Polyacetylene Derivatives from the Polypore Fungus (Fistulina hepatica, Agaricomycetes) and Their Antimicrobial Activity.

Chemical investigation of the polypore fungus Fistulina hepatica resulted in the isolation of five compounds, including four new polyacetylenic fatty acid derivatives - isocinnatriacetin B (1), isocinnatriacetin A (2), cinna-triacetin C (3) and ethylcinnatriacetin A (4) together with one known polyacetylene fatty acid derivative - cinnatriacetin A (5). The structures were elucidated using spectroscopic methods (UV, NMR, HR-ESIMS) along with comparison to literature data. Antibacterial activity screening of compounds 1-5 against ESKAPE bacterial strains in vitro with zones of inhibition (ZOI) was performed and MIC values were established for the most active compounds (3 and 4). Together with that morphological and growth parameters under solid-phase cultivation were also researched.

New benzoquinone pigments from the hydnoid fungus Sarcodontia setosa and their biosynthetic relationship.

Chemical investigation of the hydnoid fungus Sarcodontia setosa resulted in the isolation of five compounds, including two new sarcodontic acid derivatives - setosic acid (1) and 7,8-dehydrohomosarcodontic acid (2) along with three known benzoquinone pigments - sarcodontic acid (3), 4,5-dehydrosarcodontic acid (4) and dihydrosarcodontic acid (5). The structures were elucidated using spectroscopic methods (UV, NMR and HR-ESIMS). The biosynthetic relationship of the isolated compounds is proposed and discussed. Antibacterial activity screening of compounds 1-5 against ESKAPE bacterial strains in vitro with zones of inhibition was performed and MIC values were established for the most active compounds (3 and 5).

Gold vs Light: Chemodivergent Reactivity of Diazoesters toward 2H-Azirine-2-carboxylic Acids.

An orthogonal reactivity of diazo compounds toward azirine-2-carboxylic acids, switching with the reaction conditions, is demonstrated. A gold-catalyzed reaction is N-selective and produces 1,3-oxazin-6-ones, whereas a blue light activation leads to O-H insertion products, azirine-2-carboxylic esters. The observed chemodivergence is explained by the metal-bound and metal-free carbenes exhibiting different electronic properties in these reactions. In addition, a high antibacterial potential of the 1,3-oxazin-6-ones synthesized is shown.

External oxidant-free and transition metal-free synthesis of 5-amino-1,2,4-thiadiazoles as promising antibacterials against ESKAPE pathogen strains.

A new route to 5-amino-1,2,4-thiadiazole derivatives via reaction of N-chloroamidines with isothiocyanates has been proposed. The advantages of this method are high product yields (up to 93%), the column chromatography-free workup procedure, scalability and the absence of additive oxidizing agents or transition metal catalysts. The 28 examples of 5-amino-1,2,4-thiadiazole derivatives obtaining via the proposing protocol were evaluated in vitro against ESKAPE pathogens strains (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae). It was found that compounds 5ba, 5bd, 6a, 6d and 6c have potent antibacterial activity (MIC values 0.09-1.5 µg mL-1), which is superior to the activity of commercial antibiotics such as pefloxacin (MIC 4-8 µg mL-1) and streptomycin (MIC 2-32 µg mL-1). The additional cytotoxic assay of hit compounds on PANC-1 cell line demonstrated the low or non-cytotoxicity activity at the same level of concentrations. Thus, these 5 compounds are promising starting point for further antimicrobial drug development.

In-Vitro Antibacterial Activity of Curcumin-Loaded Nanofibers Based on Hyaluronic Acid against Multidrug-Resistant ESKAPE Pathogens.

Bacterial infections have accompanied humanity throughout its history and became vitally important in the pandemic area. The most pathogenic bacteria are multidrug-resistant strains, which have become widespread due to their natural biological response to the use of antibiotics, including uncontrolled use. The current challenge is finding highly effective antibacterial agents of natural origin, which, however, have low solubility and consequently poor bioavailability. Curcumin, derived from Curcuma longa, is an example of a natural biologically active agent with a wide spectrum of biological effects, particularly against Gram-positive bacteria. However, curcumin exhibits extremely low antibacterial activity against Gram-negative bacteria. Curcumin's hydrophobicity limits its use in medicine. As such, various polymeric systems have been used, especially biopolymer-based electrospun nanofibers. In the present study, the technological features of the fabrication of curcumin-loaded hyaluronic acid-based nanofibers are discussed in detail, their morphological characteristics, wettability, physico-chemical properties, and curcumin release profiles are demonstrated, and their antibacterial activity against multi-drug resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are evaluated. It is noteworthy that the fibers containing a stable HA-curcumin complex showed high antibacterial activity against both Gram-positive and Gram-negative bacteria, which is an undeniable advantage. It is expected that the results of this work will contribute to the development of antibacterial drugs for topical and internal use with high efficacy and considerably lower side effects.

Azirine-containing dipeptides and depsipeptides: synthesis, transformations and antibacterial activity.

Azirine-containing dipeptides and depsipeptides with a wide range of substituents have been synthesized in high yields via the Passerini and Ugi multicomponent reactions (MCRs) using 2H-azirine-2-carboxylic acids as the acid component. The obtained MCR adducts have been transformed to lactam-fused aziridines, as well as pyrrole, imidazole, aziridine, and other derivatives, containing the dipeptide or depsipeptide moiety. The azirine-containing depsipeptides exhibit antibacterial activity against the ESKAPE pathogens, especially Gram-positive bacterial strains (E. faecium - MIC 16 µg mL-1, S. aureus - MIC 9 µg mL-1).

Mutually Isomeric 2- and 4-(3-nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens.

Starting from the structure of antimycobacterial screening hit OTB-021 which was devoid of activity against ESKAPE pathogens, we designed, synthesized and tested two mutually isomeric series of novel simplified analogs, 2- and 4-(3-nitro-1,2,4-triazol-1-yl)pyrimidines, bearing various amino side chains. These compounds demonstrated a reverse bioactivity profile being inactive against M. tuberculosis while inhibiting the growth of all ESKAPE pathogens (with variable potency patterns) except for Gram-negative P. aeruginosa. Reduction potentials (E1/2, V) measured for selected compounds by cyclic voltammetry were tightly grouped in the -1.3--1.1 V range for a reversible single-electron reduction. No apparent correlation between the E1/2 values and the ESKAPE minimum inhibitory concentrations was established, suggesting possible significance of other factors, besides the compounds' reduction potential, which determine the observed antibacterial activity. Generally, more negative E1/2 values were displayed by 2-(3-nitro-1,2,4-triazol-1-yl)pyrimidines, which is in line with the frequently observed activity loss on moving the 3-nitro-1,2,4-triazol-1-yl moiety from position 4 to position 2 of the pyrimidine nucleus.

Attachment of a 5-nitrofuroyl moiety to spirocyclic piperidines produces non-toxic nitrofurans that are efficacious in vitro against multidrug-resistant Mycobacterium tuberculosis.

A selectively antimycobacterial compound belonging to the nitrofuran class of antimicrobials has been developed via conjugation of the nitrofuran moiety to a series of spirocyclic piperidines through an amide linkage. It proved to have comparable activity against drug-sensitive (H37Rv) strain as well as multidrug-resistant, patient-derived strains of Mycobacterium tuberculosis. The compound is druglike, showed no appreciable cytotoxicity toward human retinal pigment epithelial cell line ARPE-19 in concentrations up to 100 µM and displayed low toxicity when evaluated in mice.

Non-natural 2H-azirine-2-carboxylic acids: an expedient synthesis and antimicrobial activity.

Non-natural 2H-azirine-2-carboxylic acids were obtained in high yields by FeCl2-catalyzed isomerization of 5-chloroisoxazoles to azirine-2-carbonyl chlorides followed by their hydrolysis. The 3-aryl- and 3-heteroaryl-substituted acids are stable during prolonged storage, exhibit antibacterial activity against ESKAPE pathogens and show a low level of cytotoxicity.

Ancient genomes suggest the eastern Pontic-Caspian steppe as the source of western Iron Age nomads.

For millennia, the Pontic-Caspian steppe was a connector between the Eurasian steppe and Europe. In this scene, multidirectional and sequential movements of different populations may have occurred, including those of the Eurasian steppe nomads. We sequenced 35 genomes (low to medium coverage) of Bronze Age individuals (Srubnaya-Alakulskaya) and Iron Age nomads (Cimmerians, Scythians, and Sarmatians) that represent four distinct cultural entities corresponding to the chronological sequence of cultural complexes in the region. Our results suggest that, despite genetic links among these peoples, no group can be considered a direct ancestor of the subsequent group. The nomadic populations were heterogeneous and carried genetic affinities with populations from several other regions including the Far East and the southern Urals. We found evidence of a stable shared genetic signature, making the eastern Pontic-Caspian steppe a likely source of western nomadic groups.

Conjugation of a 5-nitrofuran-2-oyl moiety to aminoalkylimidazoles produces non-toxic nitrofurans that are efficacious in vitro and in vivo against multidrug-resistant Mycobacterium tuberculosis.

Within the general nitrofuran carboxamide chemotype, chimera derivatives incorporating diversely substituted imidazoles attached via an alkylamino linker were synthesized. Antimycobacterial evaluation against drug-sensitive M. tuberculosis H37Rv strain identified five active druglike compounds which were further profiled against patient-derived M. tuberculosis strains in vitro. One of the compounds displayed promising potent activity (MIC 0.8 µg/mL) against one of such strains otherwise resistant to such first- and second-line TB therapies as streptomycin, isoniazid, rifampicin, ethambutol, kanamycin, ethionamide, capreomycin and amikacin. The compound was shown to possess low toxicity for mice (LD50 = 900.0 ±â€¯83.96 mg/kg) and to be similarly efficacious to etambutol, in the mouse model of drug-sensitive tuberculosis, and to neurotoxic cycloserine in mice infected with MDR tuberculosis.