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Novel Synthetic and Biological Studies on Benzothiazoles, Benzimidazoles, Oxazolidinones and Pyrazolopyrimidine Bharath Yarlagad

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Novel Synthetic and Biological Studies on Benzothiazoles, Benzimidazoles, Oxazolidinones and Pyrazolopyrimidine Bharath Yarlagad NOVEL SYNTHETIC AND BIOLOGICAL STUDIES ON BENZOTHIAZOLES, BENZIMIDAZOLES, OXAZOLIDINONES AND PYRAZOLOPYRIMIDINE A THESIS Submitted by BHARATH YARLAGADDA for the award of the degree of DOCTOR OF PHILOSOPHY DEPARTMENT OF SCIENCE AND HUMANITIES VIGNAN’S FOUNDATION FOR SCIENCE, THECHNOLOGY AND RESEARCH UNIVERSITY, VADLAMUDI GUNTUR – 522213, ANDHRA PRADESH, INDIA MAY 2017 i Dedicated To My Beloved Parents ii DECLARATION I certify that a. The work contained in the thesis is original and has been done by myself under the general supervision of my supervisor. b. I have followed the guidelines provided by the Institute in writing the thesis. c. I have conformed to the norms and guidelines given in the Ethical Code of Conduct of the Institute. d. Whenever I have used materials (data, theoretical analysis, and text) from other sources, I have given due credit to them by citing them in the text of the thesis and giving their details in the references. e. Whenever I have quoted written materials from other sources, I have put them under quotation marks and given due credit to the sources by citing them and giving required details in the references. f. The thesis has been subjected to plagiarism check using professional software and found to be within the limits specified by the University. g. The work has not been submitted to any other Institute for any degree or diploma. (Y.BHARATH) iii THESIS CERTIFICATE This is to certify that the thesis entitled “NOVEL SYNTHETIC AND BIOLOGICAL STUDIES ON BENZOTHIAZOLES, BENZIMIDAZOLES, OXAZOLIDINONES AND PYRAZOLOPYRIMIDINE” submitted by Y.BHARATH to the Vignan’s Foundation for Science, Technology and Research University, Vadlamudi. Guntur for the award of the degree of Doctor of Philosophy is a bonafide record of the research work done by him under my supervision. The contents of this thesis, in full or in parts, have not been submitted to any other Institute or University for the award of any degree or diploma. Prof. Mandava Venkata Basaveswara Rao Research Guide Professor, Dept. of chemistry, Krishna University, Machilipatnam, Andhra Pradesh, India Dr.D.Nagaraju Research Co-Guide Professor, Dept. of Science and humanities VFSTR University, Andhra Pradesh, India iv ACKNOWLEDGEMENTS It gives me a great pleasure to express my gratitude and indebtedness to my research supervisor, Prof. M. Venkata Basveswara Rao, for his inspiring guidance, and constant encouragement. I feel fortunate that during this formative period, I got to associate with him who has given me the much-needed boost and showed a direction to my career. I owe him a great deal for his inspiring guidance, wise counsel, unfailing attention without which this work would not have come to this stage. I express my deepest sense of thanks to Dr. K. Naveen Kumar, Sr.GM, Dr. D. Nagaraju, Associate professor, for his wise counsel, moral support and valuable suggestions at every instant. It is also an appropriate time to remember all my teachers and professors who at various stages of my educational carrier encouraged me to reach this level and it all is the fruit of their teaching and blessings. I am indebted to the present Director Dr. L. Rathaiah, vice chancellor, for having given me an opportunity to carry out the work and allowing me to submit in the form of thesis. I wish to express my sincere thanks to Dr. N. srinivasa Rao, Head of the department for providing the necessary facilities foe carrying out the research work. I would like to thank the Doctoral committee panel, Dr. K. Prabakara Rao, Dr. M. Shaik Annvar, M.srinivasslu and other staff of VFSTER University for their cooperation and timely help during the course of my work. I wish to express my sincere thanks to Dr. Vidhu Kampurath Poduvattil, Prof. Dr. Murthy Chavali S.S.S. Yadav, and Dr.madhusudan Rao for their cooperation and timely help in submitting my thesis. It gives me immense pleasure to thank my seniors and colleagues, Mr. G. Adisheshagiri Rao, Mr. A. Sreekanth, Mr. Ch. Raja Raghunadha Raddy, Mr. K. Vijay Gopal, Mr. G. Satish Babu who have rendered their assistance whenever needed without hesitation. My special thanks to my friends Mr. N. Kranthi & Sravanthi, Mr. Y. Krishna Sumanth & Madhavi Latha, D.Rajesh & Bharathi , for their encouragement. v I owe more than myself to my beloved parents and wife who always dreamt that I reach golden heights and sky is the only limit to my success, to them I dedicate the thesis. I am deeply grateful to my brother, sisters and brother-in-laws as a great encouragement and support throughout my research work. I wish to express my thanks to the NMR, Mass, Analytical, Library and Glass blowing sections Finally, I am grateful to VFSTER University, Mylan Laboraties ltd., Hyderabad, India. Y. BHARATH vi ABSTRACT NOVEL SYNTHETIC AND BIOLOGICAL STUDIES ON BENZOTHIAZOLES, BENZIMIDAZOLES, OXAZOLIDINONES AND PYRAZOLOPYRIMIDINE Heterocyclic compounds are important building blocks used to build up compounds of biological or medicinal chemistry interest to chemists. A huge number of heterocyclic building blocks have applications in pharmaceutical research, agriculture, and drug discovery. Keeping in view of the importance of the hetero cyclic ring containing compounds, in the present thesis describes the synthetic and biological studies on some of the important category of drug substances particularly Benzothiazole , Benzimidazole ,oxazolidinones and pyrazolopyrimidine containing hetero cyclic ring. Here the thesis containing research work on novel benzothiazole scaffolds , new synthetic method for the preparation of benzimidazole has been developed using a new catalyst Gd (OTf) 3 under microwave irradiation, C-ring modified and C-5 Substituted new oxazolidino amide/sulfonamides conjugates and the ultrasound assisted synthesis of a series of 2- alkynyl pyrazolo[1,5-a] pyrimidine derivatives . The total work carried out in the present research programme is being presented in six chapters. Chapter 1: This chapter describes a general introduction on benzothiazoles and oxazolidinones, mechanism of action, pharmacological aspects of Benzothiazoles, Benzimidazole and oxazolidinones. It also covers the preface about the Benzothiazole, Benzimidazole and oxazolidinones and their medicinal importance. Chapter 2: The second chapter describes the review on heterocyclic compounds and its importance in drug discovery. Chapter 3: Chapter three describes the synthesis of biologically active compounds which consist of two distinct pharmocophores; benzothiazoles and triazoles, Facile synthesis of N- (benzyl-1H-1,2,3-triazol-5-yl) methyl)-4-(6-methoxybenzo[d]thiazol-2-yl)-2-nitrobenzamides via click chemistry. vii Chapter 4: Efficient method Microwave irradiation for synthesis of 2-substituted benzimidazole from 1, 2- phenylenediamine and β-keto esters /1, 3-di ketones using Gd (OTf) 3 as a Catalyst. Chapter 5: This chapter deals with the importance of oxazolidinones in medicinal research, Structural Modification of Oxazolidinones via Multistep synthesis and their impact on antitubercular and antibacterial activity. Experimental procedures are also included. The activity data of compounds are included. Chapter 6: The method development for the 2-alkynyl pyrazolo [1, 5-a] pyrimidine framework might provide a template for the discovery of novel and potential anticancer agents, environmentally benign method for the preparation of pyrazolo-pyrimidine rings and experimental procedures were described . KEYWORDS: Hetero cyclic compounds, benzothiazole, benzimidazole, oxazolidinones and 2-alkynyl pyrazolopyrimidine. viii GENERAL REMARKS 1. Infrared spectra were recorded on Perkin-Elmer-683 series spectrometer with KBr optics. 2. Proton Nuclear Magnetic Resonance spectra were recorded on Bruker Avance 300, Varian Unity 400 and Avance 500 spectrometers using tetramethylsilane (TMS) as an internal standard and chemical shifts are shown in δ scale. 3. Electron Impact (EI), ESI, HR MS and Chemical ionization mass spectra (CIMS) were recorded on VG micro mass 70-70 H instrument 70 ev. 4. Melting points were recorded on Buchi-510 melting point apparatus and are uncorrected. 5. Elemental analyses were carried out on Elemental Vario Micro Cube Elementar instrument (Germany) apparatus. 6. Microwave irradiations were carried out on 300W (CEM-discover, model number- 908010). 7. Silica gel 60/120(120-125 micron) mesh and 100/200 (75-120 micron) mesh used for column chromatography was purchased from Avra synthesis chemical company. 8. All reactions were monitored by thin layer chromatography (TLC) on precoated silica gel 60G F254 (20x20 cm.) (Merck); spots were visualized with UV light (254 nm). ix CONTENTS List of Tables xiii-xiv List of Figures xv-xvi List of Abbreviations xvii-xviii Page No. CHAPTER 1: INTRODUCTION OF HETEROCYCLES 1- 25 1.1 Benzothiazole 1.2 Importance Of Benzothiazole Nucleus 1.3 Characteristics Of Nucleus 1.4 Applications 1.5 Benzimidazoles 1.6 Importance of Benzimidazoles 1.7 Oxazolidinones 1.8 Current Strategies 1.9 Present Work CHAPTER 2: REVIEW ON HETEROCYCLIC COMPOUNDS 26 - 55 2.1. Introduction 2.2. Nitrogen Containing Heterocycles 2.3. Oxygen Containing Heterocycles 2.4. Sulfur Containing Heterocycles 2.5. Heterocyclic Molecules with More Than One Atom CHAPTER 3: SYNTHESIS OF BENZOTHIAZOLE -TRIZOLES HYBRIDS COMPOUNDS via CLICK CHEMISTRY 56- 90 3.1. Introduction 3.2. General methods for the synthesis of benzothiazoles x 3.3. Present Work 3.4. Experimental Procedure 3.5. Biological Evaluation 3.6. Conclusion 3.7. Spectrums CHAPTER 4: MICROWAVE IRRADIATION FOR
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