| Summary: | Despite the large number of peptidomimetics with incorporated heteroannularly functionalized ferrocenes, few studies have investigated their bioactivity. Here, we report the biological evaluation and conformational analysis of enantiomeric dipeptides derived from 1′-aminoferrocene-1-carboxylic acid (Fca) and hydrophobic amino acids (AA = Val, Leu, Phe). The conformational properties of Y-AA-Fca-OMe (Y = Ac, Boc) were elucidated by experimental (IR, NMR, CD, and X-ray) and theoretical (DFT) methods. The prepared dipeptides were screened for their antimicrobial activity against selected Gram-positive and Gram-negative bacteria, lactic acid bacteria and yeasts, while their antioxidant activity was tested by DPPH and FRAP methods. Of all compounds tested, dipeptide <span style="font-variant: small-caps;">d</span>-<b>2a</b> showed the best antibacterial properties against <i>S. aureus</i>, <i>B. subtilis,</i> and <i>P. aeruginosa</i> at a concentration of 2 mM. The time–kill curves showed that antibacterial activity was concentration- and time-dependent. Chirality (<span style="font-variant: small-caps;">d</span>-) and a more polar-protecting group (Ac) were found to affect the biological activity, both antimicrobial and antioxidant. All investigated peptides are considered to be highly hydrophobic and chemically stable in both acidic and buffer media. Dipeptides <span style="font-variant: small-caps;">d</span>-<b>1a</b>–<b>3a</b>, which showed biological activity, were subjected to the determination of proteolytic activity, revealing very good resistance to proteolysis in the presence of chymotrypsin.
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