New Biocides Based on N4-Alkylcytidines: Effects on Microorganisms and Application for the Protection of Cultural Heritage Objects of Painting.

The rapid increase in the antibiotic resistance of microorganisms, capable of causing diseases in humans as destroying cultural heritage sites, is a great challenge for modern science. In this regard, it is necessary to develop fundamentally novel and highly active compounds. In this study, a series of N4-alkylcytidines, including 5- and 6-methylcytidine derivatives, with extended alkyl substituents, were obtained in order to develop a new generation of antibacterial and antifungal biocides based on nucleoside derivatives. It has been shown that N4-alkyl 5- or 6-methylcytidines effectively inhibit the growth of molds, isolated from the paintings in the halls of the Ancient Russian Paintings of the State Tretyakov Gallery, Russia, Moscow. The novel compounds showed activity similar to antiseptics commonly used to protect works of art, such as benzalkonium chloride, to which a number of microorganisms have acquired resistance. It was also shown that the activity of N4-alkylcytidines is comparable to that of some antibiotics used in medicine to fight Gram-positive bacteria, including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis. N4-dodecyl-5- and 6-methylcytidines turned out to be the best. This compound seems promising for expanding the palette of antiseptics used in painting, since quite often the destruction of painting materials is caused by joint fungi and bacteria infection.

New 2,4-dihydro-1H-1,2,4-triazole-3-selones and 3,3'-di(4H-1,2,4-triazolyl)diselenides. Synthesis, biological evaluation, and in silico studies as antibacterial and fungicidal agents.

The reaction of aromatic ring-substituted isoselenocyanates with 2-thiopheacetic and 4-pyridinecarboxylic acid hydrazides yielded selenosemicarbazides which were further converted into previously unknown 1,2,4-triazole-3-selones and 3,3'-di(4H-1, 2,4-triazolyl)diselenides. The structures of the obtained compounds were studied by NMR spectroscopy, IR spectroscopy, and high-resolution mass spectroscopy (HR-MS). The bactericidal and fungicidal activity of some obtained compounds was evaluated in molecular modeling studies such as docking and simulation studies. The compound 3ba was reported as the most promising compound to show robust binding energy with different antibacterial and antifungal compounds. The compounds were observed in strong hydrophilic and hydrophobic interactions and remained in stable binding conformation with the receptor enzymes. Furthermore, the interatomic interaction energies were dominated by Van der Waals and electrostatic energies indicating the formation of stable complexes.

Friunavirus Phage-Encoded Depolymerases Specific to Different Capsular Types of Acinetobacter baumannii.

Acinetobacter baumannii is a critical priority nosocomial pathogen that produces a variety of capsular polysaccharides (CPSs), the primary receptors for specific depolymerase-carrying phages. In this study, the tailspike depolymerases (TSDs) encoded in genomes of six novel Friunaviruses, APK09, APK14, APK16, APK86, APK127v, APK128, and one previously described Friunavirus phage, APK37.1, were characterized. For all TSDs, the mechanism of specific cleavage of corresponding A. baumannii capsular polysaccharides (CPSs) was established. The structures of oligosaccharide fragments derived from K9, K14, K16, K37/K3-v1, K86, K127, and K128 CPSs degradation by the recombinant depolymerases have been determined. The crystal structures of three of the studied TSDs were obtained. A significant reduction in mortality of Galleria mellonella larvae infected with A. baumannii of K9 capsular type was shown in the example of recombinant TSD APK09_gp48. The data obtained will provide a better understanding of the interaction of phage-bacterial host systems and will contribute to the formation of principles of rational usage of lytic phages and phage-derived enzymes as antibacterial agents.

In Planta, In Vitro and In Silico Studies of Chiral N6-Benzyladenine Derivatives: Discovery of Receptor-Specific S-Enantiomers with Cytokinin or Anticytokinin Activities.

Cytokinins, classical phytohormones, affect all stages of plant ontogenesis, but their application in agriculture is limited because of the lack of appropriate ligands, including those specific for individual cytokinin receptors. In this work, a series of chiral N6-benzyladenine derivatives were studied as potential cytokinins or anticytokinins. All compounds contained a methyl group at the α-carbon atom of the benzyl moiety, making them R- or S-enantiomers. Four pairs of chiral nucleobases and corresponding ribonucleosides containing various substituents at the C2 position of adenine heterocycle were synthesized. A nucleophilic substitution reaction by secondary optically active amines was used. A strong influence of the chirality of studied compounds on their interaction with individual cytokinin receptors of Arabidopsis thaliana was uncovered in in vivo and in vitro assays. The AHK2 and CRE1/AHK4 receptors were shown to have low affinity for the studied S-nucleobases while the AHK3 receptor exhibited significant affinity for most of them. Thereby, three synthetic AHK3-specific cytokinins were discovered: N6-((S)-α-methylbenzyl)adenine (S-MBA), 2-fluoro,N6-((S)-α-methylbenzyl)adenine (S-FMBA) and 2-chloro,N6-((S)-α-methylbenzyl)adenine (S-CMBA). Interaction patterns between individual receptors and specific enantiomers were rationalized by structure analysis and molecular docking. Two other S-enantiomers (N6-((S)-α-methylbenzyl)adenosine, 2-amino,N6-((S)-α-methylbenzyl)adenosine) were found to exhibit receptor-specific and chirality-dependent anticytokinin properties.

Capsule-Targeting Depolymerases Derived from Acinetobacter baumannii Prophage Regions.

In this study, several different depolymerases encoded in the prophage regions of Acinetobacter baumannii genomes have been bioinformatically predicted and recombinantly produced. The identified depolymerases possessed multi-domain structures and were identical or closely homologous to various proteins encoded in other A. baumannii genomes. This means that prophage-derived depolymerases are widespread, and different bacterial genomes can be the source of proteins with polysaccharide-degrading activities. For two depolymerases, the specificity to capsular polysaccharides (CPSs) of A. baumannii belonging to K1 and K92 capsular types (K types) was determined. The data obtained showed that the prophage-derived depolymerases were glycosidases that cleaved the A. baumannii CPSs by the hydrolytic mechanism to yield monomers and oligomers of the K units. The recombinant proteins with established enzymatic activity significantly reduced the mortality of Galleria mellonella larvae infected with A. baumannii of K1 and K92 capsular types. Therefore, these enzymes can be considered as suitable candidates for the development of new antibacterials against corresponding A. baumannii K types.

New Derivatives of 5-Substituted Uracils: Potential Agents with a Wide Spectrum of Biological Activity.

Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2'-deoxy-5-iodocytidine and 5-bromovinyl-2'-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV. It made this modification of nucleoside analogues very promising in connection with the emergence of new viruses and the crisis of drug resistance when the task of creating effective antiviral agents of new types that act on other targets or exhibit activity by other mechanisms is very urgent. In this paper, we present the design, synthesis and primary screening of the biological activity of new nucleoside analogues, namely, 5'-norcarbocyclic derivatives of substituted 5-arylamino- and 5-aryloxyuracils, against RNA viruses.

Facile Access to 2-Selenoxo-1,2,3,4-tetrahydro-4-quinazolinone Scaffolds and Corresponding Diselenides via Cyclization between Methyl Anthranilate and Isoselenocyanates: Synthesis and Structural Features.

A practical method for the synthesis of 2-selenoxo-1,2,3,4-tetrahydro-4-quinazolinone was reported. The latter compounds were found to undergo facile oxidation with H2O2 into corresponding diselenides. Novel organoselenium derivatives were characterized by the 1H, 77Se, and 13C NMR spectroscopies, high-resolution electrospray ionization mass spectrometry, IR, elemental analyses (C, H, N), and X-ray diffraction analysis for several of them. Novel heterocycles exhibited multiple remarkable chalcogen bonding (ChB) interactions in the solid state, which were studied theoretically.

Complex Carbohydrates and Glycoconjugates: Structure, Functions and Applications.

The study of carbohydrates has a long history: for two centuries, the researches performed the way from "sweet matter" to glycomics [...].

Acinetobacter baumannii K106 and K112: Two Structurally and Genetically Related 6-Deoxy-l-talose-Containing Capsular Polysaccharides.

Whole genome sequences of two Acinetobacter baumannii clinical isolates, 48-1789 and MAR24, revealed that they carry the KL106 and KL112 capsular polysaccharide (CPS) biosynthesis gene clusters, respectively, at the chromosomal K locus. The KL106 and KL112 gene clusters are related to the previously described KL11 and KL83 gene clusters, sharing genes for the synthesis of l-rhamnose (l-Rhap) and 6-deoxy-l-talose (l-6dTalp). CPS material isolated from 48-1789 and MAR24 was studied by sugar analysis and Smith degradation along with one- and two-dimensional 1H and 13C NMR spectroscopy. The structures of K106 and K112 oligosaccharide repeats (K units) l-6dTalp-(1→3)-D-GlcpNAc tetrasaccharide fragment share the responsible genes in the respective gene clusters. The K106 and K83 CPSs also have the same linkage between K units. The KL112 cluster includes an additional glycosyltransferase gene, Gtr183, and the K112 unit includes α l-Rhap side chain that is not found in the K106 structure. K112 further differs in the linkage between K units formed by the Wzy polymerase, and a different wzy gene is found in KL112. However, though both KL106 and KL112 share the atr8 acetyltransferase gene with KL83, only K83 is acetylated.

Tandem Electrospray Mass Spectrometry of Cyclic N-Substituted Oligo-ß-(1→6)-D-glucosamines.

High-resolution electrospray mass spectra (MS and MS/MS CID) of positive ions of a series of protonated, ammoniated, and metallated molecules of cyclic N-substituted oligo-ß-(1→6)-D-glucosamines differing in cycle size and N-acyl substituents were registered and interpreted. It was shown that the main type of fragmentation is a cleavage of glycosidic bonds of a cycle, and in some cases fragmentation of amide side chains is possible. If labile fragments in substituents (e.g., carbohydrate chains) are present, a decay of the cycle and an elimination of labile fragments are of comparable possibility. It was found that in some cases rearrangements with loss of an internal carbohydrate residue (IRL), or an internal part of a side chain, are feasible.

Gas-Phase Fragmentation of Cyclic Oligosaccharides in Tandem Mass Spectrometry.

Modern mass spectrometry, including electrospray and MALDI, is applied for analysis and structure elucidation of carbohydrates. Cyclic oligosaccharides isolated from different sources (bacteria and plants) have been known for decades and some of them (cyclodextrins and their derivatives) are widely used in drug design, as food additives, in the construction of nanomaterials, etc. The peculiarities of the first- and second-order mass spectra of cyclic oligosaccharides (natural, synthetic and their derivatives and modifications: cyclodextrins, cycloglucans, cyclofructans, cyclooligoglucosamines, etc.) are discussed in this minireview.

1,6-Bis[(benzyloxy)methyl]uracil derivatives-Novel antivirals with activity against HIV-1 and influenza H1N1 virus.

A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation.

Toward the discovery of dual HCMV-VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides.

The need for novel therapeutic options to fight herpesvirus infections still persists. Herein we report the design, synthesis and antiviral evaluation of a new family of non-nucleoside antivirals, derived from 1-[ω-(4-bromophenoxy)alkyl]uracil derivatives--previously reported inhibitors of human cytomegalovirus (HCMV). Introduction of the N-(4-phenoxyphenyl)acetamide side chain at N(3) increased their potency and widened activity spectrum. The most active compounds in the series exhibit submicromolar activity against different viral strains of HCMV and varicella zoster virus (VZV) replication in HEL cell cultures. Inactivity against other DNA and RNA viruses, including herpes simplex virus 1/2, points to a novel mechanism of antiviral action.

Scaffold hopping: exploration of acetanilide-containing uracil analogues as potential NNRTIs.

In order to identify novel nonnucleoside inhibitors of HIV-1 reverse transcriptase two series of amide-containing uracil derivatives were designed as hybrids of two scaffolds of previously reported inhibitors. Subsequent biological evaluation confirmed acetamide uracil derivatives 15a-k as selective micromolar NNRTIs with a first generation-like resistance profile. Molecular modeling of the most active compounds 15c and 15i was employed to provide insight on their inhibitory properties and direct future design efforts.

Synthesis of sialyl halides with various acyl protective groups.

Glycosyl halides are historically one of the first glycosyl donors used in glycosylation reactions, and interest in glycosylation reactions involving this class of glycosyl donors is currently increasing. New methods for their activation have been proposed and effective syntheses of oligosaccharides with their participation have been developed. At the same time, the possibilities of using these approaches to the synthesis of sialosides are restricted by the limited diversity of known sialyl halides (previously, mainly sialyl chlorides, less often sialyl bromides and sialyl fluorides, with acetyl (Ac) groups at the oxygen atoms and AcNH, Ac2N and N3 groups at C-5 were used). This work describes the synthesis of six new N-acetyl- and N-trifluoroacetyl-sialyl chlorides and bromides with O-chloroacetyl and O-trifluoroacetyl protective groups. Preparation of N,O-trifluoroacetyl protected derivatives was made possible due to development of the synthesis of sialic acid methyl ester pentaol with N-trifluoroacetyl group.

Synthesis and anti-HCMV activity of 1-[ω-(phenoxy)alkyl]uracil derivatives and analogues thereof.

HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[ω-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC50 values within 5.5-12µM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure-activity relationship for the linker region.

Inhibition of Mycobacterium tuberculosis strains H37Rv and MDR MS-115 by a new set of C5 modified pyrimidine nucleosides.

Two sets of pyrimidine nucleoside derivatives bearing extended alkyloxymethyl or alkyltriazolidomethyl substituents at position 5 of the nucleobase were synthesized and evaluated as potential antituberculosis agents. The impact of modifications at 3'- and 5'-positions of the carbohydrate moiety on the antimycobacterial activity and cytotoxicity was studied. The highest effect was shown for 5-dodecyloxymethyl-2'-deoxyuridine, 5-decyltriazolidomethyl-2'-deoxyuridine, and 5-dodecyltriazolidomethyl-2'-deoxycytidine. They effectively inhibited the growth of two Mycobacterium tuberculosis strains in vitro, laboratory H37Rv (MIC99=20, 10, and 20µg/mL, respectively) and clinical MDR MS-115 resistant to five top antituberculosis drugs (МIC99=50, 10, and 10µg/mL, respectively).

A highly facile approach to the synthesis of novel 2-(3-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-N-phenylacetamides.

A series of heterocyclic compounds were designed as potential nonnucleoside HIV reverse transcriptase inhibitors. Although the compounds ultimately proved inactive against HIV, during the course of the synthesis, a new and highly facile method to realize N-phenylacetamides was developed. Notably, the new route avoids the intractable workups and byproducts previously reported procedures have been associated with, thereby making this approach highly attractive to adaptation with other heterocyclics.

TIPS group-assisted isomerization of benzyl protected d-manno- and d-glucopyranose to d-fructofuranose derivatives.

Base-promoted (MeONa in MeOH or imidazole in DMF) isomerization of a series of 3,4,6-tri-O-benzyl-d-gluco- and d-mannopyranose derivatives with triisopropylsilyl (TIPS) substituents was studied. The presence of a bulky TIPS group at O-1 or O-2 was shown to be favorable for the isomerization of benzyl protected d-gluco- and d-mannopyranose derivatives to d-fructofuranose derivatives, in which the bulky silyl group occupies less sterically hindered primary position. The highest yield (33%) of the fructofuranose derivative was achieved when 3,4,6-tri-O-benzyl-2-O-triisopropylsilyl-d-mannopyranose was treated with MeONa in MeON at 50 °C.

Complete chemical structure of the K135 capsular polysaccharide produced by Acinetobacter baumannii RES-546 that contains 5,7-di-N-acetyl-8-epipseudaminic acid.

A structurally diverse capsular polysaccharide (CPS) in the outer cell envelope plays an important role in the virulence of the important bacterial pathogen, Acinetobacter baumannii. More than 75 different CPS structures have been determined for the species to date, and many CPSs include isomers of a higher sugar, namely 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acid. Recently, a novel isomer having the d-glycero-l-manno configuration (5,7-di-N-acetyl-8-epipseudaminic acid; 8ePse5Ac7Ac) has been identified in the CPS from A. baumannii clinical isolate RES-546 [Carbohydr. Res. 513 (2022) 108,531]. Here, the complete chemical structure of this CPS, designated K135, was elucidated. The CPS was found to have a branched tetrasaccharide K unit and to include the higher sugar as part of a 8ePse5Ac7Ac-(2 â†’ 6)-α-Gal disaccharide branching from a →3)-α-D-GlcpNAc-(1 â†’ 3)-ß-D-GlcpNAc-(1→ main chain. Assignment of glycosyltransferases encoded by the CPS biosynthesis gene cluster in the RES-546 genome enabled the first sugar of the K unit, and hence the topology of the K135 CPS, to be determined.