The introduction of fluorine atoms or trifluoromethyl groups in short cationic peptides enhances their antimicrobial activity Diana Gime ´nez, a Cecilia Andreu, a, * MarcelÆlı ´ del Olmo, b Teresa Varea, a Dolores Diaz c and Gregorio Asensio a a Departament de Quı ´mica Orga ` nica, Facultat de Farma ` cia, Universitat de Vale ` ncia, 46100 Burjassot, Vale `ncia, Spain b Departament de Bioquı ´mica i Biologia Molecular, Facultat de Biologia, Universitat de Vale `ncia, 46100 Burjassot, Vale `ncia, Spain c Centro de Investigaciones Biolo ´ gicas, CSIC, 28040 Madrid, Spain Received 10 April 2006; revised 7 June 2006; accepted 14 June 2006 Available online 30 June 2006 Abstract—The effect of introducing fluorine atoms or trifluoromethyl groups in either the peptidic chain or the C-terminal end of cationic pentapeptides is reported. Three series of amide and ester peptides were synthesised and their antimicrobial properties evaluated. An enhanced activity was found in those derivatives whose structure contained fluorine, suggesting an increase in their hydrophobicity. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction The widespread use of antibiotics led to the development of numerous multidrug resistant strains, resulting in an urgent need to develop new effective antimicrobial agents capable of being established as therapies for bac- terial infections. 1 These molecules should be as natural as possible with a wide range of action over several pathogens, easy to produce and not prone to inducing resistance. Native peptide molecules known as anti- microbial peptides (AMPs) completely fit this description. 2 This group of molecules, termed as ‘natural antibiotics,’ are endogenous peptides that are found in a wide range of eukaryotic organisms. They are mobilised shortly after microbial infection to neutralise a broad range of microbes and constitute a primitive immune defence mechanism. 3 Antimicrobial peptides show great structural diversity, but some features common to them all are their relatively small size (usually less than 50 amino acid residues), their cationic nature due to multiple R and/or K residues and a substantial portion of hydrophobic amino acids (around 50%). 4 The exact action mechanism is not totally established for all cationic peptides, although there is a consensus in considering that these peptides selectively disrupt cell membranes, possibly by transient pore formation or dis- ruption of lipid packing. 5 The majority of these peptides are unstructured in solution; upon binding to bacterial membranes however, most of them will adopt a well- defined amphipathic structure 6 that plays an important role in the peptide-membrane interaction. 2–4,7 The preferential activity against bacteria over mammalian cells could be owing to the different nature and net charge of the anionic lipids in each case. 7 Natural AMPs have excellent properties that could make them the best candidates to be used as therapeu- tic agents, for example, a decreased potential for resis- tance induction. 8 Despite this however, there are many other obstacles for their utilisation. 9 One main obsta- cle is their size as they are very large, which results in a high production cost. For this reason, the investiga- tion has been centered on the production of smaller peptides with significant antibiotic activity, which led to the necessity of establishing the minimal structural requirements for it. Some approaches to the problem have been taken by using combinatorial libraries that allow for the identification of short active sequences. 10 Other investigations have been carried out by taking complex AMPs such as Lactoferrin 11 or truncated analogues of Indolicin, 12 or Tritrypticin 13 as starting material. These studies revealed that short fragments 0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2006.06.027 Keywords: Cationic peptides; Fluorine; Antimicrobial activity; Peptide design. * Corresponding author. Tel.: +34 963543048; fax +34 963544939; e-mail: cecilia.andreu@uv.es Bioorganic & Medicinal Chemistry 14 (2006) 6971–6978