A series of new oxindole-based spiro-heterocycles bearing the benzo[b]thiophene motif were synthesized via a 1,3-dipolar cycloaddition reaction and their acetylcholinesterase (AChE) inhibitory activity was evaluated. All the synthesized compounds exhibited moderate inhibitory activities against AChE, while IIc was found to be the most active analog with an IC₅₀ value of 20,840 µM·L⁻¹. Its molecular structure was a 5-chloro-substituted oxindole bearing benzo[b]thiophene and octahydroindole moieties. Based on molecular docking studies, IIc was strongly bound to the catalytic and peripheral anionic sites of the protein through hydrophilic, hydrophobic, and π-stacking interactions with Asp74, Trp86, Tyr124, Ser125, Glu202, Ser203, Trp236, Trp286, Phe297, Tyr337, and Tyr341. These interactions also indicated that the multiplicity of the IIc aromatic core significantly favored its activity.

The emergence of multidrug-resistant (MDR) pathogens and the gradual depletion of available antibiotics have exacerbated the need for novel antimicrobial agents with minimal toxicity. Herein, we report functionally substituted pyridine carbohydrazide with remarkable antimicrobial effect on multi-drug resistant strains. In the series, compound 6 had potent activity against four MDR strains of Candida spp., with minimum inhibitory concentration (MIC) values being in the range of 16–24 µg/mL and percentage inhibition up to 92.57%, which was exceptional when compared to broad-spectrum antifungal drug fluconazole (MIC = 20 µg/mL, 81.88% inhibition). Substitution of the octyl chain in 6 with a shorter butyl chain resulted in a significant anti-bacterial effect of 4 against Pseudomonas aeruginosa (ATCC 27853), the MIC value being 2-fold superior to the standard combination of ampicillin/cloxacillin. Time-kill kinetics assays were used to discern the efficacy and pharmacodynamics of the potent compounds. Further, hemolysis tests confirmed that both compounds had better safety profiles than the standard drugs. Besides, molecular docking simulations were used to further explore their mode of interaction with target proteins. Overall results suggest that these compounds have the potential to become promising antimicrobial drugs against MDR strains.

Cyclin-dependent kinase 2 (CDK2) is a key mediator of multiple oncogenic signalling pathways. Its activity is crucial for loss of proliferative control during tumorigenesis1. Initial interest in dr...

Hepatocellular carcinoma (HCC) is a malignant liver cancer that continues to increase deaths worldwide owing to limited therapies and treatments. Computational drug repurposing is a promising strategy to discover potential indications of existing drugs. In this study, we present a systematic drug repositioning method based on comprehensive integration of molecular signatures in liver cancer tissue and cell lines. First, we identify robust prognostic genes and two gene co-expression modules enriched in unfavorable prognostic genes based on two independent HCC cohorts, which showed great consistency in functional and network topology. Then, we screen 10 genes as potential target genes for HCC on the bias of network topology analysis in these two modules. Further, we perform a drug repositioning method by integrating the shRNA and drug perturbation of liver cancer cell lines and identifying potential drugs for every target gene. Finally, we evaluate the effects of the candidate drugs through an in vitro model and observe that two identified drugs inhibited the protein levels of their corresponding target genes and cell migration, also showing great binding affinity in protein docking analysis. Our study demonstrates the usefulness and efficiency of network-based drug repositioning approach to discover potential drugs for cancer treatment and precision medicine approach.

Overall, drug design is a dynamic and evolving field, with researchers constantly working to improve their understanding of molecular interactions, develop new computational methods, and explore innovative techniques for creating effective and safe medications. The process can involve steps such as the identification of targets, the discovery of lead compounds, lead optimization, preliminary testing, human trials, regulatory approval and finally post-marketing surveillance, all aimed at bringing a new drug from concept to market. In this article, the synthesis of the novel triazolequinoxalin (TZQ) 1-((1-hexyl-1H-1,2,3-triazol-5-yl)methyl)-3-phenylquinoxalin-2(1H)-one (4) is reported. The structure has been identified with a variety of spectroscopic methods (1H, 13C NMR, and LC-MS) and finally, the structure has been determined by X-ray diffraction (XRD) studies. The TZQ molecule has crystallized in the monoclinic space C2/c group with unit cell dimensions a = 41.201(2) Å, b = 10.6339(6) Å, c = 9.4997(4) Å, β = 93.904(4). The crystal structure is stabilized by intermolecular interactions (N–H ⋯ O and N–H … Cg) occurring within the molecule. The presence of these intermolecular interactions is evaluated through analysis of Hirshfeld surfaces (HS) and two-dimensional (2D) chemical fingerprints map. Additionally, energy frameworks were employed to identify the prevailing interaction energy influencing the molecular arrangement. Density Functional Theory (DFT) calculations were computed to establish concurrence between theoretical and experimental results. Furthermore, the HOMO-LUMO energy levels were determined using the B3LYP/6-31+G(d, p) level of theory. Finally, molecular docking was used to predict the anti-cancer activity of the compound (4) against PFKFB3 kinase and presented noticeable hydrophilic and hydrophobic interactions at the active site region.

N1-(α,β-Alkene)-substituted phenylpyrazolopyrimidine derivatives with acetyl and functionalized phenyl groups at α- and β-positions, respectively, were synthesized by the reaction of 3-phenylpyrazolopyrimidine (PhPP) with bromoacetone, followed by a chalcone reaction with differently substituted aromatic aldehydes. The Src kinase enzyme assay revealed modest inhibitory activity (half maximal inhibitory concentration, IC₅₀ = 21.7–192.1 µM) by a number of PhPP derivatives. Antiproliferative activity of the compounds was evaluated on human leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), breast carcinoma (MDA-MB-231), and colon adenocarcinoma (HT-29) cells in vitro. 4-Chlorophenyl carbo-enyl substituted 3-phenylpyrazolopyrimidine (10) inhibited the cell proliferation of HT-29 and SK-OV-3 by 90% and 79%, respectively, at a concentration of 50 µM after 96 h incubation. The compound showed modest inhibitory activity against c-Src (IC₅₀ = 60.4 µM), Btk (IC₅₀ = 90.5 µM), and Lck (IC₅₀ = 110 µM), while it showed no activity against Abl1, Akt1, Alk, Braf, Cdk2, and PKCa. In combination with target selection and kinase profiling assay, extensive theoretical studies were carried out to explore the selectivity behavior of compound 10. Specific interactions were also explored by examining the changing trends of interactions of tyrosine kinases with the phenylpyrazolopyrimidine derivative. The results showed good agreement with the experimental selectivity pattern among c-Src, Btk, and Lck.