Chemical Structure/Property Relationship in Single-Chain Arginine Surfactants C. Mora ´n, †,‡ P. Clape ´s, ‡ F. Comelles, † T. Garcı ´a, † L. Pe ´rez, † P. Vinardell, § M. Mitjans, § and M. R. Infante* ,† Department of Surfactant Technology, IIQAB-CSIC, J. Girona 18-26, 08034 Barcelona, Spain, Department of Peptide and Prot. Chem., IIQAB-CSIC, J. Girona 18-26, 08034 Barcelona, Spain, and Department of Fisiologia-Divisio ´ n IV, Fac. Farmacy, UB, Barcelona, Spain Received March 12, 2001. In Final Form: May 16, 2001 In this paper, a systematic investigation into the structure-property relationship of long-chain N-alkyl amide 1, O-alkyl ester arginine 2, and N-acyl arginine methyl ester analogues 3 is reported. The surface properties were studied by adsorption isotherm curves. Biological properties such as antimicrobial activity, hemolysis, ocular irritation, aquatic toxicity, and biodegradability are discussed and correlated with some specific parameters of the surfactants. These surfactants constitute a novel class of bio-based materials of low toxicity, excellent surface properties, and a wide antimicrobial activity. They selectively disrupt bacteria membranes at submicellar concentrations, but not erythrocytes or skin cell membranes. The presence of two positive cationic charges enhances the antimicrobial activity. The incorporation of ester functionality accelerates biodegradation. From the data obtained, it was concluded that the hydrophobicity is a negative parameter for the toxicity and biodegradability of these surfactants. Introduction There is currently an increased demand for novel biocompatible surfactants from natural resources pro- duced by clean and sustainable technologies (bio-based surfactants) to improve the quality of life. Bio-based products are environmentally friendlier given that they are designed to mimic natural products and are produced by less polluting processes. 1 An attempt to develop novel biocompatible surfactants from amino acids was made by our group, employing chemical or enzymatic reactions. 2-5 Enzyme technology has the advantage of being safer and environmentally friendlier and of using less energy and resources. Single-chain arginine-based cationic surfactants with chiral properties such as hydrochloride salts of long-chain N-alkyl amide (series 1 in Chart 1) and O-alkyl ester (series 2 in Chart 1) derivatives have recently been prepared on a multigram scale by enzymatic methodologies. 3 These molecules resemble N-acyl arginine methyl ester surfac- tants (series 3 in Chart 1), the chemical synthesis and unique biocompatible properties of which have been the subject of our investigations for a long time. 6,7 In this paper, a systematic investigation into the structure-property relationship of long-chain N-alkyl amide 1, O-alkyl ester arginine 2, and N-acyl arginine methyl ester analogues 3 is reported. The target com- pounds consist of a cationic arginine residue as the hydrophilic moiety linked to a saturated alkyl chain of different length through amide and ester bonds, which are susceptible to hydrolytic and biodegradable decom- position. 8 A dibasic amino acid such as arginine was selected to introduce antimicrobial activity into the * To whom correspondence should be addressed. Tel: 34-93 400 61 64. Fax: 34-93 204 59 04. † Department Surfactant Technology. ‡ Department Peptide and Prot. Chem. § Department Fisiologia-Divisio ´n IV. (1) Novel Surfactants: Preparation, Applications and Biodegrad- ability; Holmberg, K., Ed.; Marcel Dekker: New York, 1998. (2) Infante, M. R.; Pinazo, A.; Seguer, J. Colloids Surf., A 1997, 123- 124, 49-70. (3) Clape ´ s, P.; Mora ´ n, M. C.; Infante, M. R. Biotechnol. Bioeng. 1999, 63, 333-343. (4) Pe ´rez, L.; Torres, J. L.; Manresa, A.; Solans, C.; Infante, M. R. Langmuir 1996, 12, 5296-5301. (5) Piera, E.; Erra, P.; Infante, M. R. J. Chem. Soc., Perkin Trans. 2 1998, 335-342. (6) Infante, M. R.; Garcia Dominguez, J. J.; Erra, P.; Julia, M. R.; Prats, M. Int. J. Cosmet. Sci.1984, 6, 275-282. (7) Kunieda, H.; Nakamura, K.; Infante, M. R.; Solans, C. Adv. Mater. 1992, 4, 291-293. (8) Kirk, O.; Pedersen, F. D.; Fuglsang, C. C. J. Surfactants Deterg. 1998, 1, 37-40. Chart 1. Molecular Structures of Surfactants Series 1, 2, and 3 5071 Langmuir 2001, 17, 5071-5075 10.1021/la010375d CCC: $20.00 © 2001 American Chemical Society Published on Web 07/07/2001