Hydroxamic Acids

Satya P. GuptaEditor

Hydroxamic Acids

A Unique Family of Chemicals withMultiple Biological Activities

123

EditorSatya P. GuptaDepartment of Pharmaceutical TechnologyMeerut Institute of Engineering and TechnologyMeerutIndia

ISBN 978-3-642-38110-2 ISBN 978-3-642-38111-9 (eBook)DOI 10.1007/978-3-642-38111-9Springer Heidelberg New York Dordrecht London

Library of Congress Control Number: 2013943569

� Springer-Verlag Berlin Heidelberg 2013This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part ofthe material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformation storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodology now known or hereafter developed. Exempted from this legal reservation are briefexcerpts in connection with reviews or scholarly analysis or material supplied specifically for thepurpose of being entered and executed on a computer system, for exclusive use by the purchaser of thework. Duplication of this publication or parts thereof is permitted only under the provisions ofthe Copyright Law of the Publisher’s location, in its current version, and permission for use mustalways be obtained from Springer. Permissions for use may be obtained through RightsLink at theCopyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law.The use of general descriptive names, registered names, trademarks, service marks, etc. in thispublication does not imply, even in the absence of a specific statement, that such names are exemptfrom the relevant protective laws and regulations and therefore free for general use.While the advice and information in this book are believed to be true and accurate at the date ofpublication, neither the authors nor the editors nor the publisher can accept any legal responsibility forany errors or omissions that may be made. The publisher makes no warranty, express or implied, withrespect to the material contained herein.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Preface

Hydroxamic acids, which can be represented by a general formula RCONR0OH,where R, R0 may be aryl or substituted aryl moiety, constitute a very unique familyof chemicals that possess a wide spectrum of biological activities. They act asselective inhibitors of many enzymes, such as matrix metalloproteinases (MMPs),peroxidases, hydrolases, ureases, lipoxygenases, cyclooxygenases, histone deace-tylase and peptide deformylases, and consequently possess hypotensive, anti-cancer, anti-malarial, anti-tuberculosis and anti-fungal properties. Their CONHOHmoiety has been identified as a key functional group to develop potential thera-peutic agents targeting cardiovascular diseases, HIV, Alzheimer’s disease, allergicdiseases, metal poisoning and iron overload. Hydroxamic acids are also usedindustrially as anti-oxidants, inhibitors of corrosion, for the extraction of toxicelements, as a means of flotation of minerals and even for their ability to serve asredox switches for electronic devices. They can also act as nitric oxide donors.This versatility of hydroxamic acids depends on their ability to act as a bidentateligand to chelate with metal ions such as Fe2? and Zn2? at the active site of theenzymes. Their hydroxamic acid moiety, CONHOH, is not only a strong metal-binding group but also possesses multiple sites for potential hydrogen bondinteractions with the enzymes. Thus, the metal-chelating property and multiplehydrogen-bond formation ability of hydroxamic acids have made them anintriguing family of compounds with a wide spectrum of therapeutic roles. One ofthe first therapeutic roles of hydroxamic acids was associated with their use assiderophores, a class of low molecular weight iron-sequestering agents. Sidero-phores have vast therapeutic potential to deal with iron overload in transfusion-dependent patients, such as those suffering from thalassemia. Because of theseenormous therapeutic applications, the hydroxamic acids have greatly drawn theattention of both theoretical and experimental chemists to make studies on themfor the design and development of drugs against a number of diseases. This booktherefore presents some very interesting chapters on them, written by experts,covering their various chemical and pharmaceutical aspects.

The book contains 11 chapters in total. Since the multi-faceted activity of hy-droxamic acids depends on the chemical aspects of these compounds, the very firstchapter written by Gupta and Anjana describes in detail The Chemistry ofHydroxamic Acids covering their synthesis, structure, chelating, hydrogen-bonding

v

and nitric oxide releasing properties, and general mechanism of inhibition of var-ious enzymes. The second chapter written by Kakkar on Theoretical Studies onHydroxamic Acids further adds to their chemistry, discussing their conformation,tautomerism, metal ion selectivity, and complexation.

Among the various enzymes which have been found to be inhibited byhydroxamic acids, the carbonic anhydrases (CAs), MMPs and histone deacetylases(HDACs) have been most widely studied. Therefore, the three consecutiveChaps. 3–5, namely Hydroxamic Acids as Carbonic Anhydrase Inhibitors bySupuran, Structure–Activity Relationships of Hydroxamic Acids as MatrixMetalloproteinase Inhibitors by Patil and Gupta and Hydroxamic Acidsas Histone Deacetylase Inhibitors by Thaler et al. describe vividly the differenttypes of hydroxamic acids inhibiting these enzymes and their structure–activityrelationships. However, no less important have been hydroxamic acids acting asinhibitors of ribonucleotide reductase, as the inhibitors of this enzyme have beendeveloped as potent anticancer agents. Therefore, Chap. 6 Hydroxamic Acidsas Ribonucleotide Reductase Inhibitors written by Basu and Sinha presents a fewkinds of hydroxamates that inhibit carbonucleotide reductase, their mode of action,and progress in computer-aided SAR studies on them leading to the developmentof anticancer drugs.

Inhibitors of MMPs, HDACs, and ribonucleotide reductase have been devel-oped as potent anticancer drugs. Therefore, a discussion of the inhibitors of theseenzymes that belong particularly to hydroxamic acid class and have been eval-uated against cancers have been nicely presented by Gupta et al. in Chap. 7 entitledas Hydroxamic Acid Derivatives as Anticancer Agents. These authors also discussin this chapter the future prospects of design of potent anticancer agents based onhydroxamic acids.

Since HDAC inhibitors have been most attractive as anticancer agents, detailedquantitative structure–activity relationship (QSAR) studies have also been madeon them in order to find the physicochemical and structural properties of thecompounds governing their activity, so that the design of potent anticancer drugsmay be rationalized. Hadjipavlau-Litina and Pontiki, therefore, presented inChap. 8 entitled as Quantitative Structure-Activity Relatioship Studies on Hydro-xamic Acids Acting as Histone Deacetylase Inhibitors a detailed account ofQSAR studies on hydroxamic acids acting as HDAC inhibitors. All 2D and 3DQSAR studies pointed out that anticancer activity of these compounds are basi-cally controlled by their hydrophobic and streric properties.

The activity of the enzyme urease, which is produced in the body by a bac-terium called Helicobacter pylori (H. pylori), plays a critical role in the patho-genesis of several diseases, such as urinary tract infections, urolithiasis,pyelonephritis, hepatic encephalopathy, hepatic coma, cancer, etc. Therefore, theinhibitors of urease have been greatly studied and hydroxamic acids have occupiedthe foremost position among the urease inhibitors. Thus Chap. 9 HydroxamicAcids as Inhibitors of Urease in the Treatment of Helocobactor pylori Infectionswritten by Muri and Barros gives a detailed account of hydroxamic acids acting asurease inhibitors and of their structure–activity relationships. The chapter also

vi Preface

describes the new technologies for the delivery of effective urease inhibitors in thebody.

Hydroxamic acid derivatives have recently been recommended for the thera-peutic treatment of several diseases, such as hypertension, cancer, as well asinflammations and infectious diseases, due to their ability to chelate metals,especially in metalloenzymes. In Chap. 10 entitled as Therapeutic Potentialof Hydroxamic Acids for Microbial Diseases, Rodrigues et al. therefore present thepotential use of hydroxamates and their derivatives for the treatment and control ofsuch diseases, along with a general overview of their structure, synthesis andinhibition mechanism. Application of hydroxamic acids as chelating mineralcollectors for ore beneficiation is a unique area of their use and has attracted theattention of limited workers in this unique area. Therefore, a review of the use ofalkyl and aryl hydroxamic acids in mineral processing is finally presented byNatarajan in Chap. 11 entitled as Hydroxamic Acids as Chelating MineralCollectors. In this chapter, basic information on mineral flotation chemistry isprovided for the non-expert.

Thus an attempt has been made to cover all aspects of hydroxamic acids, aunique class of chemicals having multiple biological activities. Articles covered inthis book are not only of interest to those working in this area but also to generalreaders. As an editor of this book, I have greatly enjoyed reading all the chaptersand also hope the readers will do so. I greatly acknowledge the interest and zeal ofall the authors for contributing such interesting and useful chapters.

Meerut (U.P), India Satya P. Gupta

Preface vii

Contents

The Chemistry of Hydroxamic Acids . . . . . . . . . . . . . . . . . . . . . . . . . 1Satya P. Gupta and Anjana Sharma

Theoretical Studies on Hydroxamic Acids . . . . . . . . . . . . . . . . . . . . . 19Rita Kakkar

Hydroxamates as Carbonic Anhydrase Inhibitors . . . . . . . . . . . . . . . . 55Claudiu T. Supuran

Structure–Activity Relationship Studies of HydroxamicAcids as Matrix Metalloproteinase Inhibitors . . . . . . . . . . . . . . . . . . . 71Vaishali M. Patil and Satya P. Gupta

Hydroxamic Acids as Histone Deacetylase Inhibitors . . . . . . . . . . . . . 99Florian Thaler, Vaishali M. Patil and Satya P. Gupta

Hydroxamates as Ribonucleotide Reductase Inhibitors . . . . . . . . . . . . 153Arijit Basu and Barij Nayan Sinha

Hydroxamic Acid Derivatives as Potential Anticancer Agents . . . . . . . 173Manish K. Gupta, Gagandip Singh and Swati Gupta

Quantitative Structure–Activity Relationship Studies onHydroxamic Acids Acting as Histone Deacetylase Inhibitors . . . . . . . . 205Dimitra Hadjipavlou-Litina and Eleni Pontiki

Hydroxamic Acids as Inhibitors of Urease in the Treatmentof Helicobacter pylori Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241E. M. F. Muri and T. G. Barros

ix

Therapeutic Potential of Hydroxamic Acids for Microbial Diseases . . . 255Giseli Capaci Rodrigues, Flavia Alexandra Gomes de Souza,Whei Oh Lin and Alane Beatriz Vermelho

Hydroxamic Acids as Chelating Mineral Collectors . . . . . . . . . . . . . . 281Ramanathan Natarajan

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

x Contents