Potent antibacterial lysine–peptoid hybrids identified from a positional scanning combinatorial library

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 13; pp. 4444 - 4451
• Main Authors: Ryge, Trine S., Hansen, Paul R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.07.2006; Elsevier Science
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Cyclohexanes - chemistry; Cyclohexanes - isolation & purification; Cyclohexanes - pharmacology; Erythrocytes - drug effects; Escherichia coli; Escherichia coli - drug effects; Hemolysis - drug effects; Humans; Lysine - chemistry; Lysine–peptoid hybrids; Medical sciences; N-substituted Glycines - chemistry; N-substituted Glycines - isolation & purification; N-substituted Glycines - pharmacology; Oligopeptides - chemistry; Oligopeptides - isolation & purification; Oligopeptides - pharmacology; Peptide Library; Peptoids - chemistry; Peptoids - isolation & purification; Peptoids - pharmacology; Pharmacology. Drug treatments; Positional scanning soluble combinatorial library; Solid-phase synthesis; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staphylococcus aureus; Staphylococcus aureus - drug effects; DMSO; MHB; ACTH; MTT; Solid-phase synthesis; ATCC; DIPCDI; TFA; BSA; CFU; S. aureus; Boc; HOBt; PS-SCL; Antibacterial activity; Fmoc; Positional scanning soluble combinatorial library; E. coli; HPLC; PBS; Lysine–peptoid hybrids; MALDI-TOF-MS; MIC; LC–MS; NMP; C. albicans; TIS; Peptides; Toxicity; Escherichia coli; Combinatorial chemistry; Amides; Cytotoxicity; Blood; Structure activity relation; Chemical compound library; Bacteria; Micrococcales; Micrococcaceae; Chemical synthesis; Staphylococcus aureus; Enterobacteriaceae; Human; Hemolysis; Red blood cell; Heptapeptide; In vitro; Screening; Lysine-peptoid hybrids; Solid phase; Antibacterial agent
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.02.034

We describe the synthesis and screening of a positional scanning library made up of N-alkylglycines and lysines. Compounds with potent antibacterial activity and low hemolytic activity were identified including [ N-(cyclohexylmethyl)glycyl]-[ N-(1-methylhexyl)glycyl]-[ N-(4-methylbenzyl)glycyl]-[ N-(2-(3-chlorophenyl)ethyl)glycyl]-lysyl-lysyl-lysine amide. In this paper, we describe the synthesis and screening of a biased positional scanning library made up of peptoids ( N-alkylglycines) and lysines. The library consisted of 100 mixtures divided into four sub-libraries; OXXXKKK, XOXXKKK, XXOXKKK, and XXXOKKK, O being a defined peptoid building block and X a mixture of 25 peptoid building blocks. A theoretical number of 390,625 compounds were synthesized. The compound mixtures were screened against the American Type Culture Collection (ATCC) Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 bacterial strains, and the cytotoxic activities were assessed using a human blood hemolytic assay. The results from each sub-library were examined to identify the most potent amine at each position. On the basis of this knowledge eight new lysine–peptoid hybrids were synthesized and tested in the biological assays. One compound in particular, [ N-(cyclohexylmethyl)glycyl]-[ N-(1-methylhexyl)glycyl]-[ N-(4-methylbenzyl)glycyl]-[ N-(2-(3-chlorophenyl)ethyl)glycyl]-lysyl-lysyl-lysine amide, showed high antibacterial activity and low toxicity toward red blood cells.