Design and synthesis of benzimidazole-based derivatives with antimicrobial activity: mechanistic insights into ROS-mediated oxidative damage, hemolytic assessment, and molecular docking studies.

A HIF-1 Target, ATIA, Protects Cells from Apoptosis by Modulating the Mitochondrial Thioredoxin, TRX2

Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth.

The majority of bacteria and archaea contains Toxin-Antitoxin system (TA) that codes for the stable Toxin and unstable Antitoxin components forming a complex. The Antitoxin inhibits the catalytic activities of the Toxin. In general, the Antitoxin will be degraded by the proteases leading to the Toxin activation that subsequently targets essential cellular processes, including transcription, translation, replication, cell division, and cell wall biosynthesis. The Zeta Toxin-Epsilon Antitoxin system in ESKAPE pathogen stabilizes the resistance plasmid and promotes pathogenicity. The known TA system in Acinetobacter baumannii are known to be involved in the replication and translation, however, the mechanism of Zeta Toxin-Epsilon Antitoxin in cell wall biosynthesis remains unknown. In the present study, molecular docking and molecular dynamic (MD) simulations were employed to demonstrate whether Zeta Toxin can impair cell wall synthesis in A. baumannii. Further, the degradation mechanism of Antitoxin in the presence and absence of adenosine triphosphate (ATP) molecules are explained through MD simulation. The result reveals that the cleavage of Antitoxin could be possible with the presence of ATP by displaying its response from 20 ns, whereas the Zeta Toxin/Epsilon was unstable after 90 ns. The obtained results demonstrate that Zeta Toxin is "temporarily favorable" for ATP to undergo phosphorylation at UNAG kinase through the substrate tunneling process. The study further evidenced that phosphorylated UNAG prevents the binding of MurA, the enzyme that catalyzes the initial step of bacterial peptidoglycan biosynthesis. Therefore, the present study explores the binding mechanism of Zeta Toxin/Epsilon Antitoxin, which could be beneficial for preventing cell wall biosynthesis as well as for unveiling the alternative treatment options to antibiotics.

Synthesis and biological evaluation of geniposide derivatives as inhibitors of hyperuricemia, inflammatory and fibrosis

MRSA infection is one of the alarming diseases in the current scenario. Identifying newer molecules to treat MRSA infection is of urgent need. In the present study, we have designed fluorinated thiazolidinone derivatives with various aryl/heteroaryl units at 5th position of the thiazolidinone core as promising anti-MRSA agents. All the compounds were screened for antibacterial activity against four bacterial strains. Among the tested compounds, the halogenated compounds with simple arylidene ring, (5Z)-5-[(3-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4b), (5Z)-5-[(4-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4c), (5Z)-5-[(3-fluoro-4-methylphenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4f) and (5Z)-5-[(3,5-difluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4g) showed excellent activity with MIC 3.125-6.25 μg/mL against S. aureus and P. aeruginosa organism. Furthermore, these potent compounds were screened against MRSA strains, ESKAPE panel organism, and H37Rv mycobacterium strain. Compounds 4c (MIC 0.39 μg/mL), and 4f (MIC 0.39 and 0.79 μg/mL) displayed promising activity against MRSA strains (ATCC and clinical isolates, respectively). The most potent compounds, 4c and 4f eradicated the growth of bacterial colonies in a time-kill assay indicated that these are bactericidal in nature. The preliminary toxicity study of the potent molecules revealed that these compounds are non-hemolytic in nature as they did not induce lysis in human RBCs. In addition, the molecular docking and dynamics studies of compounds 4b, 4c, 4f and 4g were carried out on MurB protein of S. aureus (PDB code: 1HSK). Docking results demonstrated remarkable hydrogen bonding interaction with key amino acids ARG310, ASN83, GLY79 and π-π interactions with TYR149 which confirm the mode of action of the molecules.

The present work deals with the sequence of Novel Pyrazole fused Indole derivatives(4a-4l) were synthesized by simple conventional method andscreened for anthelmintic, antibacterial and anticancer activities. The molecular docking studies were also performed. All of the newly synthesizedcompounds were structurally characterized on the basis of IR, 1HNMR and Mass spectral analysis. Further, all of the newly prepared pyrazole fusedindole derivatives were screened for anthelmintic activity by using Albendazole as standard drug. The antibacterial activity was carried out by agardiffusion (Cup plate) method by using Streptomycin as standard and anticancer activity against MCF-7 cell lines by MTT assay method. The resultsshowed that some of the compounds 4b, 4c and 4f exhibited good anticancer activity. The compounds 4c, 4f, 4j showed good anthelmintic activity and4b,4h and 4i exhibited potential antibacterial activity by comparing with standard drug. Additionally, the molecular docking studies of novel pyrazolefused Indole derivatives was also carried out to explain putative bonding interaction between the active site of EGFR enzyme and synthesized NovelPyrazole fused Indole derivatives by Schrodinger suite.

A series of benzothiazole derivatives ( 3a–o ) were synthesized, structurally characterized by IR, ¹H‐NMR, ¹ 3 C‐NMR, and elemental analysis, and assessed for their in vitro antibacterial efficacy against Staphylococcus aureus , Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . The outcomes revealed differing levels of activity, with compounds 3c , 3j, and 3n identified as the most effective, exhibiting significant inhibition zones and low minimum inhibitory concentrations (MICs) that are comparable to, though typically lower than, those of the reference antibiotic ciprofloxacin. To explore the structure‐activity relationships, density functional theory (DFT) calculations were executed, delivering insights into the electronic characteristics and reactivity of the most active compounds ( 3c , 3n , 3j ). These calculations indicated a link between smaller HOMO–LUMO energy gaps and increased reactivity. Following this, molecular docking studies were performed to investigate the possible action mechanism against S. aureus tyrosyl‐tRNA synthetase (TyrRS), an essential bacterial enzyme. The docking findings displayed favorable binding energies for the active compounds, with 3j (−9.3 Kcal/mol) and 3n (−8.6 Kcal/mol) showing robust interactions, which aligned well with their observed antibacterial effectiveness. An extensive analysis of interaction profiles pinpointed key amino acid residues engaged in binding, suggesting that TyrRS inhibition is a likely mechanism. This study highlights the potential of benzothiazole derivatives, combined with urea and thiourea derivatives, as promising candidates for the development of new antibacterial agents.

Recent studies showed that hyperglycemia is the main trigger of diabetic cognitive impairment and can cause hippocampus abnormalities. The goal of this study is to explore the effects of different concentrations of high glucose for different exposure time on cell viability as well as intracellular reactive oxygen species (ROS) generation of primary cultured hippocampal neurons. Hippocampal neurons were exposed to different concentrations of high glucose (50, 75, 100, 125, and 150 mM) for 24, 48, 72 and 96 h. Cell viability and nuclear morphology were evaluated by MTT and Hoechst assays, respectively. Intracellular ROS were monitored using the fluorescent probe DCFH-DA. The results showed that, compared with control group, the cell viability of all high glucose-treated groups decreased significantly after 72 h and there also was a significant increase of apoptotic nuclei in high glucose-treated groups from 72 to 96 h. Furthermore, 50 mM glucose induced a peak rise in ROS generation at 24 h and the intracellular ROS levels of 50 mM glucose group were significantly higher than the corresponding control group from 6 to 72 h. These results suggest that hippocampal neurons could be injured by high glucose exposure and the neuronal injury induced by high glucose is potentially mediated through intracellular ROS accumulation.

Ligand-Based Design of Novel Thiazole-Quinazolinone Hybrids with Dual Antimicrobial and Anti-Virulence Activity Targeting Staphylococcal Sortase A.

Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity

Alteration of the mode of antibacterial action of a defensin by the amino-terminal loop substitution

Unlocking the bacterial membrane as a therapeutic target for next-generation antimicrobial amphiphiles

Hyperhomocysteinemia is believed to induce endothelial dysfunction and promote atherosclerosis; however, the pathogenic mechanism has not been clearly elucidated. In this study, we examined the molecular mechanism by which homocysteine (HCy) causes endothelial cell apoptosis and by which nitric oxide (NO) affects HCy-induced apoptosis. Our data demonstrated that HCy caused caspase-dependent apoptosis in cultured human umbilical vein endothelial cells, as determined by cell viability, nuclear condensation, and caspase-3 activation and activity. These apoptotic characteristics were correlated with reactive oxygen species (ROS) production, lipid peroxidation, p53 and Noxa expression, and mitochondrial cytochrome c release following HCy treatment. HCy also induced p53 and Noxa expression and apoptosis in endothelial cells from wild type mice but not in the p53-deficient cells. The NO donor S-nitroso-N-acetylpenicillamine, adenoviral transfer of inducible NO synthase gene, and antioxidants (alpha-tocopherol and superoxide dismutase plus catalase) but not oxidized SNAP, 8-Br-cGMP, nitrite, and nitrate, suppressed ROS production, p53-dependent Noxa expression, and apoptosis induced by HCy. The cytotoxic effect of HCy was decreased by small interfering RNA-mediated suppression of Noxa expression, indicating that Noxa up-regulation plays an important role in HCy-induced endothelial cell apoptosis. Overexpression of inducible NO synthase increased the formation of S-nitroso-HCy, which was inhibited by the NO synthase inhibitor N-monomethyl-l-arginine. Moreover, S-nitroso-HCy did not increase ROS generation, p53-dependent Noxa expression, and apoptosis. These results suggest that up-regulation of p53-dependent Noxa expression may play an important role in the pathogenesis of atherosclerosis induced by HCy and that an increase in vascular NO production may prevent HCy-induced endothelial dysfunction by S-nitrosylation.

Transcription factor AbrB regulates ROS generation and clearance in Bacillus licheniformis

Heat shock protein 70 (HSP70) protects against cardiac diseases such as ischemia/reperfusion injury and myocardial infarction. However, the underlying mechanisms have not yet been fully characterized. In this study, we investigated the effects of reactive oxygen species (ROS) and transforming growth factor-β-activated kinase 1 (TAK1) on HSP70-regulated cardiomyocyte protection. Cultured cardiomyocytes of neonatal rats were transfected with HSP70, TAK1 or both of them before exposure to H2O2, and the ROS generation, p38 mitogen-activated protein kinase (p38) activity and apoptosis were examined. H2O2 significantly enhanced intracellular ROS generation and apoptosis as expected, and all these cellular events were greatly abolished by overexpression of HSP70. However, H2O2-induced increments in p38 phosphorylation and cardiac cell apoptosis were largely enhanced by TAK1 overexpression, whereas the similar transfection did not affect the ROS generation in the cardiomyocytes. Moreover, inhibition of H2O2-increased ROS generation, p38 phosphorylation, and cardiomyocytes apoptosis by overexpression of HSP70 tended to disappear when the cells were cotransfected with TAK1. Our data suggest that HSP70 protects cardiomyocytes from apoptosis under oxidative stress through downregulation of intracellular ROS generation and inhibition of p38 phosphorylation. Although TAK1 itself has no effect on intracellular ROS accumulation, it may affect the inhibitory effects of HSP70 on ROS generation, p38 activity and cardiomyocyte injury.