LJMU Research Online Mohammadhosseini, M, Venditti, A, Sarker, SD, Nahar, L and Akbarzadeh, A The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review http://researchonline.ljmu.ac.uk/id/eprint/9786/ Article Citation (please note it is advisable to refer to the publisher’s version if you intend to cite from this work) Mohammadhosseini, M, Venditti, A, Sarker, SD, Nahar, L and Akbarzadeh, A (2018) The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review. Industrial Crops and Products, 129. pp. 350-394. ISSN 0926-6690 LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. 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For more information please contact [email protected] http://researchonline.ljmu.ac.uk/ 1 The genus Ferula: ethnobotany, phytochemistry and 2 bioactivities - a review 3 1* 2 4 Majid Mohammadhosseini , Alessandro Venditti , Satyajit D. 3 3 4 5 Sarker , Lutfun Nahar , and Abolfazl Akbarzadeh 6 1Department of Chemistry, Shahrood Branch, Islamic Azad University, 7 Shahrood, Iran 8 2Dipartimento di Chimica, Università di Roma “La Sapienza”, Piazzale Aldo 9 Moro 5, 00185 Rome, Italy 10 3Medicinal Chemistry and Natural Products Research Group, School of 11 Pharmacy and Biomolecular Sciences, Liverpool John Moores University, 12 Byrom Street, Liverpool L3 3AF, United Kingdom 13 4Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, 14 Iran 15 16 *Corresponding author at: Department of Chemistry, Shahrood Branch, Islamic 17 Azad University, Shahrood, Iran. Tel: +98-023-32394530; Fax: +98-023- 18 32394537 19 E-mail addresses: 20 [email protected]; [email protected]; 21 [email protected] (M. Mohammadhosseini) 1 22 The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review 23 24 Table of Contents 25 Abstract ................................................................................................................................................... 3 26 1. Introduction ......................................................................................................................................... 3 27 2. Research methodology ........................................................................................................................ 5 28 3. Ethnobotany and traditional usage of the Ferula species ................................................................... 6 29 4. Chemical profiles of the essential oils, extracts, resins and volatiles ……………………………...11 30 5. Phytochemistry of the Ferula species (2000 to March 2018) ........................................................... 15 31 5.1. Coumarin derivatives ................................................................................................................. 16 32 5.1.1. Hemiterpene coumarins .......................................................................................................... 16 33 5.1.2. Monoterpene coumarins .......................................................................................................... 16 34 5.1.3. Sesquiterpene coumarins ........................................................................................................ 17 35 5.1.4. Coumarinyl esters ................................................................................................................... 19 36 5.1.4.1. Dihydrofuranocoumarinyl esters .......................................................................................... 20 37 5.2. Prenylated benzoic acid derivatives ........................................................................................... 20 38 5.3. Sesquiterpene chromones ........................................................................................................... 20 39 5.4. Sesquiterpenes ............................................................................................................................ 21 40 5.5. Sulfur containing metabolites .................................................................................................... 24 41 5.6. Miscellaneous ............................................................................................................................ 25 42 7. The bioactivities of diverse characterized compounds from the genus Ferula ................................. 28 43 7.1. Anti-HIV activity ....................................................................................................................... 29 44 7.2. Inhibitory activity on cytokine production ................................................................................. 29 45 7.3. Inhibitory activity on NO production ......................................................................................... 30 46 7.4. The inhibitory on Epstein-Barr virus early antigen (EBV-EA) activation ................................. 30 47 7.5. Inhibitory against Plasmodium falciparum ................................................................................ 31 48 7.6. Antineuroinflammatory potential in LPS-activated BV-2 microglial cells ............................... 31 49 7.7. Cytotoxicity................................................................................................................................ 31 50 7.8. Antibacterial and antimicrobial activity ..................................................................................... 34 51 7.9. Anti-inflammatory activity ........................................................................................................ 36 52 7.10. Inhibitory behavior of transcription-activating factors for iNOS mRNA ................................ 36 53 7.11. Antiprolifertive/anticancer activity .......................................................................................... 37 54 7.12. Antioxidant activity ................................................................................................................. 40 55 7.13. The antileishmanial activity ..................................................................................................... 40 56 7.14. The ferulosis ............................................................................................................................. 41 57 8. Propagation of Ferula species........................................................................................................... 44 2 58 9. Conclusion and future perspectives .................................................................................................. 47 59 Acknowledgments ................................................................................................................................. 49 60 References ............................................................................................................................................. 51 61 62 Abstract 63 This study aims to provide a comprehensive overview of the medicinal, folkloric and 64 traditional culinary uses of Ferula species, related products and extracts in different countries 65 together with the description of recently isolated new components and the related 66 bioactivities. The phytochemical composition of the essential oils (EOs), oleo-gum-resin 67 (OGR) and the non-volatile fractions obtained from several endemic and indigenous Ferula 68 species is also reported. A special emphasis is placed on their unusual components, i.e. 69 sulfur-containing volatiles from the EOs and the new phytochemicals with mixed biogenetic 70 origins. More than 180 chemical constituents (excluding common essential oils components), 71 including sulfur-containing metabolites, terpenoids, coumarins, sesquiterpene coumarins, 72 etc., as both aglycones and glycosides, are reported, along with their occurrence and 73 biological activities when available. A large number of new secondary metabolites, belonging 74 to different classes of natural products possessing interesting biological activities, from the 75 antiproliferative to the anti-inflammatory to the neuroprotective ones, among the others, have 76 been recently found in the Ferula genus. Several of these phytochemicals are exclusive to 77 this genus; therefore may be considered chemotaxonomic markers. All these aspects are 78 extensively discussed in this review. 79 Keywords: Ferula spp.; Apiaceae; Ethnomedicine; Secondary metabolites; Traditional uses; 80 Essential oil; Non-volatile components 81 1. Introduction 3 82 The genus Ferula, the third largest genus of the Apiaceae (alt. Umbelliferae) family, is 83 composed of ca. 180 species (Yaqoob and Nawchoo, 2016), 15 of which are endemic to Iran 84 (Mozaffarian, 1996), nine species to Turkey, seven to China (Yaqoob and Nawchoo, 2016) 85 and one species to Italy (Conti et al, 2005), and the rest are indigenous entities of several 86 other countries. 87 The majority of the Ferula plants have a pungent odor and can be