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Cancer affects millions of people worldwide. PDK1 enzyme (co-crystallized with BIM-1) controls the proliferation of breast cancer cells. Aiming to resemble BIM-1's binding, quinoline-based pyrimidinediones and thiazolidinediones were synthesized starting from 2-chloro-3-formylquinoline. Compared with doxorubicin (reference), in vitro antiproliferative activity against MCF7 and HCT116 cancer cell lines showed the most potency of thiobarbiturate 3 and thiazolidinedione 4. In silico molecular docking, DFT, and pharmacokinetics simulations supported the findings. The docking analysis toward PDK1 enzyme showed that most amino acids interacting with co-crystallized ligand (BIM-1) were successfully bonded to our docked substances, especially thiobarbiturate 3 with highest S-score closer to BIM-1. In DFT calculations, this compound exhibited the lowest energy gap and highest softness leading to more response to radical surface interactions. The compounds with significant antiproliferative activity exhibited high electrophilicity values. ADME analysis showed its desirable drug-likeness and oral bioavailability. This work may contribute to developing new potent antiproliferative agents. [ABSTRACT FROM AUTHOR]

This study investigated the catalytic behavior of NHC-X ligands (X = F, Cl, Br, I) in cycloaddition reactions, focusing on both mononuclear and binuclear pathways. Using NCI (noncovalent interaction), RDG (reduced density gradient), ELF (electron localization function), and LOL (localized orbital locus) computational analyses, the electronic interactions and stability of the ligands were examined. The results showed that NHC-Cl exhibited the least steric hindrance and strongest transition state stabilization, making it the most efficient catalyst. NHC-F also demonstrated strong stabilization, particularly in the binuclear pathway. In contrast, NHC-Br showed moderate efficiency, whereas NHC-I was the least effective owing to higher Gibbs free energy values and greater steric hindrance, especially in polar solvents such as water and acetonitrile. This study emphasizes the crucial role of solvent effects and thermodynamic factors in influencing the catalytic efficiency. These findings provide a framework for optimizing NHC-based catalysts for chemical transformations. [ABSTRACT FROM AUTHOR]

Halogen bonds find application in supramolecular chemistry, DNA Holliday junction, drug design, organic catalysis and various other fields. Coumarin derivatives are high in demand due to their application in photochemotherapy, drugs and other cancer treatments. Halogenated coumarins are widely known for their biological activities. There exists a competition between the halogen bond and hydrogen bond in singly hydrated halogenated coumarins. The competition between hydrogen and halogen bonding interactions in 3-halogenated 4-hydroxyl coumarin [coumarin derivative; halogen, X = F (A), Cl (B), Br (C), I (D)] with water molecule in the corresponding binding regions C3–X and C2=O4 is studied. This study was conducted using PBE0 D3BJ with augmented correlation consistent basis set in order to include the diffuse functions. Improved findings for non-bonded distances and much more distinct intramolecular effects were obtained using BJ-damping. In the singly-hydrated systems, the water molecule forms a hydrogen bond with C2=O4 in all the halogenated molecules, whereas halogen bonding between the water oxygen and C2–X exists only in the case of X = Br (C) and I (D). The absence of a halogen-bonded structure in singly-hydrated chlorine and fluorine substituted coumarin derivative is therefore attributed to the competing hydrogen-bonding interaction with C2=O4. RDG scatter plot as well QTAIM analysis implied that halogen bond exists between water molecule and the coumarin derivative. Further, the most modern local energy decomposition (LED) analysis of intermolecular interaction was also studied using DLPNO-CCSD(T). Finally, ab initio molecular dynamics was also performed. [ABSTRACT FROM AUTHOR]

In this study, we focused on the synthesis and molecular docking investigations of hybrid derivatives containing tetrahydrobenzo[b]thiophene. Our aim was to evaluate their potential antibacterial properties. Through our analysis, we aimed to gain insights into the molecular mechanisms that underlie their effectiveness against bacterial infections. A series of tetrahydrobenzo[b]thiophene derivatives were produced through the reaction of various carbonyl groups, including 2-thiophenaldehyde, 2-naphthaldehyde, and 3-acetylindole with (2-amino-N-(4-methoxyphenyl)-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide). Additionally, the condensing starting material with benzaldehyde, a new derivative linked to substituted pyrimidines was synthesized and named tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4,5-dione. Furthermore, it underwent a reaction with monochloroacetyl chloride to produce another derivative. The production and synthesis processes all involved the use of tetrahydrobenzo[b]thiophene compounds. [ABSTRACT FROM AUTHOR]

The B3LYP/cc-pVDZ basis set was used to optimize the best results of Pacritinib whose systematic name is (E)- 44-(2-(pyrrolidin-1-yl) ethoxy) −6,11- dioxa-3- aza-2(4,2)- pyrimidine −1,4 (1,3)-dibenzenacyclododecaphan-8-ene (MJ). The NBO analysis confirm the highest stabilization energy 55.36 kcal/mol, from bonding LP (1)–N13 to anti-bonding π*(N10 - C11). The ELF, LOL, ALIE, and RDG, analysis was done by using Multiwfn software, and confirms the localization and delocalization electrons. The thermodynamical properties and electron density were calculated with help of Gaussian-16w software. Analyses of NLO parameters, MEP, UV-vis, and HOMO-LUMO were performed using five different solvents (chloroform, water, acetonitrile, ethanol and DMSO). Docking study was done, against 5C5S protein and we identify the protein-ligand interaction, the best binding score is −6.64 kcal/mol. [ABSTRACT FROM AUTHOR]

Despite the progress in comprehending molecular design principles and biochemical processes associated with thrombin inhibition, there is a crucial need to optimize efforts and curtail the recurrence of synthesis-testing cycles. Nitrogen and N-heterocycles are key features of many anti-thrombin drugs. Hence, a pragmatic analysis of nitrogen and N-heterocycles in thrombin inhibitors is important throughout the drug discovery pipeline. In the present work, the authors present an analysis with a specific focus on understanding the occurrence and distribution of nitrogen and selected N-heterocycles in the realm of thrombin inhibitors. A dataset comprising 4359 thrombin inhibitors is used to scrutinize various categories of nitrogen atoms such as ring, non-ring, aromatic, and non-aromatic. In addition, selected aromatic and aliphatic N-heterocycles have been analyzed. The analysis indicates that ~62% of thrombin inhibitors possess five or fewer nitrogen atoms. Substituted N-heterocycles have a high occurrence, like pyrrolidine (23.24%), pyridine (20.56%), piperidine (16.10%), thiazole (9.61%), imidazole (7.36%), etc. in thrombin inhibitors. The majority of active thrombin inhibitors contain nitrogen atoms close to 5 and a combination of N-heterocycles like pyrrolidine, pyridine, piperidine, etc. This analysis provides crucial insights to optimize the transformation of lead compounds into potential anti-thrombin inhibitors. [ABSTRACT FROM AUTHOR]

Effecient green tools of β-(3,4-dichlorophenyl-acrylic acid, thioglycolic acid and β-(2-oxopyrrolidin-1-yl) ethanol under ultrasonic and microwave-assisted irradiation (MW-US) as found to be a simple approach for preparing interesting Spiro derivatives. A novel class Spiro-pyrrolidine-2,3'-thieno[2,3-d]pyridazine derivatives (2–6) were efficiently synthesized via one-pot multicomponent reactions. Ethoxy acetyl Spiro pyrrolidine-2,3'-thieno[2,3-d]pyridazin-hydrazide (5) assessed as ecofriendly microbicidal and insecticidal activities to establish a structure-activity relationship. Elemental analysis and spectroscopic data were used to describe the structures of all synthesized products. The Spiro-heterocyclic compounds are exclusive non-planar structures and branded for binding to biomolecules. The microbicidal and insecticidal activities of the compounds were investigated on ATCC coded test microorganisms upon the applied dose and time was studied through two kinetic study. The interaction with these antibacterial and insect's third instar larvae was medicinal and economically valuable. The preliminary testing demonstrated flourishing microbicidal capability to prevent the growth of threatening pathogenic bacteria as well as blossoming insecticidal efficacy. Moreover, Molecular docking and density functional theory simulations can be used to validate the experimental results. Also, we utilized the docking approach with secondary bacterial infection indicated that Ethoxy acetyl Spiro hydrazide (5) and Spiro arylidene hybrid (6) have exerted the strongest docking binding value against the active sites of 6LU7. [ABSTRACT FROM AUTHOR]

Although various approaches exist for treating cancer, chemotherapy continues to hold a prominent role in the management of this disease. Besides, microtubules serve as a vital component of the cellular skeleton, playing a pivotal role in the process of cell division making it an attractive target for cancer treatment. Hence, the scope of this work was adapted to design and synthesize new anti‐tubulin tetrabromophthalimide hybrids (3‐17) with colchicine binding site (CBS) inhibitory potential. The conducted in vitro studies showed that compound 16 displayed the lowest IC50 values (11.46 µM) at the FaDu cancer cell lines, whereas compound 17 exhibited the lowest IC50 value (13.62 µM) at the PC3 cancer cell line. However, compound 7b exhibited the lowest IC50 value (11.45 µM) at the MDA‐MB‐468 cancer cell line. Moreover, compound 17 was observed to be the superior antitumor candidate against all three tested cancer cell lines (MDA‐MB‐468, PC3, and FaDu) with IC50 values of 17.22, 13.15, and 13.62 µM, respectively. In addition, compound 17 showed a well‐established upregulation of apoptotic markers (Caspases 3, 7, 8, and 9, Bax, and P53). Moreover, compound 17 induced downregulation of the antiapoptotic markers (MMP2, MMP9, and BCL‐2). Furthermore, the colchicine binding site inhibition assay showed that compounds 15a and 17 exhibited particularly significant inhibitory potentials, with IC50 values of 23.07 and 4.25 µM, respectively, compared to colchicine, which had an IC50 value of 3.89 µM. Additionally, cell cycle analysis was conducted, showing that compound 17 could prompt cell cycle arrest at both the G0‐G1 and G2‐M phases. On the other hand, a molecular docking approach was applied to investigate the binding interactions of the examined candidates compared to colchicine towards CBS of the β‐tubulin subunit. Thus, the synthesized tetrabromophthalimide hybrids can be regarded as outstanding anticancer candidates with significant apoptotic activity. [ABSTRACT FROM AUTHOR]

High-performance titanium dioxide (TiO2) thin films were successfully produced and deposited on a circular glass substrate using the spin coating process at room temperature. The deposited films were subjected to annealing at temperatures of 300, 800, 900, 1000 and 1100 °C to investigate the temperature-dependent changes in their physical characteristics. Analysis techniques, including scanning electron microscopy (SEM), atomic force microscopy (AFM), Raman spectroscopy, Fourier transform infrared spectroscopy, and ultraviolet–visible transmittance spectroscopy, were employed to examine the properties of the TiO2 films. The SEM images revealed that the films were homogeneous, consistent and dense, exhibiting minimal presence of pores and microcracks. AFM scans demonstrated that the film surfaces were uniformly smooth, with a roughness ranging from approximately 0.52 to 2.85 µm. Additionally, SEM analysis indicated that the films were crack-free, homogeneous and composed of fine grains with an average size of approximately 50 nm. The UV spectral results unveiled important optical changes in the films. The Urbach energy exhibited an increase from 1.47 to 2.5 eV, while the direct band gap energy showed a decrease from 3.90 to 3.03 eV. Regarding the hydrophilicity of the TiO2 films, the sample annealed at 300 °C displayed the lowest water contact angle among all tested samples. However, the hydrophilicity of anatase TiO2 thin films increased when subjected to annealing temperatures between 400 and 800 °C. Conversely, the presence of the rutile phase resulted in a reduction in hydrophilicity when the annealing temperature ranged from 900 to 1100 °C. It was found that by using annealing, thin spin coated TiO2 films will be more uniform and transparent. These results demonstrate the suitability of the obtained TiO2 films for use in solar cells, further supporting their potential for practical applications. [ABSTRACT FROM AUTHOR]

The 2-cyano-3-(indol-3-yl)acryloyl chloride, a building block synthon prepared in good yield, was utilized for the synthesis of various indolylacrylamide and indole-based heterocycles. Thus, the aforementioned acid chloride was allowed to react with various oxygen, sulfur, and nitrogen nucleophiles, in addition to mono- and bidentate nucleophiles. The pyrazolidine derivatives were produced on interactions with phenylhydrazine and 2-cyanoethanohydrazide. The antioxidant activity of the synthesized compounds was assessed using the phosphomolybdenum technique and ascorbic acid as a standard. The findings displayed that indolyl-based azine, pyrazolidine, cyanoacetamide, and benzodiazepine derivatives were the most active antioxidants. [ABSTRACT FROM AUTHOR]

Drug–drug interactions occur when two or more molecules interact, potentially altering their effectiveness and cause adverse effect to human health. Caffeine is known to interact with many other drug molecules. Our study was designed to shed insights on characteristics of non-covalent interaction (NCI) and quantify the prevalence of drug–drug interaction between the caffeine and ascorbic acid molecule in gas phase and solvent phase (water) using Density Functional Theory. It was found that caffeine and ascorbic acid molecules interact with one another through hydrogen bonds (HBs) in various ways which can be deduced from the optimized structures and the resulting calculation of binding energy was observed −14.65 kcal/mol and −11.62 kcal/mol in gas and water phase respectively. The Natural Bond Orbital analysis confirmed that the highest stabilization energy interactions are the same interactions which are found to be the possible hydrogen bonds. The RDG, AIM, LED analyses confirmed the delocalisation and localisation of the electron in the complex. The understanding of the non-covalent interaction between caffeine and ascorbic acid may help to further study the drug effectiveness and drug delivery systems. [ABSTRACT FROM AUTHOR]