third longest, the
first slightly shorter than the fourth; the secondaries broad and
rounded, some of the inner as long as the longest primaries, when
the wing is closed. Tail very short, small, slightly rounded, of twelve
rather weak feathers.
Bill bright yellow, as is the bare space between it and the eye; iris
pale yellow; feet and claws black. The plumage is pure white.
Length to end of tail 37 inches, to end of claws 49, to end of wings
57 1/4, to carpus 23 1/2, to end of dorsal plumes 57; bill along the
ridge 4 7/12, along the edge of lower mandible 5 5/12; wing from
flexure 16 1/2; tail 6 1/4; extent of wings 55; bare part of tibia 3 1/2;
tarsus 6 1/12; hind toe 1 1/2, its claw 1 2/12; second toe 2 8/12, its claw
7/12; third toe 3 11/12, its claw 9/12; fourth toe 3 2/12, its claw 7 1/2/12.
Weight 2 1/4 lb.

The Female is similar to the male, but somewhat smaller.

The roof of the mouth is slightly concave, with a median and two
lateral longitudinal ridges, the palate convex, the posterior aperture
of the nares linear, without an anterior slit. The mouth is rather
narrow, measuring only 8 twelfths across, but is dilatable to 1 1/2
inch, the branches of the lower mandible being very elastic. The
aperture of the ear is very small, being 2 twelfths in diameter, and
roundish. The œsophagus is 2 feet 2 inches long, 1 inch and 4
twelfths in diameter, extremely thin, the longitudinal fibres within the
transverse, the inner coat raised into numerous longitudinal ridges.
The œsophagus continues of uniform diameter, and passes as it
were directly into the stomach, there being no enlargement at its
termination indicative of the proventriculus, which however exists,
but in a modified form, there being at the termination of the gullet
eight longitudinal series of large mucous crypts, about half an inch
long, and immediately afterwards a continuous belt, 1 1/2 inch in
breadth, of small cylindrical mucous crypts with minute apertures.
Beyond this the stomach forms a hemispherical sac 1 1/2 inch in
diameter, of a membranous structure, having externally beneath the
cellular coat a layer of slender muscular fibres, convex towards two
roundish tendons, and internally a soft, thin, smooth lining,
perforated by innumerable minute apertures of glandules. The
intestine is very long and extremely slender, measuring 6 feet 7
inches in length, its average diameter 2 twelfths. The rectum, b d f, is
3 inches long; the cloaca, d e f, globular, 1 1/2 inch in diameter; the
cœcum, c, single, as in the other Herons, 3 twelfths long, and nearly
2 twelfths in diameter.
The trachea is 1 foot 9 1/4 inches long, of nearly uniform diameter,
flattened a little for about half its length, its greatest breadth 3 1/2
twelfths; the rings 285, the last four rings divided and arched. The
contractor muscles are extremely thin, the sterno-tracheal moderate,
and coming off at the distance of 1 inch from the lower extremity,
from which place also there proceeds to the two last rings a pair of
slender inferior laryngeal muscles. The bronchi are very short, of
about two half rings.

Tapayaxin.

The animal represented on the plate is the Tapayaxin of Hernandez,

Phrynosoma orbicularis of Wiegmann, Tapaya orbicularis of Cuvier.
The specimen from which it was drawn was entrusted to my care by
my friend Richard Harlan, M. D., to whom it was presented by Mr
Nuttall, who found it in California. A notice respecting this species
by Dr Harlan will be found in the American Journal of Science and
Arts, vol. xxxi.
 GLOSSY IBIS.

Ibis Falcinellus, Vieill.

PLATE CCCLXXXVII. Male.

The first intimation of the existence of this beautiful species of Ibis

within the limits of the United States is due to Mr George Ord of
Philadelphia, the friend and companion of the celebrated Alexander
Wilson. It was described by him in the first volume of the Journal of
the Academy of Natural Sciences of Philadelphia. He states that “on
the seventh of May of the present year (1817), Mr Thomas Say
received from Mr Oram, of Great Egg Harbour, a fine specimen of
Tantalus, which had been shot there. It is the first instance which has
come to my knowledge of this species having been found in the
United States. I was informed that a recent specimen of this bird
was, likewise in the month of May, presented to the Baltimore
Museum, and that two individuals were killed in the district of
Columbia.” In the sequel Mr Ord compares it with Dr Latham’s
account of the Tantalus Mexicanus of that author, and conjectures
that it is the same.
It is not a little curious to see the changes of opinion that have taken
place within these few years among naturalists who have thought of
comparing American and European specimens of the birds which
have been alleged to be the same in both continents. The Prince of
Musignano, for example, who has given a figure of the very
individual mentioned by Mr Ord, thought at the time when he
published the fourth volume of his continuation of Wilson’s
American Ornithology, that our Glossy Ibis was the one described by
the older European writers under the name of Ibis Falcinellus. Now,
however, having altered his notions so far as to seem desirous of
proving that the same species of bird cannot exist on both the
continents, he has latterly produced it anew under the name of Ibis
Ordi. This new name I cannot with any degree of propriety adopt. I
consider it no compliment to the discoverer of a bird to reject the
name which he has given it, even for the purpose of calling it after
himself.
The Glossy Ibis is of exceedingly rare occurrence in the United
States, where it appears only at long and irregular intervals, like a
wanderer who has lost his way. It exists in Mexico, however, in vast
numbers. In the spring of 1837, I saw flocks of it in the Texas; but
even there it is merely a summer resident, associating with the White
Ibis, along the grassy margins of the rivers and bayous, and
apparently going to and returning from its roosting places in the
interior of the country. Its flight resembles that of its companion, the
White Ibis, and it is probable that it feeds on the same kinds of
crustaceous animals, and breeds on low bushes in the same great
associations as that species, but we unfortunately had no
opportunity of verifying this conjecture. Mr Nuttall, in his
Ornithology of the United States and Canada, says that “a specimen
has occasionally been exposed for sale in the market of Boston.”
I have given the figure of a male bird in superb plumage, procured in
Florida, near a wood-cutter’s cabin, a view of which is also given.

Tantalus Falcinellus, Linn. Syst. Nat. vol. i. p. 241.—Lath. Ind. Ornith. vol.
ii, p. 707.
Ibis Falcinellus, Vieill. Nouv. Dict. d’Hist. Nat.—Ch. Bonaparte, Synopsis of
Birds of United States, p. 311.—Wagler, Syst. Avium.
Glossy Ibis, Ibis Falcinellus, Ch. Bonap. Amer. Ornith. vol. iv. p. 23.
 Tantalus igneus, Gmel. Syst. Nat. vol. i. p. 649.—Lath. Ind. Ornith. vol. ii. p.
708. Adult.
Tantalus viridis, Gmel. Syst. Nat. vol. i. p. 648.—Lath. Ind. Ornith. vol. ii. p.
707. Young.
Numenius castaneus, Briss. vol. v. p. 329. Adult.
Numenius viridis, Briss. vol. v. p. 326. Young.
Tantalus Mexicanus? Ord, Journal of Acad. of Sciences of Philadelphia, vol.
i. p. 53.
Bay or Glossy Ibis, Nuttall, Manual, vol. ii. p. 88.

Adult Male. Plate CCCLXXXVII.

Bill very long, slender, higher than broad, compressed, tapering,
acute, obtuse. Upper mandible with the dorsal line arched in its
whole length, the ridge convex, broader towards the end, the sides
at the base nearly erect, towards the end very convex and narrow,
the ridge separated in its whole length from the sides by a deep
narrow groove, the edges inflected and sharp. Nostrils basal, dorsal,
linear, direct. Lower mandible more slender than the upper, its angle
very narrow, and protracted in the form of a groove to the tip, the
sides convex, the edges sharp, but strong and closely approximated,
bearing only a very narrow groove between them.
Head small, compressed, oblong; neck long and slender; body
slender, deeper than broad; wings rather large. Feet very long,
slender; tibia long, bare about half its length, and covered all round
with hexagonal scales; tarsi long, slender, anteriorly covered with
numerous broad scutella, laterally with angular scales, beneath
flattened, with thick soft margins; the anterior connected at the base
by membranes, of which the outer is large; claws rather small,
slightly arched, compressed, tapering, pointed, that of the middle toe
with a sharp thin edge.
There is a bare space margining the forehead, occupying the part
before the eye, and extending a little beyond it. Feathers of the head
and neck slender lanceolate; those of the former glossy and
compact, of the latter blended, as are those of the breast and
abdomen, which are ovate. The upper parts highly glossed, with silky
lustre, the feathers generally ovate and rounded. Wings long, ample,
the first primary a quarter of an inch shorter than the second, which
is two-twelfths longer than the third, the rest moderately graduated;
the first sinuate on the inner web near the end, the second less
deeply so; some of the inner secondaries elongated, but rounded,
and when the wing is closed an inch and ten-twelfths shorter than
the longest primary. Tail short, very slightly emarginate, of twelve
rounded feathers.
Bill black; bare part of the head greyish-blue; iris hazel; feet greyish-
black, claws brown. The upper part and sides of the head are dark
glossy, with purplish reflections. The neck, a portion of the back
anteriorly, the breast, abdomen, and legs, are of a deep rich
brownish-red, or dark chestnut; part of the breast shaded with green,
the sides dusky tinged with green, as are the lower wing-coverts,
and lower tail-coverts. Excepting the anterior edge of the wing, and
the anterior scapulars, which are deep glossy brownish-red, the
upper parts are splendent dark green, glossed with purple; the
primaries black, shaded with green; the tail glossy with purple
reflections.
Length to end of tail 25 inches; to end of claws 30 1/2; bill along the
ridge 5 4/12, along the edge of lower mandible 5 2/12; wing from
flexure 11 1/4; tail 4 1/4; bare part of tibia 2 1/2; hind toe 1 1/12, its claw
5 1/4/ ; second toe 1 11/12, its claw 6
1/
/12; third toe 2 8/12, its claw
4
12
7/12; fourth toe 2 4/12, its claw 5/12.

The Female is similar to the male, but somewhat less.

The young in its second plumage, has the bill dusky, tinged with
yellow, the bare part of the head dusky; the feet blackish-brown, the
head, neck and lower parts are greyish-brown, the head and greater
part of the neck marked with small longitudinal streaks of white, of
which there are two on each feather. All the upper parts are blackish-
green, glossy in a less degree than those of the adult.
On comparing adult American specimens with others obtained on
the old continent, I can perceive no difference between them. A
young Mexican bird, and one from India, are also precisely similar. I
cannot therefore entertain a doubt as to the identity of our bird with
the Tantalus Falcinellus of Latham and other European writers,
which has been shewn by Savigny to be the Black Ibis of the
ancients.
SUBSCRIBERS TO “THE BIRDS OF AMERICA,”
OBTAINED SINCE THE PUBLICATION OF THE THIRD VOLUME.

Miss Elizabeth L. Pickman, Salem, Massachusetts.

The Salem Atheneum, Salem, Massachusetts.
Augustus Thorndike, Esq. Boston, Massachusetts.
J. J. Hughes, Esq. Manchester, Mississippi.
John Hunt, Esq. Mobile, Alabama.
L. Baldwin, Esq. Civil Engineer, Boston.
The Honourable Daniel Webster, Boston.
Samuel Swartout, Esq. New York.
James Watson Webb, Esq. New York.
Thomas H. Faile, Esq. New York.
Lewis Rogers, Esq. New York.
Henry Hitchcock, Mobile, Alabama.
Jer. Van Rensselaer, Esq. M. D., New York.
The Honourable Levy Woodbury, Washington City, for the State Departments.
Stephen A. Halsey, Hallet’s Cove, Long Island.
The State of Michigan, by Governor Mason.
Thomas Metcalf, Esq. Augusta, Georgia.
Henry Clay, junior, Esq. Ashland, Kentucky.
H. C. De Rham, junior, Esq. New York.
Benjamin Phillips, Esq., F.R.S.L., &c. &c. &c. 17 Wimpole Street, London.
Henry G. Bohn, Esq., London.
John Gould, Esq. F.L.S., &c. London.
Charles J. Warde, Esq. Welcomb, near Stratford-on-Avon.
The British Museum, London.
His Grace the Duke of Northumberland, &c. &c. &c.
Earl Hardwicke, &c. &c. &c. Wimpole, Arlington, Cambridge.
Sir Jacob Hastley, Bart., &c. &c. 7 Cavendish Square, London.
 INDEX.
Page
Alea impennis, 316
American Avoset, 168
—— Bittern, 296
—— Dipper, 493
—— Ring Plover, 256
—— White Pelican, 88
—— Widgeon, 337
Anas americana, 237
—— Breweri, 302
—— clypeata, 241
—— discors, 111
—— obscura, 15
—— strepera, 353
Anhinga, 136
Anser hyperboreus, 562
Aramus Scolopaceus, 543
Ardea cœrulea, 58
—— Egretta, 600
—— minor, 296
—— violacea, 290
—— virescens, 274
Arkansaw Flycatcher, 422
Ash-coloured Sandpiper, 130
Auk, Great, 316
Avoset, American, 168

Band-tailed Pigeon, 479

Bank Swallow, 584
Bartramian Sandpiper, 24
Bittern, American, 296
Black Skimmer, 203
Black-bellied Plover, 280
Black-cap Titmouse, 374
Black-headed Grosbeak, 519
Black-headed Gull, 118
Black-necked Stilt, 247
Black-shouldered Hawk, 367
Black-throated Bunting, 579
—— Diver, 345
Blue Heron, 58
Blue-winged Teal, 111
Bohemian Chatterer, 462
Bombycilla garrula, 462
Bonapartian Gull, 212
Brewer’s Duck, 302
Buffel-headed Duck, 217
Bunting, Black-throated, 579
Buzzard, Common, 508

Canvass-back Duck, 1
Charadrius helveticus, 280
—— montanus, 362
—— semipalmatus, 256
Chatterer, Bohemian, 462
Chestnut-backed Titmouse, 371
Chestnut-crowned Titmouse, 382
Clarke’s Nutcracker, 459
Cinclus Americanus, 493
Cleome heptaphylla, 558
Cock of the Plains, 503
Columba fasciata, 479
Colymbus arcticus, 345
—— glacialis, 43
Common Buzzard, 508
—— Gannet, 222
—— Magpie, 408
—— Tern, 74
Corvus Nuttalli, 450
—— Pica, 408
—— Stelleri, 453
—— ultramarinus, 456
Courlan, Scolopaceous, 543
Crossbill, White-winged, 467
Cygnus Buccinator, 536

Dipper, American, 493

Diver, Black-throated, 345
—— Great Northern, 43
Duck, Brewer’s, 302
—— Buffel-headed, 217
—— Canvass-back, 1
—— Dusky, 15
—— Gadwall, 353
—— Golden-eye, 318
—— Long-tailed, 103
—— Pied, 271
—— Red-headed, 198
—— Ruddy, 326
—— Shoveller, 241
—— Surf, 161
Dusky Duck, 15
Dusky Grous, 446

Egret, Great American, 600

Emberiza americana, 579
—— lapponica, 472
Evening Grosbeak, 515

Falco Buteo, 508

—— cyaneus, 396
—— dispar, 367
—— fuscus, 522
Falcon, Iceland, 476
—— Jer, 476
Finch, Macgillivray’s, 394
Flycatcher, Arkansaw, 422
—— Say’s, 420
—— Swallow-tailed, 426
Fringilla Linaria, 533
—— Macgillivraii, 394
—— melanocephala, 519
—— vespertina, 515
Fuligula Albeola, 217
—— clangula, 318
—— Ferina, 198
—— glacialis, 103
—— labradora, 271
—— perspicillata, 161
—— rubida, 326
—— valisneriana, 1
Gadwall Duck, 353
Gallinula martinica, 37
Gallinule, Purple, 37
Gannet, Common, 222
Glossy Ibis, 608
Godwit, Tell-tale, 68
Golden-eye Duck, 318
Goosander, 261
Goose, Snow, 562
Great American Egret, 600
—— Auk, 316
—— Cinereous Owl, 364
—— Northern Diver, 43
Green Heron, 274
Grous, Dusky, 446
—— Rock, 483
—— Sharp-tailed, 569
Grosbeak, Black-headed, 519
—— Evening, 515
—— Pine, 414
Guillemot, Little, 304
Gull, Black-headed, 519
—— Bonapartian, 212
—— Laughing, 118

Hawk, Black-shouldered, 367

—— Marsh, 396
—— Owl, 550
—— Sharp-shinned, 522
—— Slate-coloured, 522
Heron, Blue, 58
—— Green, 274
—— Yellow-crowned, 290
Himantopus nigricollis, 247
Hirundo riparia, 584
—— serripennis, 593
—— thalassina, 597
Humming Bird, Ruff-necked, 555

Ibis Falcinellus, 608

—— Glossy, 608
Iceland Falcon, 476

Jay, Steller’s, 453

—— Ultramarine, 456
Jer Falcon, 476

Knot, 130

Lapland Longspur, 472

Larus Atricilla, 118
—— Bonapartii, 212
Laughing Gull, 118
Least Petrel, 310
—— Tern, 175
—— Water Rail, 359
Lepus palustris, 510
Lesser Redpoll, 533
Little Guillemot, 304
—— Sandpiper, 180
Long-eared Owl, 572
Long-legged Sandpiper, 332
Longspur, Lapland, 472
Long-tailed Duck, 103
Loon, 43
Louisiana Tanager, 385
Loxia leucoptera, 467

Macgillivray’s Finch, 394

Magpie, Common, 408
—— Magpie, Yellow-billed, 450
Marsh Hare, 510
—— Hawk, 396
Martin, Sand, 584
Mergus Albellus, 350
—— Merganser, 261
Mocking Bird, Mountain, 487
Mountain Mocking Bird, 487
Muscicapa forficata, 426
—— Saya, 428
—— verticalis, 422

Northern Diver, 43
Nucifraga columbiana, 459
Nun, White, 350
Nutcracker, Clarke’s, 459

Owl, Great Cinereous, 364

—— Hawk, 550
—— Long-eared, 572
—— Tengmalm’s, 559

Parus atricapillus, 374

—— minimus, 382
—— rufescens, 371
Pelecanus Americanus, 88
Pelican, American, White, 88
—— White, 88