Lysine Scanning of Arg10-Teixobactin. Deciphering the Role of Hydrophobic and Hydrophilic Residues.

Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg10-teixobactin as a reference, where the nonproteinogenic residue l-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity

Synthesis, Crystal Structure and DFT Studies of 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione

Novel 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized and recrystallized from ethanol. The compound was characterized by 1H NMR, 13C NMR in CDCl3, DMSO-d6 and acetone-d6, elemental analysis and X-ray diffraction. The NMR data observed that the title compound exists in the enol tautomer rather than keto, and it stabilized by strong H-bond as observed form the NMR data at different temperatures. Theoretical calculations (DFT) were carried out using Gaussian09 program package and B3LYP correlation function. Full geometry optimization of the keto and enol forms were carried out using 6-311G++(d,p) basis set. The structure and energy of the transition state between these two tautomers were calculated. The frontier orbital energy and atomic net atomic charges of the tautomers were presented. The experimental results of the title compound have been compared with the theoretical results and it was found that the experimental data are in a good agreement with the calculated values. The transition state calculations also support the stability of enol form compared to keto form at room temperature

Solid-Phase Synthesis of Pyrrole Derivatives through a Multicomponent Reaction Involving Lys-Containing Peptides

The synthesis of pyrroles has received considerable attention because of their biological and pharmaceutical activities. Herein we describe a solid-phase multicomponent reaction that utilizes Lys as a N donor, β-nitrostyrenes, 1,3-dicarbonyl compounds, and FeCl₃ as an easily accessible catalyst under microwave irradiation to afford the subsequent pyrrole derivatives in high conversions. The strategy combines three of the most powerful tools in modern synthetic chemistry: the solid-phase mode, microwave activation, and a multicomponent reaction. The excellent results in terms of rapidity, versatility, and purity obtained herein support once again that this combined strategy is efficient for gaining chemical diversity

Structure-Activity Relationship of Arg10-Teixobactin: A Recently Discovered Antimicrobial Peptide

The emergence of multidrug resistant bacteria has a direct impact on global public health due to the reduced potency of existing antibiotics against pathogens [1]. [...

Green Solid-Phase Peptide Synthesis 2. 2‑Methyltetrahydrofuran and Ethyl Acetate for Solid-Phase Peptide Synthesis under Green Conditions

<i>N,N</i>-Dimethylformamide (DMF), <i>N</i>-methyl-2-pyrrolidone, and dichloromethane (DCM) are the most widely used solvents for Fmoc solid-phase peptide synthesis (SPPS). These solvents are considered hazardous chemicals and are normally used in large amounts for washing, deprotection, and coupling steps. Therefore, the use of these reagents is indeed in question. Our group recently reported the use of 2-methyltetrahydrofuran (2-MeTHF), which is a green solvent, for coupling, but using DMF for the Fmoc removal and washing steps [Jad et al. Amino Acids 2016, 48 (2), 419−426.]. Herein, total full green solvent protocols in which DMF and DCM are completely eliminated are reported. Several green solvents, such as 2-MeTHF, ethyl acetate, and isopropyl alcohol; temperature; solid supports; and peptide models were evaluated in this study. The best green protocol established is the use of 2-MeTHF for Fmoc removal, washing, and coupling steps with some more washing with EtOAc at room temperature for a short and challenging peptide (Aib-enkephalin pentapeptide). In the case of a longer and more difficult peptide (Aib-ACP decapeptide), the best protocol established was similar, except for the Fmoc removal and coupling steps that were conducted at 40 °C and in combination with the use of a polyethylene glycol resin (ChemMatrix resin)

Synthesis and Biological Evaluation of a Teixobactin Analogue

The first synthesis and biological activity of a teixobactin analogue is reported. Substitution of the unusual l-<i>allo</i>-enduracididine residue by the naturally occurring l-arginine was achieved, and the analogue gave an activity trend similar to that of teixobactin (against Gram-postive bacteria) and meropenem, which was approved by the FDA in 1996. The synthetic route used allows for the synthesis of the natural product as well as the development of a program of medicinal chemistry

Lysine Scanning of Arg₁₀–Teixobactin: Deciphering the Role of Hydrophobic and Hydrophilic Residues

Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg₁₀–teixobactin as a reference, where the nonproteinogenic residue l-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity