Molecular Modeling Investigations Research Articles

DFT molecular modeling investigation and optical properties characterization of CR-39 films

Abstract In this study, the structural and optical characteristics of CR-39 films were investigated both theoretically and experimentally. A number of parameters for the CR-39 structure were theoretically computed by the density functional theory (DFT) method at B3LYP/6–311 G (p, d) level of theory. FTIR and UV/Vis spectroscopy were used to determine the structure compositions and the optical parameters of the CR39 film, respectively. The computed and experimental findings show good concordance. It was found that the CR-39 compound’s total energy, dipole moment, and energy difference between the LUMO and HOMO were, respectively, −994.575 a.u., 2.772 Debye, and 7.045 eV. The MEP showed a progressive change in color, with blue signifying a low electron density and red denoting a high electron density linked to nucleophilic reactivity and electrophilic reactivity. Further, the positive charges on all hydrogen atoms, which range from 0.16506 to 0.22032 a.u., imply that they are acceptors. The positive H34 is strongly produced when electrons from the negatively charged C17 are taken up. Because they are donor atoms, part of the carbon atoms in the structure is negative, while the other atoms are positive. The highest electronegative atoms H23 and H24 were substituted, resulting in the extremely negative carbon atom C7 (−0.32436). According to the experimentally determined absorption coefficient and energy gap values, CR-39 films may find application in optoelectronic devices.

Luminescent Pentacene‐Loaded Carbon Nanodots with Red‐Light Triggered Photothermal and Photosensitizing Properties

The development of multifunctional nanosystems for photo‐induced hyperthermia and photodynamic effect is a challenging topic in the research of advanced materials for application in biomedical field. Here, we report red‐luminescent carbon‐nanodots (CDs‐PNM/PTC) derived from entrapment of pentacene (PTC) in nanodots prepared from poly(N‐isopropylacrylamide) polymer (CDs‐PNM) by an easy and reagent‐free method. The CD‐PNM/PTC nanosystem was characterized by different techniques (UV‐Vis spectrophotometry, fluorescence, NMR, AFM). Molecular modelling investigations were performed to unveil stability, structures and energy of the CD‐PNM/PTC supramolecular adducts at 298 K and 315 K. The nanosized CDs–PNM/PTC exhibited excellent water‐dispersibility, good photothermal conversion efficiency and photosensitizing effect at 680 nm. No significant toxicity and eukaryotic cell uptake are features that open to potential applications in photothermal‐photodynamic treatments.

Towards identification of therapeutics against multi-infections and cancers causing Propionibacterium acnes: Molecular modeling and dynamics simulation investigation

Skin conditions related to Propionibacterium acnes are a noteworthy health concern affecting millions globally. However, recent studies suggest that P. acne is also linked to other serious health conditions such as various kinds of cancer such as prostate cancer, breast cancer, and gastric cancer. The P. acnes sialidase enzyme plays an important role in the pathogenesis of this infection by supporting bacterial invasion and adhesion to the host tissues. In the current study, Medicinal Fungi Secondary Metabolites and Therapeutics (MeFSAT) consisting of 1830 compounds were put through comprehensive computational analysis to identify the strongest inhibitors that target the primary pathogenic enzyme that triggers the dermal infection. Upon analyzing docking studies, it is anticipated that most of these compounds are strongly attached to the specific protein vital for bacterial infection based on their binding score (threshold < −7 kcal/mol). The top 3 compounds were selected as MSID000006, MSID000010, and MSID000012 as strong inhibitors based on their binding score. Furthermore, every compound showed an excellent ADMET profile and adhered to Lipinski’s rule. Next, Density Functional Theory (DFT) analysis was carried out to analyze compounds’ optimized structures and electrostatic interactions with high accuracy. Subsequently, molecular dynamics simulations (MDS) were carried out to evaluate compound stability. The particular compounds showed better stability under a dynamic environment. Furthermore, principal component analysis (PCA) and hydrogen bond analysis was carried out to understand the complexity of vast datasets and the stability of the compounds respectively. Moreover, in salt bridge analysis, Asp-Arg were the most observed interactions, suggesting better electrostatic interaction and good stability. Secondary structure analysis was conducted for better comprehension of protein structure. MMPBSA/GBSA analysis was performed to calculate the free energies of simulation trajectories as MSID000006 favorable binding energy as compared to the MSID000010 and MSID000012. WaterSwap validated the MMPBSA findings by calculating the binding free energies of the compounds upon swapping the water molecule with the ligand. In the end, entropy energy was estimated to figure out the disorder in the process. The entropy results showed that MSID00006 has greater stability as compared to MSID000010 due to lesser disorder in the process. Our findings revealed the compounds MSID000006, MSID000010, and MSID000012 could play favorable roles in the management of P. acnes disease by showing their potential as strong inhibitors.

Novel 3,5‐Dimethylpyrazole‐Linked 1,2,4‐Triazole‐3‐thiols as Potent Antihyperglycemic Agents: Synthesis, Biological Evaluation, and In Silico Molecular Modelling Investigations

AbstractIn this work, a series of pyrazole‐linked 1,2,4‐triazole‐3‐thiol derivatives (3a–i) were prepared and identified by 13C NMR, 1H NMR, and mass spectrometry (ESI‐MS) data. The newly synthesized molecules were also evaluated in vitro for their α‐amylase and α‐glucosidase inhibitory potential. All newly synthesized compounds exhibited potent α‐glucosidase inhibition activity with IC50 in the range of 1.016 ± 0.70 to 24.40 ± 0.02 µM and good α‐amylase inhibitory with IC50 in the range of 49.91 ± 0.32 to 500 µM, as compared to acarbose. The most potent compound among this series is derivative 3e, with IC50 value of 1.016 ± 0.70 µM, which is many folds more than that of acarbose. In addition, in docking studies, both compounds exhibited good interactions at the active region of target proteins. Therefore, this study may lead via structural modifications to the discovery of new potent α‐amylase and α‐glucosidase inhibitors useful in the diabetes treatment.

Novel curcumin-based analogues as potential VEGFR2 inhibitors with promising metallic loading nanoparticles: synthesis, biological evaluation, and molecular modelling investigation.

VEGFR2 inhibition has been established as a therapeutic approach for managing cancer. A series of curcumin-based analogues were designed, synthesized, and screened for their anticancer activity against MCF-7 and HepG-2 cell lines and WISH normal cells. Compounds 4b, 4d, 4e, and 4f showed potent cytotoxicity against MCF-7 with IC50 values of 0.49, 0.14, 0.01, and 0.32 μM, respectively, compared to curcumin (IC50 = 13.8 μM) and sorafenib (IC50 = 2.13 μM). Interestingly, compound 4e, the most active compound, exhibited potent VEGFR2 inhibition with an IC50 value of 11.6 nM (96.5% inhibition) compared to sorafenib with an IC50 value of 30 nM (94.8% inhibition). Additionally, compound 4e significantly induced apoptotic cell death in MCF-7 cells by 41.1% compared to a control group (0.8%), halting cell division during the G2/M phase by 39.8% compared to the control (21.7%). Molecular docking-coupled dynamics simulations highlighted the bias of the VEGFR2 pocket towards compound 4e compared to other synthesized compounds. Predicting superior binding affinities and relevant interactions with the pocket's key residues recapitulated in vitro findings towards higher inhibition activity for compound 4e. Furthermore, compound 4e with adequate pharmacokinetic and drug-likeness profiles in terms of ADME and safety characteristics can serve as a promising clinical candidate for future lead optimization and development. Notably, 4e-Fe2O3-humic acid NPs exhibited potent cytotoxicity with IC50 values of 2.41 and 13.4 ng mL-1 against MCF-7 and HepG-2 cell lines, respectively. Hence, compound 4e and its Fe2O3-humic acid-NPs could be further developed as promising anti-breast cancer agents.

Synergistic Action of Vanillic Acid-Coated Titanium Oxide Nanoparticles: Targeting Biofilm Formation Receptors of Dental Pathogens and Modulating Apoptosis Genes for Enhanced Oral Anticancer Activity.

The prevalence of bacterial and fungal infections is caused byS. aureus, S. mutans, E. faecalis, and Candida albicans are often associated with dental illnesses. In the present study, a unique strategy was used to combat these diseases by fabricatingtitanium dioxide nanoparticles (TiO2 NPs) conjugated with the plant-based molecule vanillic acid (VA).Molecular modeling investigations were performed to better understand the interactions among vanillic acid and dental pathogen receptors using the Autodock program. The findings indicated that VA-TiO2 NPs exhibited strong free radical scavenging activity. Additionally, they showed excellent antibacterial action towards dental pathogens, with a minimum inhibition level of 60 μg/mL. Furthermore, at doses of 15 μg/mL, 30 μg/mL, 60 μg/mL, and 120 μg/mL, VA-TiO2 NPs demonstrated concentration-dependent apoptotic impacts on human oral carcinoma cells. Apoptotic gene over-expression was identified by the molecular perspectives that revealed the anticancer mechanism of VA-TiO2 NPs on KB cells. This study highlights the promising suitability of VA-TiO2 NPs for dental applications due to their robust antioxidant, anticancer, and antimicrobial characteristics. These nanoparticles present an evident prospect for addressing oral pathogen challenges and improving overall oral health.

Force Fields, Quantum-Mechanical- and Molecular-Dynamics-Based Descriptors of Radiometal-Chelator Complexes.

Radiopharmaceuticals are currently a key tool in cancer diagnosis and therapy. Metal-based radiopharmaceuticals are characterized by a radiometal-chelator moiety linked to a bio-vector that binds the biological target (e.g., a protein overexpressed in a particular tumor). The right match between radiometal and chelator influences the stability of the complex and the drug's efficacy. Therefore, the coupling of the radioactive element to the correct chelator requires consideration of several features of the radiometal, such as its oxidation state, ionic radius, and coordination geometry. In this work, we systematically investigated about 120 radiometal-chelator complexes taken from the Cambridge Structural Database. We considered 25 radiometals and about 30 chelators, featuring both cyclic and acyclic geometries. We used quantum mechanics methods at the density functional theoretical level to generate the general AMBER force field parameters and to perform 1 µs-long all-atom molecular dynamics simulations in explicit water solution. From these calculations, we extracted several key molecular descriptors accounting for both electronic- and dynamical-based properties. The whole workflow was carefully validated, and selected test-cases were investigated in detail. Molecular descriptors and force field parameters for the complexes considered in this study are made freely available, thus enabling their use in predictive models, molecular modelling, and molecular dynamics investigations of the interaction of compounds with macromolecular targets. Our work provides new insights in understanding the properties of radiometal-chelator complexes, with a direct impact for rational drug design of this important class of drugs.

Exploring Novel Coumarin-Tethered Bis-Triazoles: Apoptosis Induction in Human Pancreatic Cancer Cells, Antimicrobial Effects, and Molecular modelling Investigations.

In the present study, we identified that two representative compounds (7c and 9f) of our newly synthesized coumarin-tagged bis-triazoles induced apoptosis in human pancreatic cells (PANC-1) by caspase 3/7mediated pathway. Both 7c and 9f (IC50 = 7.15 ± 1.19 and 6.09 ± 0.79 µM, respectively) were found to be ~100 times superior against PANC-1 as compared to the standard drug Gemcitabine (IC50 = >500 µM), without showing any toxicity to the normal pancreatic epithelial cells (H6C7). Molecular docking studies further endorsed them as potential pancreatic cancer therapeutics due to their strong hydrogen bonding interactions with the epidermal growth factor receptor (EGFR) enzyme, which is overexpressed in cancerous cells including pancreatic cancer. Additionally, these compounds also showed moderate inhibitory activity against a panel of microbial strains. Overall, our findings reveal that the coumarin hybrids 7c and 9f are viable chemotypes to be adopted as templates for the development of new anticancer drugs, particularly against pancreatic cancer.

Novel Insights into the Antimicrobial and Antibiofilm Activity of Pyrroloquinoline Quinone (PQQ); In Vitro, In Silico, and Shotgun Proteomic Studies.

Microbial infections pose a significant global health threat, affecting millions of individuals and leading to substantial mortality rates. The increasing resistance of microorganisms to conventional treatments requires the development of novel antimicrobial agents. Pyrroloquinoline quinone (PQQ), a natural medicinal drug involved in various cellular processes, holds promise as a potential antimicrobial agent. In the present study, our aim was, for the first time, to explore the antimicrobial activity of PQQ against 29 pathogenic microbes, including 13 fungal strains, 8 Gram-positive bacteria, and 8 Gram-negative bacteria. Our findings revealed potent antifungal properties of PQQ, particularly against Syncephalastrum racemosum, Talaromyces marneffei, Candida lipolytica, and Trichophyton rubrum. The MIC values varied between fungal strains, and T. marneffei exhibited a lower MIC, indicating a greater susceptibility to PQQ. In addition, PQQ exhibited notable antibacterial activity against Gram-positive and -negative bacteria, with a prominent inhibition observed against Staphylococcus epidermidis, Proteus vulgaris, and MRSA strains. Remarkably, PQQ demonstrated considerable biofilm inhibition against the MRSA, S. epidermidis, and P. vulgaris strains. Transmission electron microscopy (TEM) studies revealed that PQQ caused structural damage and disrupted cell metabolism in bacterial cells, leading to aberrant morphology, compromised cell membrane integrity, and leakage of cytoplasmic contents. These findings were further affirmed by shotgun proteomic analysis, which revealed that PQQ targets several important cellular processes in bacteria, including membrane proteins, ATP metabolic processes, DNA repair processes, metal-binding proteins, and stress response. Finally, detailed molecular modeling investigations indicated that PQQ exhibits a substantial binding affinity score for key microbial targets, including the mannoprotein Mp1P, the transcriptional regulator TcaR, and the endonuclease PvuRTs1I. Taken together, our study underscores the effectiveness of PQQ as a broad-spectrum antimicrobial agent capable of combating pathogenic fungi and bacteria, while also inhibiting biofilm formation and targeting several critical biological processes, making it a promising therapeutic option for biofilm-related infections.

Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein–ligand interactions at COX-2 active sites indicative of therapeutic potential.

Remediation of cationic dye from aqueous solution through adsorption utilizing natural Haloxylon salicornicum: An integrated experimental, physical statistics and molecular modeling investigation

Wastewater emanating from declining industrial processes often presents a vexing challenge due to its intricate composition replete with hazardous chemicals. The quest for environmentally sustainable methods to remediate such wastewater has led to the exploration of biomaterials as adsorbents and co-substrates within diverse treatment systems. In this study, we harnessed the abundant and cost-effective adsorbent, Haloxylon salicornicum (HS), as a potent agent for the removal of the pernicious triphenylmethane dye, crystal violet, from aqueous mediums. The adsorbent was characterised using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and scanning electron microscopy (SEM), while Brunauer-Emmett-Teller (BET) analysis yielded a specific surface area (SBET) of 85.23 m2 g−1, highlighting its advantageous mesoporous structure for adsorption. Comprehensive investigations were conducted across various operational parameters, encompassing initial dye concentration, contact time, HS adsorbent dosage, initial pH, and temperature, with a keen focus on their influence on dye removal efficiency. The results unveiled several key trends, demonstrating that elevated initial dye concentration, prolonged contact time, and higher initial pH levels substantially enhanced the efficiency of dye removal, while ionic strength and temperature exhibited comparatively modest impacts. The kinetics of dye adsorption were rigorously examined, revealing a closer adherence to the pseudo-second-order model in comparison to the PFO model, thereby offering deeper insights into the adsorption dynamics. To further unravel the intricate mechanism underpinning the adsorption of CV on HS, we employed a single-layer model linked to SLMRG. In conjunction, DFT calculations, encompassing COSMO-RS, NCI, Molecular Dynamics (MD) simulations and QTAIM calculations, were applied to probe the interactions between adsorbed CV and the adsorbent-molecules, providing compelling evidence of robust binding interactions. These theoretical insights were subsequently aligned with empirical observations, affirming a significant relation between the theoretical and experimental data. This multifaceted study not only advances our understanding of CV removal using HS but also underscores the robustness of this adsorbent within the context of wastewater treatment. Furthermore, it demonstrates the synergy of empirical investigations and theoretical modeling in unraveling the intricacies of adsorption processes.

Discovery of new quinoline derivatives bearing 1-aryl-1,2,3-triazole motif as influenza H1N1 virus neuraminidase inhibitors

Sporadically and periodically, influenza outbreaks threaten global health and the economy. Antigen drift-induced influenza virus mutations hamper antiviral drug development. Thus, a novel antiviral agent is urgently needed to address medication inefficacy issues. Herein, sixteen new quinoline-triazole hybrids 6a-h and 9a-h were prepared and evaluated in vitro against the H1N1 virus. In particular, 6d, 6e, and 9b showed promising H1N1 antiviral activity with selective index (SI) CC50/IC50 values of 15.8, 37, and 29.15. After that, the inhibition rates for various mechanisms of action (virus replication, adsorption, and virucidal activity) were investigated for the most efficient candidates 6d, 6e, and 9b. Additionally, their ability to inhibit neuraminidase was evaluated. With an IC50 value of 0.30 µM, hybrid 6d demonstrated effective and comparable inhibitory activity to Oseltamivir. Ultimately, molecular modeling investigations, encompassing molecular docking and molecular dynamic simulations, were conducted to provide a scientific basis for the observed antiviral results.

Investigation on Anti‐plasmodial Agents Against wild‐type PfDHFR Through In Silico Computational Tools

AbstractMalaria is the most severe and common parasitic infection, with P. falciparum responsible for the majority of cases and deaths each year. As anti‐malarial drug resistance continues to increase, novel compounds with anti‐ P. falciparum activity must be identified. In search of a new molecule to cure the resistant malarial parasite, a total of 1,70,269 ligands from the Asinex BioDesign library 2021.2 were virtually screened using AutoDock Vina against wild‐type P. falciparum dihydrofolate reductase‐thymidylate synthase (PfDHFR‐TS). The computational molecular modeling investigations indicated the discovery of seventeen new compounds (2‐18) with higher binding energy compared to the PfDHFR‐TS inhibitor, pyrimethamine (1). Furthermore, the study employing drug‐likeness criteria and their ADMET profile suggested that these hits were the most promising drug candidates due to higher absorption and druggability. Furthermore, GROMACS 2023.4 was used to perform the molecular dynamics simulations on the foremost compound (2) having sufficient stability, leading to a key step towards the search of novel PfDHFR‐TS inhibitors against malaria.

HSADab: A comprehensive database for human serum albumin

Human Serum Albumin (HSA), the most abundant protein in human body fluids, plays a crucial role in the transportation, absorption, metabolism, distribution, and excretion of drugs, significantly influencing their therapeutic efficacy. Despite the importance of HSA as a drug target, the available data on its interactions with external agents, such as drug-like molecules and antibodies, are limited, posing challenges for molecular modeling investigations and the development of empirical scoring functions or machine learning predictors for this target. Furthermore, the reported entries in existing databases often contain major inconsistencies due to varied experiments and conditions, raising concerns about data quality. To address these issues, a pioneering database, HSADab, was established through an extensive review of >30,000 scientific publications published between 1987 and 2023. The database encompasses over 5000 affinity data points at multiple temperatures and >130 crystal structures, including both ligand-bound and apo forms. The current HSADab resource (www.hsadab.cn) serves as a reliable foundation for validating molecular simulation protocols, such as traditional virtual screening workflows using docking, end-point, and al-chemical free energy techniques. Additionally, it provides a valuable data source for the implementation of machine learning predictors, including plasma protein binding models and plasma protein-based drug design models.

Evaluation of Compound Hordenine (Hordeum vulgare): In-vitro, Gene Expression, and Molecular Modeling Investigations

This study aims to investigate the effects of a compound named hordenine on cells. We examined its impact on gene expression, inflammation, and cell proliferation. To do this, we took unique steps. We started by examining how effectively cells were developing. To gauge how quickly they were multiplying, we conducted a test. We also counted the number of cells by using a machine. Then, we performed a specialized test to evaluate the inflammatory marker IL-6. We also used a technique called RT-PCR to examine particular genes in the cells. Additionally, we used a computer simulation to examine how hordenine interacts with the specific protein MMP1. The findings demonstrated that even a modest amount of hordenine significantly aided cell growth. It also diminished. The stuff called hordenine helped lower inflammation more than another thing called rotenone. Cells treated with hordenine made less of something called IL-6. When we looked at certain genes in skin cells that were treated with hordenine, they seemed more active. Hordenine also binds well to a protein with an energy of -4.5 Kcal/mol. Because of all this, we think hordenine is good for cells. It helps cells grow and can triplicate when they're not working well.

Synthesis, Characterization, Antimicrobial and In Silico Studies of Isatin Schiff Base Linked 1,2,3-Triazole Hybrids.

A new series of isatin-Schiff base linked 1,2,3-triazole hybrids has been synthesized using CuAAC approach from (E)-3-(phenylimino)-1-(prop-2-yn-1-yl)indolin-2-one derivatives in high yield (73-91 %). These synthesized derivatives were characterized using FT-IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectral techniques. The in vitro antimicrobial activity assay demonstrated that most of the tested hybrids exhibited promising activity. Compound 5 j displayed significant antibacterial efficacy against P. aeruginosa and B. subtilis with MIC value of 0.0062 μmol/mL. While, 5 j also showed better antifungal potency against A. niger with MIC value of 0.0123 μmol/mL. The docking studies of most promising compounds were performed with the well-known antibacterial and antifungal targets i. e. 1KZ1, 5TZ1. Molecular modelling investigations demonstrated that hybrids 5 h and 5 l exhibited good interactions with 1KZN and 5TZ1, with binding energies of -9.6 and -11.0 kcal/mol, respectively. Further, molecular dynamics studies of the compounds showing promising binding interactions were also carried out to study the stability of complexes of these hybrids with both the targets.

Structural and functional impacts of neonicotinoids analogues on Apis mellifera's chemosensory protein: Insights from spectroscopic and molecular modeling investigations

In the intricate web of ecological relationships, pollinators such as the Italian honeybee (Apis mellifera) play a crucial role in maintaining biodiversity and agricultural productivity. This study focuses on the interactions between three neonicotinoid compounds and the honeybee's chemosensory protein 3 (CSP3), a key player in their olfactory system. Employing advanced spectroscopic techniques and molecular modeling, we explore the binding dynamics and conformational changes in CSP3 upon exposure to these pesticides. The research reveals that all three neonicotinoids considerably quench CSP3's fluorescence through a dynamic and static mixing mechanism, indicating a strong binding affinity, predominantly driven by hydrophobic interactions. UV–visible absorption, synchronous fluorescence, and 3D fluorescence spectra support slight changes in the microenvironment around the aromatic amino acids of CSP3. Circular dichroism spectra indicate a reduction in CSP3's α-helix content, suggesting structural alterations. Molecular docking and dynamics simulations further elucidate the binding modes and stability of these interactions, highlighting the role of specific amino acids in CSP3's binding cavity. Findings provide critical insights into molecular mechanisms by which neonicotinoids may impair honeybee chemosensory function, offering implications for designing safer pesticides and understanding the broader ecological impact of these chemicals on pollinator health.

Evaluation of 3,4-diethoxy substituted thioureas and their thiazole derivatives as potent anti-Alzheimer's agents: Synthesis, DFT, biological activity and molecular modeling investigations

The current research project aims to develop 3, 4-diethoxy substituted thioureas (15–20) and thiazoles (22–23, 25–26) analogs as potential anti-Alzheimer's agents. A total of ten derivatives were synthesized and were further characterized with TLC, FTIR, and NMR techniques. In addition, density functional theory (DFT) calculations and molecular modeling were performed to evaluate the electronic properties and anti-Alzheimer's disease potential of the compounds within the active pockets of the targeted enzymes, respectively. During in-vitro testing, it was determined that all analogs exhibited some degree of inhibitory potential, and analogs (15), (16), (19), and (26) were found to have excellent potency in inhibiting Alzheimer's disease-related enzymes i.e., monoamine oxidase-A, monoamine oxidase-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Analog (15) demonstrated an IC50 of 1.33 ± 0.04 µM for MAO-A; (16) showed an IC50 of 1.67 ± 0.06 µM for MAO-B, (19) represented an IC50 of 0.31 ± 0.02 µM for AChE, and (26) showed an IC50 of 0.51 ± 0.01 µM for BChE. These compounds have shown a comparable potential with the reference compounds i.e., Clorgyline (for MAO-A), Deprenyl (for MAO-B) and donepezil in case of AChE and BChE, respectively. The study also established a structure-activity relationship and determined that the potency of the analogs depends on the nature, position, number, and electron-donating/-withdrawing effects of the phenyl ring substituents. The identified compounds also exhibited strong binding interactions during molecular docking investigations. Moreover, the most potent complexes of respective targets were found stable during molecular dynamics simulation studies. The findings of the current study revealed that new thioureas and thiazoles analogs exhibited a reactive electronic property, which is essential for anti-cholinesterase activity.

The Suppressive Effect of Novel Hydrazones‐Tethered Imidazoles in HCT‐116 and HT‐29 Colorectal Cancer Cells: Synthesis, Biological Activity and Molecular Modeling Studies

AbstractA series of hybrid compounds containing both the imidazole ring and the hydrazone moiety have been synthesized. Synthesized compounds were characterized by various spectral techniques, including FT‐IR, 1H‐NMR, 13C‐NMR, and HRMS. The compounds were evaluated for their antiproliferative activities on colorectal cancer cells HCT‐116 and HT‐29 in a time‐dependent manner. Among them, some compounds exhibited remarkable anti‐cancer activity with a less cytotoxic effect on non‐cancerous cell lines, especially HRK‐2 with IC50 value of 1.35±0.18 μM in HCT‐116 cells and HRK‐5 with IC50 value of 2.67±0.61 μM in HT‐29 cells. Investigations of colon cancer cell death were performed, and the most active compounds were found to trigger cell death via nuclear localization and induce S phase arrest of the colon cancer cell. Moreover, molecular modeling studies for the synthesized compounds was performed to predict their binding affinities toward the active site of BCL‐2. The findings of the molecular modeling investigations were highly consistent with those of the cytotoxicity results.

New Ciprofloxacin–Pyrazolopyrimidine Hybrids as Topoisomerase IV and Gyrase Inhibitors against MRSA AUMC 261

AbstractEleven novel ciprofloxacin–pyrazolopyrimidine hybrids 4 a–k were synthesized and structurally elucidated using NMR, elemental analysis, and mass spectrometry. The antibacterial screening showed that the newly synthesized compounds revealed a remarkable shifting of antibacterial activity from Gram–negative toward Gram–positive bacteria. Most of the synthesized hybrids displayed good to excellent activity against Staph aureus ATCC 6538 especially hybrids 4 a and 4 g which revealed MICs of 12.5 and 6.25 μg/ml, respectively, compared to the ciprofloxacin MIC, 25 μg/ml as a reference drug. In addition, both hybrids displayed potent activity toward MRSA AUMC 261 with MICs, 71 and 36 μg/ml respectively, compared to the ciprofloxacin MIC, 190 μg/ml as a reference drug. Additionally, hybrids, 4 a and 4 g exhibited effective inhibitory activity against DNA gyrase and topoisomerase IV enzymes with IC50 values, 0.404, 1.626 μM and 3.647 and 3.791 μM, respectively, compared to ciprofloxacin IC50 values 0.661 and 8.159. A molecular modeling investigation showed a high fitting affinity of hybrids 4 a and 4 g toward gyrase and topoisomerase IV active sites compared to ciprofloxacin.