Phytochemical and pharmacological analysis of certain plants applied in the Iranian and European folk medicine Ph.D. Thesis Javad Mottaghipisheh Szeged 2020 University of Szeged Faculty of Pharmacy Department of Pharmacognosy PHYTOCHEMICAL AND PHARMACOLOGICAL ANALYSIS OF CERTAIN PLANTS APPLIED IN THE IRANIAN AND EUROPEAN FOLK MEDICINE Ph.D. Thesis Javad Mottaghipisheh Supervisor: Assoc. Prof. Dr. Dezső Csupor Szeged, Hungary 2020 University of Szeged Doctoral School of Pharmaceutical Sciences Pharmacognosy Ph.D programme Programme director: Prof. Dr. Judit Hohmann Pharmacognosy Department Supervisor: Assoc. Prof. Dr. Dezső Csupor Javad Mottaghipisheh Phytochemical and pharmacological analysis of certain plants applied in the Iranian and European folk medicine Defence Board: Chair: Prof. Dr. Judit Hohmann Member: Dr. Attila Hunyadi, Dr. Gábor Janicsák Assessment Board: Chair: Prof. Dr. Zsolt Szakonyi, DSc Opponents: Dr. Gábor Janicsák, PhD Dr. Sándor Gonda, PhD Members: Dr. Györgyi Horváth, PhD Dr. Tamás Sovány, PhD Dedication I wish to dedicate this work to my wife, Nasim who her patience that cannot be underestimated, my parents, who have always urged me, the soul of my brother, and my nephews. This thesis would not have been possible without their love, encouragement, and appreciation for higher education. Acknowledgments I wish to express my sincere appreciation to my supervisor, Assoc. Prof. Dr. Dezső Csupor, who has the substance of a genius: he convincingly guided and encouraged me to be professional and do the right thing even when the road got tough. Without his persistent help, the goal of this project would not have been realized. I am deeply indebted to Prof. Judit Hohmann as head of the Department of Pharmacognosy for providing me all the opportunities to perform experimental work. My special thanks to all of my friends in the lab, whose assistance was a milestone in the completion of this project Dr. Tivadar Kiss, Attila Horváth, Dr. Zoltán Péter Zomborszki, Dr. Martin Vollár, Dr. Diána Kerekes, Balázs Kovács, and Háznagyné Dr. Erzsébet Radnai, besides whole the staff members at the Department of Pharmacognosy for their valuable help and support, specifically Dr. Norbert Kúsz and Dr. Yu-Chi Tsai for the NMR experiments. I am very grateful to Department of Pharmacology and Pharmacotherapy, Department of Pharmacognosy, and Department of Surgery, University of Pécs, Pécs, Hungary, and Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary for assessing the pharmacological activities, and Department of Horticultural Science, Faculty of Agriculture, Shahid Chamran University of Ahvaz, Ahvaz, Iran, for analysing the essential oils. LIST OF PUBLICATIONS RELATED TO THE THESIS I. Sándor Z1, Mottaghipisheh J1, Veres K, Hohmann J, Bencsik T, Horváth A, Kelemen D, Papp R, Barthó L, Csupor D. Evidence supports tradition: the in vitro effects of Roman chamomile on smooth muscles. Frontiers in Pharmacology Ethnopharmacology 2018, 9: 323. Impact factor (2017): 4.4, D1 II. Mottaghipisheh J, Nové M, Spengler G, Kúsz N, Hohmann J, Csupor D. Antiproliferative and cytotoxic activities of furocoumarins of Ducrosia anethifolia. Pharmaceutical Biology 2018, 56: 658-664. Impact factor (2017): 1.91, Q1 III. Piri E, Mahmoodi Sourestani M, Khaleghi E, Mottaghipisheh J, Zomborszki ZP, Hohmann J, Csupor D. Chemo-diversity and antiradical potential of twelve Matricaria chamomilla L. accessions from Iran: a proof of ecological effects. Molecules 2019, 24, pii: E1315. Impact factor (2018): 3.060, Q1 IV. Mottaghipisheh J, Mahmoodi Sourestani M, Kiss T, Horváth A, Tóth B, Ayanmanesh M, Khamushi A, Csupor D. Comprehensive chemotaxonomic analysis of saffron crocus tepal and stamen samples, as raw materials with potential antidepressant activity. Journal of Pharmaceutical and Biomedical Analysis 2020, 184, 113183. Impact factor (2018): 2.983, Q1 1 Both authors contributed equally to this work TABLE OF CONTENTS 1. INTRODUCTION ............................................................................................................................... 1 2. AIMS OF THE STUDY ........................................................................................................................ 2 3. LITERATURE OVERVIEW .................................................................................................................. 3 3.1. CHAMAEMELUM NOBILE (L.) ALL. .......................................................................................... 3 Taxonomy of C. nobile .................................................................................................... 3 Phytochemistry of C. nobile ............................................................................................ 3 Folk medicinal use of C. nobile ....................................................................................... 3 Bioactivities of C. nobile .................................................................................................. 3 3.2. MATRICARIA CHAMOMILLA L. ................................................................................................ 4 Taxonomy of M. chamomilla .......................................................................................... 4 Phytochemistry of M. chamomilla .................................................................................. 4 Folk medicinal use of M. chamomilla ............................................................................. 5 Bioactivities of M. chamomilla ........................................................................................ 5 3.3. DUCROSIA ANETHIFOLIA (DC.) BOISS. .................................................................................... 5 Taxonomy of D. anethifolia ............................................................................................. 5 Phytochemistry of D. anethifolia .................................................................................... 5 Folk medicinal use of the Ducrosia genus and D. anethifolia ......................................... 7 Bioactivities of the Ducrosia genus and D. anethifolia ................................................... 7 3.4. EREMURUS PERSICUS (JAUB. & SPACH) BOISS. ...................................................................... 8 Taxonomy of E. persicus ................................................................................................. 8 Phytochemistry of the Eremurus genus and E. persicus ................................................. 8 Folk medicinal use of the Eremurus genus and E. persicus ............................................ 8 Bioactivities of the Eremurus genus and E. persicus ...................................................... 8 3.5. CROCUS SATIVUS L. ................................................................................................................. 9 Taxonomy of saffron crocus ............................................................................................ 9 Folk medicinal application of saffron crocus stigma ....................................................... 9 Phytochemistry of saffron crocus ................................................................................. 10 Pharmacological activities of saffron crocus ................................................................. 12 4. MATERIALS AND METHODS .......................................................................................................... 13 4.1. SCIENTIFIC DATA COLLECTION .............................................................................................. 13 4.2. IDENTIFICATION AND COLLECTION OF THE PLANT MATERIALS ........................................... 13 Chamaemelum nobile ................................................................................................... 13 Matricaria chamomilla .................................................................................................. 14 Ducrosia anethifolia ...................................................................................................... 14 Eremurus persicus ......................................................................................................... 14 Crocus sativus ............................................................................................................... 14 4.3. PHYTOCHEMICAL AND BIOACTIVITY ANALYSIS .................................................................... 14 Chamaemelum nobile ................................................................................................... 14 Matricaria chamomilla .................................................................................................. 16 Ducrosia anethifolia ...................................................................................................... 18 Eremurus persicus ......................................................................................................... 22 4.4. CHARACTERIZATION AND STRUCTURE ELUCIDATION .......................................................... 24 4.5. ANALYSIS OF C. sativus l. samples ......................................................................................... 24 Extract preparation ....................................................................................................... 24 HPLC apparatus and measurement conditions ............................................................. 25 System validation .........................................................................................................