3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds.

Fusidic acid (FA) is an antibiotic with high activity against Staphylococcus aureus; it has been used in clinical practice since the 1960s. However, the narrow antimicrobial spectrum of FA limits its application in the treatment of bacterial infections. In this regard, this work aims both at the study of the antimicrobial effect of a number of FA amines and at the identification of their potential biological targets. In this way, FA analogues containing aliphatic and aromatic amino groups and biogenic polyamine, spermine and spermidine, moieties at the C-3 atom, were synthesized (20 examples). Pyrazinecarboxamide-substituted analogues exhibit a high antibacterial activity against S. aureus (MRSA) with MIC ≤ 0.25 µg/mL. Spermine and spermidine derivatives, along with activity against S. aureus, also inhibit the growth and reproduction of Gram-negative bacteria Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa, and have a high fungicidal effect against Candida albicans and Cryptococcus neoformans. The study of the membrane activity demonstrated that the spermidine- and spermine-containing compounds are able to immerse into membranes and disorder the lipidsleading to a detergent effect. Moreover, spermine-based compounds are also able to form ion-permeable pores in the lipid bilayers mimicking the bacterial membranes. Using molecular docking, inhibition of the protein synthesis elongation factor EF-G was proposed, and polyamine substituents were shown to make the greatest contribution to the stability of the complexes of fusidic acid derivatives with biological targets. This suggests that the antibacterial effect of the obtained compounds may be associated with both membrane activity and inhibition of the elongation factor EF-G.

NbCl5-Mg Reagent System in Regio- and Stereoselective Synthesis of (2Z)-Alkenylamines and (3Z)-Alkenylols from Substituted 2-Alkynylamines and 3-Alkynylols.

The reduction of N,N-disubstituted 2-alkynylamines and substituted 3-alkynylols using the NbCl5-Mg reagent system affords the corresponding dideuterated (2Z)-alkenylamine and (3Z)-alkenylol derivatives in high yields in a regio- and stereoselective manner through the deuterolysis (or hydrolysis). The reaction of substituted propargylamines and homopropargylic alcohols with the in situ generated low-valent niobium complex (based on the reaction of NbCl5 with magnesium metal) is an efficient tool for the synthesis of allylamines and homoallylic alcohols bearing a 1,2-disubstituted double bond. It was found that the well-known approach for the reduction of alkynes based on the use of the TaCl5-Mg reagent system does not work for 2-alkynylamines and 3-alkynylols. Thus, this article reveals a difference in the behavior of two reagent systems-NbCl5-Mg and TaCl5-Mg, in relation to oxygen- and nitrogen-containing alkynes. A regio- and stereoselective method was developed for the synthesis of nitrogen-containing E-ß-chlorovinyl sulfides based on the reaction of 2-alkynylamines with three equivalents of methanesulfonyl chloride in the presence of stoichiometric amounts of niobium(V) chloride and magnesium metal in toluene.

Cp2ZrCl2 - Et3Al reagent system in the homo-coupling of trimethylsilyl-substituted alkynes.

The reaction of trimethylsilyl-substituted alkynes with 0.5 equivalents of Cp2ZrCl2 and 1 equivalent of Et3Al in toluene at room temperature for 18 hours gives, after hydrolysis/deuterolysis or iodination, functionalized products of the homo-coupling of silyl-substituted alkynes in good yield. Trimethylsilyl-substituted α,ω-diynes react with the Cp2ZrCl2 - Et3Al reagent system to give (1Z,2Z)-1,2-bis(iodo(trimethylsilyl)methylene)cycloalkanes after iodinolysis.

Niobium- and zirconium-catalyzed reactions of substituted 2 alkynylamines with Et2Zn.

The NbCl5-EtMgBr-catalyzed reaction of N,N-disubstituted 2-alkynylamines with Et2Zn followed by hydrolysis or deuterolysis affords (2Z)-alkenylamines (reduction products of alkyne) in high yields. The reaction of N,N-disubstituted 2-alkynylamines with Et2Zn catalyzed by the Cp2ZrCl2-EtMgBr system occurs as 2-zincoethylzincation, resulting, after deuterolysis or iodinolysis, in the regio- and stereoselective formation of the corresponding dideuterated and diiodinated 2-alkenylamine derivatives with a trisubstituted double bond. This study demonstrates the difference between the catalytic effects of NbCl5 and Cp2ZrCl2 on the pathway of reaction of tertiary 2-alkynylamines with Et2Zn in the presence of catalytic amounts of EtMgBr.

Synthesis of heteroatom-containing pyrrolidine derivatives based on Ti(O-iPr)4 and EtMgBr-catalyzed carbocyclization of allylpropargyl amines with Et2Zn.

The Ti(O-iPr)4 and EtMgBr-catalyzed regio and stereoselective carbocyclization of N-allyl-substituted 2-alkynylamines with Et2Zn, followed by deuterolysis or hydrolysis, affords the corresponding methylenepyrrolidine derivatives in high yields. It was found that Ti-Mg-catalyzed carbocyclization of N-allyl-substituted 2-alkynylamines with Et2Zn is equally selective in dichloromethane, hexane, toluene, and diethyl ether. The reaction was tolerant to the presence of aryl, alkyl, trimethylsilyl, methoxymethyl and aminomethyl substituents on the alkyne. A selective method was proposed for the preparation of bis-pyrrolidine derivatives using Ti-Mg-catalyzed carbocyclization of bis-allylpropargyl amines with Et2Zn.

Molecular rearrangements of poststerone derivative steroid core with formation of unique D-homostructures of pregnane and androstane series.

20R-Hydroxy short-chain ecdysteroids were synthesized by chemo- and stereoselective reduction of poststerone acetonide with L-Selectride or LiAlH4. The same reaction with the excess of L- Selectride followed by the treatment of the reaction mixture with hydrochloric acid is accompanied by (8R)-13(14 → 8)abeo- rearrangements, which resulted in the contraction/expansion of C/D pregnane rings. The reaction of 20R-hydroxy poststerone analogs with (diethylamino)sulfur trifluoride (DAST) proceeds through intramolecular rearrangements and provides D-homo- or 13,14-seco- androstane structures.