Published: March 28, 2011 r2011 American Chemical Society 4822 dx.doi.org/10.1021/jf104903t | J. Agric. Food Chem. 2011, 59, 4822–4827 ARTICLE pubs.acs.org/JAFC Synthesis of a Combinatorial Library of Amides and Its Evaluation against the Fall Armyworm, Spodoptera frugiperda Thais C. Castral, Andreia P. Matos, Julia L. Monteiro, Fernanda M. Araujo, Tatiani M. Bondancia, Luciane G. Batista-Pereira, Jo ~ ao B. Fernandes, Paulo C. Vieira, M. Fatima G. F. da Silva, and Arlene G. Corr ^ ea* Departament of Chemistry, Federal University of S ~ ao Carlos, 13565-905 S ~ ao Carlos, SP, Brazil ABSTRACT: The fall armyworm Spodoptera frugiperda is a polyphagous pest that causes important damage in different regions of America and mainly affects corn crops in both tropical and subtropical areas. Currently, control relies on both transgenic plants and/ or chemical pesticides. In this work we describe the preparation of an indexed combinatorial library of amides and its toxic effect by contact against S. frugiperda.(E)-1-(1-Piperidinyl)-3-[4-(trifluoromethoxy)phenyl]-2-propen-1-one was the most active compound with an LD 50 = 0.793 μg mg 1 of larva. This amide was also evaluated by ingestion and at the lowest concentration (1 mg kg 1 ) achieved 83.3% mortality. KEYWORDS: Spodoptera frugiperda, Lepidoptera, insecticidal activity, combinatorial library, piperamides ’ INTRODUCTION The fall armyworm Spodoptera frugiperda Smith and Abbott (Lepidoptera: Noctuidae) is a polyphagous pest that causes important damage in different regions of America and mainly affects corn crops in both tropical and subtropical areas. 13 Currently, control relies on both transgenic plants and/or chemical pesticides. 4 In the two last decades, emphasis has been placed on the discovery of new, ecologically safe pesticides, in the hope that the use of more damaging synthetic pesticides can be reduced. Thus, several alternative methods have been investi- gated, as biological control, 5 pheromones, 6 and natural products from plants. 2,7 The genus Piper (Piperaceae) has been widely studied, due to the biological properties of secondary metabolites from these plants. 8 Dyer et al. tested the effect of three amides isolated from Piper cenocladum: piplartine (1), 4 0 -desmethylpiplartine (2), and cenocladamide (3) (Figure 1). 9,10 On S. frugiperda they observed that amide mixtures caused decreased pupal weights and survi- vorship and increased development times. Castro et al. evaluated the insecticidal potential of the aqueous extract of fresh fruit dehydrated P. tuberculatum on S. frugiperda. 11 We have synthe- sized 10 amides, including two natural isolated from P. piresii, and evaluated their toxic effect against S. frugiperda. The most active amide was the natural piperidine derivative 4 with an LD 50 of 1.07 μg mg 1 of larva. 12 On the basis of these results, we describe herein the prepara- tion of an indexed combinatorial library of amides and its insecticidal activity against the fall armyworm, S. frugiperda. ’ RESULTS AND DISCUSSION In order to screen a large number of candidates and evaluate the potential of this class of compounds as insecticides, we prepared an indexed solution phase combinatorial library 13 of amides (Table 1). The possibility to prepare the library through a simple, highly effective coupling protocol, an amidation reac- tion between an acyl chloride and an amine, which does not generate any significant byproduct that could interfere with the biological assay, was of major relevance. Therefore, this methodology is a very simple approach to readily identify lead compounds from mixture screenings. Thus, a 200-member library of amides 7[110,110] was prepared employing 10 amines 5[110] and 10 acyl chlorides 6[110], as shown in Scheme 1 and Table 1. The library was prepared in a 0.2 mmol scale of each component in the mixture and was fully analyzed by GC-MS. The analysis of the GC-MS chromatograms confirms that most of the designed library members were formed, although this validation strategy does not allow the quantitative determina- tion of each of their components. Figure 2 shows a chromato- gram of one of the prepared mixtures, 7[110,3], and the MS spectrum of one of the compounds of this mixture, 7[2,3]. In Figure 3, GC-MS analysis of the mixture 7[1,110] and the assignments of the peaks to the correspondent piperidine amine are shown in Table 2. Mixture 7[110,2] presented the worst results among all, as shown in Figure 4. Only one of the desired amides could be observed (16.01 min), probably due to the low acyl chloride reactivity. The toxic effects of the amide library on second instar larvae S. frugiperda were determined. In the topical application bioassays were veri fied that mixtures 7[1,110] and 7[110,8] caused statistically significant mean mortality, 68 and 20%, respectively (Tables 3 and 4). Thus, of the library deconvolution through the cross-analysis of the results we propose that amide 7[1,8], contain- ing the piperidine and 4-(trifluoromethoxy)benzoyl groups, would Received: December 22, 2010 Accepted: March 28, 2011 Revised: March 28, 2011