Investigation on the Synergy between Membrane Permeabilizing Amphiphilic α-Hydrazido Acids and Commonly Used Antibiotics against Drug-Resistant Bacteria.

The growth of (multi)drug resistance in bacteria is among the most urgent global health issues. Monocationic amphiphilic α-hydrazido acid derivatives are structurally simple mimics of antimicrobial peptides (AMPs) with fewer drawbacks. Their mechanism of membrane permeabilization at subtoxic concentrations was found to begin with an initial electrostatic attraction of isolated amphiphile molecules to the phospholipid heads, followed by a rapid insertion of the apolar portions.

Identification of a novel nitroflavone-based scaffold for designing mutant-selective EGFR tyrosine kinase inhibitors targeting T790M and C797S resistance in advanced NSCLC.

The inhibition of the Epidermal Growth Factor (EGFR) represents one of the most promising strategies in non-small cell lung cancer (NSCLC) therapy. The recently identified C797S mutation causes resistance of EGFR against osimertinib, the latest approved third generation EGFR inhibitor. The identification of small molecules capable of selectively inhibiting the T790M mutations also in the late-onset C797S mutation is a desirable strategy and novel chemical structures might provide new insight in the overcoming resistance mechanisms.

The Diverse World of Foldamers: Endless Possibilities of Self-Assembly.

Different classes of foldamers, which are synthetic oligomers that adopt well-defined conformations in solution, have been the subject of extensive studies devoted to the elucidation of the forces driving their secondary structures and their potential as bioactive molecules. Regardless of the backbone type (peptidic or abiotic), the most important features of foldamers are the high stability, easy predictability and tunability of their folding, as well as the possibility to endow them with enhanced biological functions, with respect to their natural counterparts, by the correct choice of monomers. Foldamers have also recently started playing a starring role in the self-assembly of higher-order structures.

Simple amphiphilic α-hydrazido acids: Rational design, synthesis, and in vitro bioactivity profile of a novel class of potential antimicrobial compounds.

Pursuing the search for a new class of structurally simple mimics of antimicrobial peptides, we optimized a short, cheap and high-yielding synthesis of mono-charged amphiphilic α-hydrazido acid derivatives. The most active derivatives furnished MICs that are among the best values reported in literature for synthetic amphiphilic membranolytic compounds. They exhibited a broad-spectrum in vitro activity against a variety of Gram-positive and Gram-negative bacteria, including two multidrug-resistant strains.

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine.

Starting from chiral-protected 4-hydroxymethyl pyrrolidin-2-ones, the otherwise elusive 3,4-trans-3,3,4-trisubstituted isosteres of α-methyl homoserine, tethered on a γ-lactam ring, were prepared exploiting stereoselective electrophilic aminations. These reactions led to the isolation and characterization of a novel type of atropisomers, exceedingly stable at room temperature, that were directly converted to the desired products by a novel non-reductive N-N bond cleavage reaction.

Synthesis of a cyclic isostere of α-methyl homoserine by a stereoselective acylation-alkylation sequence of a chiral γ-lactam.

Starting from a chiral 4-hydroxymethyl pyrrolidin-2-one, an isostere of α-methyl homoserine tethered on a γ-lactam ring was prepared exploiting a stereoselective acylation-methylation sequence, followed by Curtius rearrangement, and structural assignment was confirmed by n.O.e.

β-Peptoids: synthesis of a novel dimer having a fully extended conformation.

Chiral imines 1a,b, already synthesized in our laboratory, were converted in good yield by reduction into the corresponding N-benzyl-γ-lactams 2a,b. Desilylation followed by oxidation of the hydroxymethyl functionality gave the N-benzyl-β-amino acids 5a,b in good yield and high purity. Starting from compound 6a, the corresponding β-peptoid dimer 8 was prepared, together with its derivatives 9 and 10, these latter displaying conformational restriction about the peptide bond, as evidenced by NMR data.

Diastereoselective functionalization of Baylis-Hillman adducts: a convenient approach to alpha-methyl-alpha-amino acids.

The N-tosyl carbamates 4a-e, easily prepared starting from the Baylis-Hillman adducts 3a-e, underwent cyclization carried out with I(2)/NIS in the presence of NaH, to give the corresponding 2-oxo-1,3-oxazolidines 5a-e in good yield and total stereoselection when the substituent at C-5 is Ar. After the removal of tosyl group, followed by the cleavage of the heterocyclic ring, the alpha-methyl-alpha-amino acids 8a,b and 10 were obtained in good yield as hydrochlorides.

Enantiopure derivatives of aza-Baylis-Hillman adducts by subsequent SN'-SN' reactions of acylcarbamates bearing a chiral auxiliary.

Reactions of(4S,5R)-1-(3,4-Dimethyl-2-oxo-5-phenylimidazolidine)carbonyl-isocyanate (4) with appropriate Baylis-Hillman adducts 5 gave the corresponding acyl carbamates 6,7 as equimolar diastereomeric mixtures. These mixtures were treated with DABCO, to afford with moderate diastereoselection easily separable [2-(3",4"-dimethyl-2"-oxo-5"-phenylimidazolidine-1-carboxamido)(aryl)methyl]acrylates 8 and 9.

Analogues of both Leu- and Met-enkephalin containing a constrained dipeptide isostere prepared from a Baylis-Hillman adduct.

An efficient route was developed for the synthesis of the Fmoc-protected dipeptide 4, isostere of Gly-Gly containing an alpha-methylene beta-amino acid; the conformationally restricted analogues of Leu-enkephalin, 3a, and Met-enkephalin, 3b, respectively, were prepared by changing 4 for Gly(2)-Gly(3) in the native compounds 3a and 3b whose biological activities were significantly lower than the parent compounds.

Computational DFT investigation of vicinal amide group anchimeric assistance in ether cleavage.

Density functional theory (DFT) computations in solvent have been used to investigate the mechanism of anchimeric assistance (by a vicinal amide group) in the acid-induced ether cleavage. The calculations were carried out at the B3LYP/6-31G* level of theory via full geometry optimizations within the IEF-PCM continuum solvent model. Two different mechanisms have been investigated here that were previously hypothesized for the rate-determining step of this process: the first (mechanism A1) involves a protonated amide and an ethereal oxygen as the nucleophile, while the second (mechanism A2) involves protonation of the ethereal oxygen followed by a nucleophilic attack of the amide.

Synthesis and structural characterisation as 12-helix of the hexamer of a beta-amino acid tethered to a pyrrolidin-2-one ring.

Starting from (3S,4R,1'S)-3-amino-2-oxo-1-[1'-(4-methoxyphenylethyl)]pyrrolidine carboxylic acid (2), the first synthesis of a beta-foldamer containing pyrrolidin-2-one rings is described, whose 12-helix conformation is assigned by NMR analysis and confirmed by molecular dynamics (MD) simulations.

Stereoselective iodocyclization of 3-acylamino-2-methylene alkanoates: synthesis of analogues of N-benzoyl-syn-phenylisoserine.

[reaction: see text] A convenient approach to racemic analogues of N-benzoyl-syn-phenylisoserine was realized via the stereoselective iodocyclization of amides obtained from Baylis-Hillman adducts.

Conformational studies by dynamic NMR. 88.(1) stereomutation processes in the diastereoisomers of a representative amino alcohol and related amide precursors.

The barriers for three internal motions (i.e., phenyl and tert-butyl rotation as well as N-inversion) have been determined by dynamic NMR spectroscopy in the two diastereoisomeric forms of a typical amino alcohol [dimethylamino-2,4,4-trimethyl-3-phenyl-3-pentanol, Me(2)NCH(2)CHMeC(OH)PhBu(t)].