Mol Divers (2012) 16:113–119 DOI 10.1007/s11030-011-9334-1 FULL-LENGTH PAPER Multicomponent synthesis of acylated short peptoids with antifungal activity against plant pathogens Matías D. Galetti · Adriana M. Cirigliano · Gabriela M. Cabrera · Javier A. Ramírez Received: 13 April 2011 / Accepted: 30 August 2011 / Published online: 16 September 2011 © Springer Science+Business Media B.V. 2011 Abstract In this article, we describe the synthesis of a small library of short peptoids composed of four glycine residues and acylated with a fatty acid that showed a remarkable in vitro activity against two fungal plant pathogens. Their straightforward synthesis implied two consecutive Ugi reac- tions and can be efficiently extended to the construction of highly diverse libraries. Keywords Acylated peptoids · Multicomponent reaction · Plant pathogen · Antifungal Plants are constantly exposed to a variety of pathogenic microorganisms present in their environments. Diseases caused by pathogens, including bacteria, fungi, and viruses, significantly contribute to the overall loss in crop yield world- wide and constitute an emerging threat to the global food security [1]. Many of the currently available antimicrobial agents for agriculture are highly toxic and non-biodegrad- able and cause extended environmental pollution [2]. Antimicrobial peptides (AMPs) (12–50 amino acids long), known also as innate immunity host defense peptides or innate defense regulators, are key components of the innate immune system in all phyla, providing a fast-acting defense against invading pathogens [3, 4]. A subfamily of AMPs with strong antimicrobial activity includes lipopeptides, which Electronic supplementary material The online version of this article (doi:10.1007/s11030-011-9334-1) contains supplementary material, which is available to authorized users. M. D. Galetti · A. M. Cirigliano · G. M. Cabrera · J. A. Ramírez (B ) Departamento de Química Orgánica and UMYMFOR (CONICET—Facultad de Ciencias Exactas y Naturales), Universidad de Buenos Aires, Pabellón 2, Piso 3, Ciudad Universitaria, C1428EGA, Buenos Aires, Argentina e-mail: jar@qo.fcen.uba.ar are produced non-ribosomally in bacteria and fungi. Lipo- peptides consist of a short linear or cyclic peptide sequence to which a fatty acid moiety is covalently attached at the N terminus [5]. Recently, a new family of synthetic ultrashort lipopep- tides (Fig. 1) composed of only four amino acid residues conjugated to long-chain aliphatic acids has been reported. These compounds have a broad spectrum of in vivo and in vitro antimicrobial activity against human-pathogenic yeasts, fungi, and bacteria [6], also affecting phytopathogenic fungi and bacteria [7]. Peptoids are a class of oligomeric N-substituted glycines that mimic the primary natural structure of peptides [8, 9]. They are attractive non-natural molecules for drug discovery approaches because of their many biological activities and proteolytic stability. Many peptoids have been shown to be capable of acting as protein ligands with high affinity [10]. The most common method for the preparation of peptoids is the solid-phase submonomer procedure [11]. This method involves an iterative acylation reaction, with an R-haloacetyl moiety that is common to all backbone elongation processes and an iterative amination reaction using the commercially available primary amines, and has been recently employed to synthesize peptoid mimetics of antimicrobial lipopeptides [12]. An alternative approach involves the use of the Ugi four- component reaction (U-4CR) [13], which is a versatile tool for the construction of peptoid and mixed peptoid–peptide backbones. Repetitive or consecutive Ugi reactions have been used in the synthesis of peptide nucleic acid oligomers and in one-pot macrocyclizations [14, 15]. However, the assembly of pure peptoid backbones in a consecutive fashion has not been extensively explored [16, 17]. In this article, we describe the synthesis of a small library of N-substituted tetraglycines acylated with a long-chain alkyl residue. The structures resemble those of the antifungal 123