Contents lists available at ScienceDirect Phytochemistry Letters journal homepage: www.elsevier.com/locate/phytol Anti-inflammatory metabolites from endophytic fungus Fusarium sp Maan T. Khayat a , Sabrin R.M. Ibrahim b,c , Gamal A. Mohamed d,e, ⁎ , Hossam M. Abdallah d,f a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia b Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah Al Munawwarah 30078, Saudi Arabia c Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt d Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia e Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt f Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt ARTICLEINFO Keywords: Fusarium sp. Ergosterol Fusaristerol Endophytic fungi Anti-inflammatory 5-Lipoxygenase inhibitory Structural activity relationship ABSTRACT Three new ergosterol derivatives, namely, fusaristerols B [(22E,24R)-3-palmitoyl-19(10→6)-abeo-ergosta- 5,7,9,22-tetraen-3β-ol] (1),C[(22E,24R)-ergosta-7,22-diene-3β,6β,9α-triol] (3),andD[(22E,24R)-ergosta-7,22- diene-3β,5α,6β,9α-tetraol 6-acetate] (4),alongwith(22E,24R)-5β,8β-epidioxyergosta-22-en-3β-yl decanoate (2) and(22E,24R)-ergosta-7,22-dien-3β-ol(5),wereisolatedandcharacterizedfromtheendophyticfungus Fusarium sp. isolated from Mentha longifolia L. (Labiatae) roots growing in Saudi Arabia. The structures of the isolated metabolites were verified based on UV, IR, NMR (1D and 2D), HRMS, and a comparison with the literature. All the metabolites were assessed for 5-lipoxygenase (5-LOX) inhibitory potential. Compounds 1 and 2 possessed 5- LOX inhibitory potential with an IC 50 sof3.61and2.45μM,respectively,comparedtothatofindomethacin(IC 50 1.17 μM). In addition, their structure-activity relationship was discussed. 1. Introduction The inflammation process is regulated by a precisely modulated reaction between the cells and inflammatory mediators (Chen et al., 2018). The inflammatory mediators include lipoxygenase (LOXs) and cyclo-oxygenases (COX-1 and 2) enzymes, cytokines, such as tumour necrosis factor (TNF)-α and the interleukins (ILs), nitric oxide (NO), prostaglandin E2 (PGE2), and the transcription factor designated as the nuclear factor (NF)-κB. They are released from the activated in- flammatory cells (neutrophils, eosinophils, mononuclear phagocytes, and macrophages) (Al-Attas et al., 2015; Nguyen et al., 2015). The 5- LOX enzyme catalyses the biosynthesis of leukotrienes (LTs) from ara- chidonic acid (AA) (Rådmark et al., 2015). The LTs play a significant role in numerous inflammatory diseases, such as rheumatoid arthritis, ulcerative colitis, asthma, and atherosclerosis, as well as several types of cancers (Akdis et al., 2016; Radmark et al., 2007). Therefore, 5-LOX inhibition has become the focus of many therapeutic approaches to treat many proliferative and inflammatory diseases (Mashima and Okuyama, 2015). Recently, the search for bioactive secondary meta- bolites from edible and medicinal fungi and the study of their me- chanisms on chronic diseases, such as inflammatory disorders, have progressively increased (Chenetal.,2017). Endophytic microorganisms are bacteria or fungi that live inside plant tissues without causing da- mage or disease symptoms to their hosts (Elkhayat et al., 2016; Ibrahim et al., 2015). Early investigations of the genus Fusarium have proven that it is a rich source of secondary metabolites with diverse bioactiv- ities (Ibrahim et al., 2016a,b,c; 2018a,b,c,d,e). Our previous study of Fusarium sp. led to the isolation of tetracyclic triterpenoids, a peptide, and ergosterol derivatives (Ibrahim et al., 2016b, c; 2018a,c,e). During our ongoing research to discover potentially active compounds from Fusarium sp., the chemical investigation of its CHCl 3 /MeOH extract resulted in the separation and identification of three new metabolites, fusaristerols B–D (1, 3,and 4), together with two known compounds (2 and 5). Their structures were verified by various spectroscopic methods. In addition, the 5-LOX inhibitory capacity of these metabo- lites was assessed and their structure-activity relationship was dis- cussed. 2. Results and discussion 2.1. Purification of the metabolites The endophytic fungus Fusarium sp. was cultured on rice medium. The rice culture CHCl 3 /MeOH extract was submitted to various https://doi.org/10.1016/j.phytol.2018.11.024 Received 21 October 2018; Received in revised form 21 November 2018; Accepted 27 November 2018 ⁎ Corresponding author at: Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. E-mail address: gahussein@kau.edu.sa (G.A. Mohamed). Phytochemistry Letters 29 (2019) 104–109 1874-3900/ © 2018 Phytochemical Society of Europe. Published by Elsevier Ltd. All rights reserved. T