pubs.acs.org/JAFC Published on Web 07/24/2009 © 2009 American Chemical Society J. Agric. Food Chem. 2009, 57, 7417–7421 7417 DOI:10.1021/jf901052e Structure-Activity Relationship in the Interaction of Substituted Perinaphthenones with Mycosphaerella fijiensis WILLIAM HIDALGO, † LUISA DUQUE, ‡ JAIRO SAEZ, ‡ RAFAEL ARANGO, † JESU  S GIL, † BENJAMI ´ N ROJANO, † BERND SCHNEIDER, § AND FELIPE OTA  LVARO* ,‡ † Universidad Nacional de Colombia sede Medellı´n, Autopista Norte, Calle 64 Cra 65, AA 1027 Medellı´n, Colombia, ‡ Instituto de Quı´mica, Universidad de Antioquia, Calle 67 # 53-108, AA 1226 Medellı´n, Colombia, and § Max Planck Institut f :: ur Chemische :: Okologie, Beutenberg Campus, Hans-Kn :: oll-Strasse 8, 07745 Jena, Germany The levels of native fungitoxic perinaphthenone phytoalexins in susceptible Musa varieties (banana), which are commercially grown in large plantations, are too low to provide plants with long-lasting protection against highly pathogenic fungi. Novel strategies for plant protection are necessary to reduce crop losses and to prevent the development of resistant fungal strains. The synthesis of novel fungicides based on the structures of perinaphthenone natural products is considered to be a promising strategy. Thirteen substituted perinaphthenones, among them two known natural products (1, 2) and 11 synthetics (3-13), were evaluated for their activity against Mycosphaerella fijiensis, and their half-maximal inhibitory concentrations (IC 50 ) were calculated to establish structure-activity relationships (SAR). A SAR trend was hypothesized, leading to the design of a new compound, 4-methoxy-2-nitro-1H-phenalen-1-one (14); the new compound displayed significantly enhanced in vitro activity against M. fijiensis compared to other perinaphthenone derivatives. The activity of 14 was comparable to that of two commercial fungicides. KEYWORDS: Mycosphaerella fijiensis; banana; perinaphthenone; phenalenone; phototoxicity; reactive oxygen species INTRODUCTION Bananas are among the most important crops worldwide; they are a staple food in many developing countries and a crucial economic factor for the communities that produce them ( 1). Nearly all currently grown cultivars of Musa (banana) are derived from two species, Musa acuminata (A genome) and Musa balbisiana (B genome), and belong to the “Cavendish” subgroup. The commercial cultivation of genetically closely related clones of the Cavendish banana in monocultures has boosted outbreaks of invading insects and nematodes and resulted in devastating fungal infections. The appearance of phytopathogenic fungi such as Fusarium oxysporum and Mycosphaerella fijiensis and their global proliferation has caused the Panama disease and Black Sigatoka disease, among others. Detrimental crop losses have led to a debate about the future of banana production ( 1- 3). Phenalenones (perinaphthenones) and their phenyl derivatives and oxidative transformation products have been identified as native defense compounds and are reported as phytoalexins of Musa ( 4- 6). Resistant Musa varieties accumulate perinaphthe- nones to much higher levels in their tissue than susceptible varieties do ( 7). Hence, the enhancement of the biosynthetic potential for native perinaphthenones by either conventional breeding or genetic modification is considered to be a possible way to improve Musa plants; the susceptibility of such improved plants to fungal infection would be greatly reduced. Here, another promising approach, namely, designing synthetic fungitoxic agents based on the perinaphthenone structure, is reported. Recently, some natural perinaphthenones, among them compounds 1 and 2 in Musa acuminata cv. ’Yangambi’, were identified as the most potent class of compounds isolated from this plant; they are active against the ascomycetous fungal pathogen Mycosphaerella fijiensis. As a result, the perinaphthe- none nucleus has come to be seen as an interesting structural motif for the development of a new class of fungicides ( 7). One reason for the interest in the perinaphthenone moiety is its plausible phototoxic mode of action ( 8- 10): perinaphthenone, a well-known photosensitizer ( 1), is presumed to generate singlet molecular oxygen ( 1 O 2 ) and act as a catalyst for the production of other reactive oxygen species, which may in turn cause cell damage to the pathogen ( 8). To produce singlet oxygen ( 3 O 2 f 1 O 2 ), the photon-excited perinaphthenone must undergo intersystem crossing to a triplet state from which deactivation can occur by different competing energy transfer processes such as phosphorescence, thermal decay, or radical reactions with other compounds ( 12). Therefore, suitable experimental conditions have to be designed for each particular plant pathosystem ( 13) to prove the involvement of 1 O 2 . Previous bioassays with natural perinaphthenones active against M. fijiensis were conducted in the dark ( 7). Because phototoxicity cannot be assessed under conditions of light exclusion, it was not clear if the tested compounds displayed *Corresponding author (telephone 05742195653; fax 05742330120; e-mail pipelion@quimica.udea.edu.co).