An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity

Abstract

This protocol describes the manual solid-phase synthesis of linear peptoids that contain two differently functionalized cationic monomers. In this procedure amino functionalized 'lysine' and guanido functionalized 'arginine' peptoid monomers can be included within the same peptoid sequence. This procedure uses on-resin (N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) or Dde protection, orthogonal conditions to the Boc protection of lysine monomers. Subsequent deprotection allows an efficient on-resin guanidinylation reaction to form the arginine residues. The procedure is compatible with the commonly used submonomer method of peptoid synthesis, allowing simple peptoids to be made using common laboratory equipment and commercially available reagents. The representative synthesis, purification and characterization of two mixed peptoids is described. The evaluation of these compounds as potential anti-infectives in screening assays against Leishmania mexicana is also described. The protozoan parasite L. mexicana is a causative agent of cutaneous leishmaniasis, a neglected tropical disease that affects up to 12 million people worldwide.

Anti-Leishmanial and Cytotoxic Activities of a Series of Maleimides: Synthesis, Biological Evaluation and Structure-Activity Relationship

“…Among them, the IC 50 s of 16 and 42 were less than 0.0128 μg/mL, much less than those of amphotericin B (IC 50 = 0.12 μg/mL) and pentamidine (IC 50 = 0.64 μg/mL), which reached nanogram grade. These activities were stronger than most compounds in literature [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. There were another eight candidate compounds ( 1 , 3 , 6, 7 , 8 , 13 , 14 , and 41 ) which had better activities than amphotericin B.…”

“…Recently, other candidate compounds, including buparvaquone [ 8 ], aminoquinolines [ 9 ], peptoids [ 10 ], (4-arylpiperazin-1-yl)(1-(thiophen-2-yl)-9H-pyrido[3,4-b]indol-3-yl) methanone derivatives [ 11 ], amino acid-triazole hybrids [ 12 ], biscoumarins [ 13 ], triazolyl quinoline derivatives [ 14 ], benzopiperidine, benzopyridine and phenyl piperazine based compounds [ 15 ], 2,5-diarylidene cyclohexanones [ 16 ], natamycin [ 17 ], piperazinyl-β-carboline derivatives [ 18 ], thiosemicarbazones [ 19 ], and so on, were evaluated and investigated. But for most of them, the IC 50 s of anti-leishmanial activities still remained to be in micromolar ranges except thiosemicarbazones (two compounds had the IC 50 s of 0.060 μg/mL and 0.068 μg/mL against promastigotes of L. major .)…”

Synthesis of Antibacterial Nisin–Peptoid Hybrids Using Click Methodology

“…Peptoids 2a N prp N spe N spe( N ae N spe N spe) 4 and 2b N prp N spe N spe[( N Lys N pfb N pfb)( N Lys N spe N spe)] 2 were prepared via the submonomer procedure for the solid phase synthesis of peptoids, which utilizes successive acylation and displacement cycles (see Scheme 1 ). An alkyne tail was added to the sequence using propargylamine ( N prp) under standard coupling conditions [ 34 , 42 , 43 ]. Peptoids 2a and 2b were then cleaved from the resin and purified by RP-HPLC prior to the click reactions being performed.…”

“…A strategy that is more commonly being utilized to stabilize peptide-based therapeutics is the synthesis of stable peptidomimetics such as peptoids ( N -substituted glycines) ( Figure 2 ) [ 18 , 19 , 20 ]. Peptoids have shown activity as antibacterial [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ], antifungal [ 29 , 30 , 31 ] and antiparasitic [ 32 , 33 , 34 , 35 ] compounds and most importantly they display increased resistance to protease action compared to α-peptides [ 31 , 36 ]. In particular, peptoids have demonstrated antibacterial properties against a range of clinically relevant Gram negative and Gram positive bacteria, with activities that equal or surpass those achieved by many antimicrobial peptides (AMPs) [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

Synthesis and Mass Spectrometry Analysis of Oligo-peptoids

“…In each addition cycle, a resin-bound amine is acetylated by a haloacetic acid (typically bromoacetic acid, BMA), and this is followed by a displacement reaction with a primary amine. Although automated synthesis protocols have been routinely applied for peptoid synthesis, peptoids can be synthesized manually with excellent yields in a standard chemistry laboratory 16,18,19,20 .…”