Naturally Occurring Isocoumarins Derivatives from Endophytic Fungi: Sources, Isolation, Structural Characterization, Biosynthesis, and Biological Activities
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molecules Review Naturally Occurring Isocoumarins Derivatives from Endophytic Fungi: Sources, Isolation, Structural Characterization, Biosynthesis, and Biological Activities Ahmad Omar Noor 1, Diena Mohammedallam Almasri 1, Alaa Abdullah Bagalagel 1 , Hossam Mohamed Abdallah 2,3 , Shaimaa Gamal Abdallah Mohamed 4, Gamal Abdallah Mohamed 2,5 and Sabrin Ragab Mohamed Ibrahim 6,7,* 1 Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; [email protected] (A.O.N.); [email protected] (D.M.A.); [email protected] (A.A.B.) 2 Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; hmafifi[email protected] (H.M.A.); [email protected] (G.A.M.) 3 Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt 4 Faculty of Dentistry, British University, El Sherouk City, Suez Desert Road, Cairo 11837, Egypt; [email protected] 5 Pharmacognosy Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt 6 Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah Al-Munawwarah 30078, Saudi Arabia 7 Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt * Correspondence: [email protected]; Tel.: +966-581183034 Received: 9 December 2019; Accepted: 13 January 2020; Published: 17 January 2020 Abstract: Recently, the metabolites separated from endophytes have attracted significant attention, as many of them have a unique structure and appealing pharmacological and biological potentials. Isocoumarins represent one of the most interesting classes of metabolites, which are coumarins isomers with a reversed lactone moiety. They are produced by plants, microbes, marine organisms, bacteria, insects, liverworts, and fungi and possessed a wide array of bioactivities. This review gives an overview of isocoumarins derivatives from endophytic fungi and their source, isolation, structural characterization, biosynthesis, and bioactivities, concentrating on the period from 2000 to 2019. Overall, 307 metabolites and more than 120 references are conferred. This is the first review on these multi-facetted metabolites from endophytic fungi. Keywords: endophytes; isocoumarins; dihydroisocoumarins; biosynthesis; biological activities 1. Introduction The search for new metabolites for the agrochemical and pharmaceutical industries is an on-going work that needs continual optimization. Fungi are eukaryotic microorganisms that reside in almost all environmental types in nature where they have key roles in preserving the ecological balance [1,2]. Endophytes primarily inhabit their hosts without causing any harm to the hosts [3–6]. These endophytic fungi have played pivotal roles in their host’s survival through supplying nutrients and producing plenty of bioactive metabolites to prevent the danger of phytopathogenic bacteria on the host [7,8]. Endophytic fungi have gained loads of attention in natural products chemistry field due to their sustainability to biosynthesize structurally diverse and bioactive molecules, some of which are important agrochemicals and pharmaceuticals [9,10]. Isocoumarins (1H-2-benzopyran-1-ones or isochromene derivatives) are a class of biosynthetically, structurally, and pharmacologically intriguing natural products, which Molecules 2020, 25, 395; doi:10.3390/molecules25020395 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 109 chemistry field due to their sustainability to biosynthesize structurally diverse and bioactive molecules,Molecules 2020 some, 25, 395 of which are important agrochemicals and pharmaceuticals [9,10]. Isocoumarins2 of 94 (1H-2-benzopyran-1-ones or isochromene derivatives) are a class of biosynthetically, structurally, and pharmacologically intriguing natural products, which are coumarins isomers with a reversed lactoneare coumarins moiety isomersthat could with possess a reversed 6,8-dioxygenated lactone moiety pattern, that could3-(un)substituted possess 6,8-dioxygenated phenyl ring or pattern,3-alkyl 3-(un)substituted phenyl ring or 3-alkyl chain (C1-C17)[11,12]. The oxygenation could exist at one chain (C1-C17) [11,12]. The oxygenation could exist at one or more of the six free positions of the isocoumarinor more of the skeleton. six free positionsThe oxygen of theatoms isocoumarin may be in skeleton. the form The ofoxygen ethereal, atoms phenolic, may beorin glycosidic the form functionalities.of ethereal, phenolic, Additionally, or glycosidic C-3 substituents functionalities. are Additionally,found more commonly C-3 substituents on both are natural foundmore and syntheticcommonly isocoumarins on both natural derivatives. and synthetic Substituents isocoumarins that exist derivatives. on the isocoumarin Substituents ring that may exist involve on the alkyl,isocoumarin halogen, ring heterocyclic, may involve aryl alkyl,, or halogen, other groups heterocyclic, [13]. Furthermore, aryl, or other groupsthe saturation [13]. Furthermore, of C-3/C-4 thein isocoumarinssaturation of C-3will/C-4 give in 3,4-dihydroisocoumarins isocoumarins will give 3,4-dihydroisocoumarins (DHICs) analogs (Figure (DHICs) 1). analogs (Figure1). Figure 1. Isocoumarin,Isocoumarin, 3,4-dihydroisocoumarin, 3,4-dihydroisocoumarin, coumarin, coumarin, and isochr isochromanoman skeletons. Moreover, isocoumarinsisocoumarins andand DHICsDHICs possess possess a a close close relation relation with with isochromans, isochromans, they they are are known known as asisochromen-1-one isochromen-1-one and isochroman-1-ones,and isochroman-1-ones, respectively, respectively, since the since C-1 activethe C-1 methylene active inmethylene isochromans in isochromanscan be easily oxidizedcan be easily to the oxidized related isocoumarins to the related derivatives. isocoumarins Most derivatives. of the natural Most isocoumarins of the natural and isocoumarinsDHICs are given and trivial DHICs names, are given which trivial are derivednames, which mainly are from derived the name mainly of the from species the name or genus of the of speciesthe host or organisms. genus of Theythe host have organisms. been reported They from have a broadbeen scopereported of natural from a sources, broad scope including of natural plants, sources,microbes, including marine organisms, plants, microbes, bacteria, marine insects, organism liverworts,s, bacteria, and fungi insects, (e.g., soil, liverworts, endophytic, and andfungi marine (e.g., soil,fungi) endophytic, [14,15]. Isocoumarins and marine are fungi) considered [14,15]. as Isocou importantmarins intermediates are considered in the as synthesisimportant of intermediates a wide range inof carbo-the synthesis and heterocyclic of a wide compounds range of carbo- such as and isoquinolines, heterocyclic isochromenes, compounds such and diasff erentisoquinolines, aromatic isochromenes,compounds [16 and]. Thus, different isocoumarin aromatic framework compounds has [16]. been exploredThus, isocoumarin in various areas,framework including has drugbeen exploreddiscovery, in pharmaceutical various areas, including and medicinal drug chemistry, discovery, and pharmaceutical organic synthesis and medicinal [13]. It has chemistry, been reported and organicthat these synthesis metabolites [13]. possessIt has been various reported bioactivities: that these antimicrobial, metabolites cytotoxic, possess algicidal,various bioactivities: antiallergic, antimicrobial,immunomodulatory, cytotoxic, antimalarial, algicidal, plantantiallerg growthic, regulatory,immunomodulatory, and acetylcholinesterase antimalarial, plant and proteasegrowth regulatory,inhibitors [ 11and,17 –acetylcholinesterase20]. This review aims and to protease give a highlight inhibitors on [11,17–20]. the naturally This occurring review aims isocoumarins to give a highlightderivatives on reported the naturally from endophytic occurring fungi,isocoumarins focusing derivatives on the period reported from2000 from to endophytic July 2019.Herein, fungi, focusing307 naturally on the occurring period isocoumarinsfrom 2000 to derivatives July 2019. haveHerein, been 307 listed naturally most of occurring them are reportedisocoumarins from derivativesAspergillus and havePenicillium been listedgenera most (Figure of them2). are reported from Aspergillus and Penicillium genera (Figure 2). Molecules 2020, 25, 395 3 of 94 Molecules 2020, 25, x 3 of 109 Figure 2. Distribution of isocoumarin derivatives in different fungal genus. Figure 2. Distribution of isocoumarin derivatives in different fungal genus. TheThe reportedreported fungalfungal isocoumarinisocoumarin derivativesderivatives areare drawndrawn accordingaccording toto theirtheir similaritysimilarity inin thethe isocoumarinisocoumarin skeleton, skeleton, as as well well as as nomenclature nomenclature (Figures (Figures3– 3–30).30). Molecules 2020, 25, 395 4 of 94 Molecules 2020, 25, x 4 of 109 Figure 3. Structures of isocoumarin derivatives 1–16. Figure 3. Structures of isocoumarin derivatives 1–16. Molecules 2020, 25, 395 5 of 94 Molecules 2020, 25, x 5 of 109 Figure 4. Structures of isocoumarin derivatives 17–33. Figure 4. Structures of isocoumarin derivatives 17–33. Molecules 2020, 25, 395 6 of 94 Molecules 2020, 25, x 6 of 109 Figure 5. Structures of isocoumarin derivatives 34–44. Figure 5. Structures of isocoumarin derivatives 34–44. Molecules 2020, 25, 395 7 of 94 Molecules 2020, 25, x 7 of 109 Figure 6. Structures of isocoumarin derivatives 45–53.