Interaction Of Compounds Research Articles

Towards targeted cancer therapy: Synthesis, characterization, and biological activity of a new Cu(II)-ibuprofen-2,2'-dipyridylamine metal complex.

This work reports the synthesis of a copper metal complex with the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and 2,2'-dipyridylamine employing microwave-assisted synthesis (MWAS). To the best of authors knowledge, this is the first study reporting a NSAID-based complex achieved through MWAS. The coordination compound was characterised by elemental analysis, Fourier transform infrared spectroscopy, thermogravimetry, and ultraviolet-visible spectrophotometry. Additionally, the crystal structure of the copper metal complex was elucidated using single-crystal X-ray diffraction with synchrotron radiation. The compound's interaction with the biomolecules bovine serum albumin (BSA) and calf-thymus DNA (CT-DNA), was assessed through UV-Vis, circular dichroism, and fluorescence spectroscopy. Our findings demonstrate that the metal complex effectively binds to BSA, causing a reduction in its intrinsic fluorescence and α-helical content, and shows a capacity for intercalation between CT-DNA base pairs. Finally, the copper compound exhibited promising in vitro antitumoral activities against human breast cancer cell lines (MCF-7 and MDA-MB-231), as evaluated by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay (although a similar cytotoxic effect against a non-tumoral epithelial cancer cell line, MCF-12A, was found), and increased oxidative stress levels as assessed by the TBARS (thiobarbituric acid reactive substances) assay and by evaluating glutathione levels. The results suggest that the metal complex promotes lipid peroxidation by increasing oxidative stress levels, leading to a reduction in viability of the two breast cancer cell lines.

Isoindolinedione-Benzamide Pyridinium Derivatives for Targeting Alzheimer's Disease.

An Isoindolinedione-benzamide pyridinium derivatives were designed through a structure-based strategy and synthesized as novel multifunctional anti-Alzheimer agents. The inhibitory activities of all 17 derivatives against acetylcholinesterase and butyrylcholinesterase were evaluated. Results exhibited that compound 7j displayed promising AChE inhibitory activity with an IC50 value of 0.26 ± 0.07 μM, and compound 7c exhibited an IC50 value of 0.08 ± 0.01 μM against BChE with 132-fold better inhibitory activity in comparison with positive control. Next, the enzyme kinetics studies and detailed binding mode via molecular docking were performed for the most potent compounds. Additionally, molecular dynamics simulations were accomplished to further investigate the potent compound's interaction, orientation, and conformation over the related enzymes. The neurotoxicity of the most potent derivative was executed against SH-SY5Y, and the mRNA levels of GSK-3α and GSK-3β after treatment with 7c on SH-SY5Y were evaluated. Results exhibited the mRNA levels of GSK-3β were decreased compared to the control group. All these results indicate that 7c is a good starting point for developing a multifunctional anti-Alzheimer compound.

Experimental, quantum chemical spectroscopic investigation, topological, molecular docking/dynamics and biological assessment studies of 2,6-Dihydroxy-4-methyl quinoline

The present work is a comprehensive investigation of the spectral, electronic structure, bonding, and reactivity of the 2,6-dihydroxy-4-methylquinoline (26DH4MQ) molecule through a wide range of experimental and quantum chemical spectroscopic calculations techniques, along with its applications as nonlinear optical materials and biological assessments. The study utilized density functional theory (DFT) and time-dependent density functional theory (TD-DFT) with the B3LYP method and the 6-311G++(d,p) basis set to analyze the structural and molecular properties of 26DH4MQ. The findings from UV–Vis, FT-IR, and FT-NMR spectroscopy show a strong agreement between the experimentally obtained vibrational frequencies and chemical shifts and those predicted by computational methods. Local reactivity descriptors, such as the dual descriptor, Fukui functions, and the molecular electrostatic potential (MEP) map, were used to identify the reactive regions of the molecule. Additionally, natural bond orbital (NBO) analysis provided insights into the charge transfer characteristics of 26DH4MQ, which helps to stabilize the molecular system. The study also revealed notable nonlinear optical (NLO) properties, with polarizability (18.52 × 10–24e.s.u.) and first-order hyperpolarizability (2.26 × 10–30e.s.u.) values that surpass those of standard organic compounds, suggesting significant potential for optoelectronic applications. The biological evaluation of 26DH4MQ assessed its drug-likeness, toxicity, enzyme inhibition, and ADME (Absorption, Distribution, Metabolism, and Excretion) parameters, highlighting its pharmaceutical potential. Furthermore, molecular docking and dynamics studies illustrated the compound's interaction with proteins, indicating its potential role as an insulin inhibitor.

Molecular drug design, theoretical, experimental approaches and new framework of novel oxazol dihydroquinoxaline (ODQ): Efficient synthesis, crystallographic, computational investigation, DFT calculation, ADME analysis and antiangiogenic molecular docking

Drug design, also known as rational drug design, is a methodical procedure that seeks to discover and develop novel chemicals with therapeutic potential. The process entails the identification and modification of molecular structures that can efficiently interact with biological targets in order to achieve a desired therapeutic effect. The title compound, 1-([3-(4-chlorophenyl)-4,5-dihydro-1,2-oxazol-5-yl]methyl)-3-phenyl-1,2-dihydroquinoxalin-2-one ODQ (c), was synthesized with good yield by adding the solution of 1-allyl-3-phenylquinoxalin-2(1H)-one and 4-chlorobenzaldehyde oxime in dichloromethane. This mixture was then mixed with an excess of aqueous sodium hypochlorite solution while stirring at 0–5 °C. The resulting mixture was dried to obtain a crude product. The structure of the compound was confirmed by NMR and LC-MS spectra. The single-crystal X-ray studies conform to the 3D structure of the molecule. The molecule crystallizes in the triclinic system with the space group P-1. Hirshfeld surface analysis confirms the intermolecular interactions of the type CH…O and CH…N contacts. DFT calculations were performed to determine the electronic properties of the molecule. MEP analysis predicts the chemical reactive sites around oxygen and nitrogen atoms. This investigation has provided valuable insights that could drive significant advancements in molecular science and drug design. Additionally, the molecular docking studies elucidated the compound's interactions with various biological targets. The notable binding affinities observed for these targets highlight the potential therapeutic relevance of the synthesized compound across a range of disease conditions.

Structural and theoretical exploration of a multi-methoxy chalcone: Synthesis, quantum theory, electrostatics, molecular packing, DFT analysis, and in-silico anti-cancer evaluation

This study explores the pharmacological potential of chalcones through a multidisciplinary approach, including synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations. The synthesized compound, analyzed via single crystal X-ray diffraction, crystallized in the triclinic system (space group P-1) with C–H⋯O interactions stabilizing its structure. Hirshfeld surface analysis confirms these interactions, with H–H contacts dominating (45.1 %). Molecular electrostatics analysis reveals charge distribution, and a 3.10 eV HOMO-LUMO energy gap indicates bioactivity. Molecular docking identifies the compound (3a) showed a maximum Gscore of HTNF-α (−9.81 kcal/mol); Tubulin (−7.96 kcal/mol); COX2 (−7.88 kcal/mol), EGFR (−6.72 kcal/mol), and VEGFR1(-2.50 kcal/mol). Where compound (3c) showed maximum binding at the putative binding site with dock scores for VEGFR2 (−9.24 kcal/mol). This research not only advances molecular science but also holds promise for diverse applications, including drug design. The significance of this study lies in its comprehensive exploration of the pharmacological potential of chalcones using a multidisciplinary approach. Through the integration of synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations, we have extensively explored the structural and biochemical characteristics of these compounds. This investigation has revealed valuable insights that have the potential to lead to significant advancements in the fields of molecular science and drug design. Moreover, the molecular docking studies shed light on the compound's interaction with various biological targets. The significant binding affinities observed for these targets underscore the potential therapeutic relevance of the synthesized compound in diverse disease conditions.

Mode of the Interaction of Efflux Inhibitor Phenylalanyl-arginyl-β-naphtylamide with Bacterial Cells.

An increased efflux activity is one of the major reasons for bacterial antibiotic resistance. The usage of efflux pump inhibitors could be a promising approach to restoring the activity of inefficient antibiotics. The interaction of the RND family efflux pump inhibitor phenylalanyl-arginyl-β-naphthylamide (PAβN) with Salmonella enterica ser. Typhimurium cells was assayed using traditional microbiological techniques and a novel PAβN-selective electrode. Monitoring the PAβN concentration in the medium using the electrode enabled the real-time measurements of this compound's interaction with bacterial cells. We showed that S. Typhimurium cells accumulate a high amount of PAβN because of its high affinity to lipopolysaccharides (LPSs), the major constituent of the outer layer of the outer membrane, and does not affect the functioning of the plasma membrane. EDTA enhanced the binding of PAβN to S. Typhimurium cells and the purified E. coli LPSs, but the energization of the cells by glucose does not affect the cell-bound amount of this inhibitor. Polycationic antibiotic Polymyxin B released both the cells accumulated and the suspended LPS-bound PAβN.

Multitargeted Docking, DFT-Based Optimisation, Pharmacokinetics, and MD Simulation Reveal 6-Oxidopamine HBr as a Multitargeted Inhibitor of Cervical Cancer Proteins.

Cervical cancer originates in the cervix, the lower part of the uterus, and results from the uncontrolled growth of abnormal cervical cells, forming malignant tumours. It poses a major global health challenge, calling for innovative drug design strategies to enhance treatment outcomes. In this study, we have screened the FDA-approved drug library against four proteins, MCM10, MCM6, DNA polymerase epsilon subunit-2, and TBK1, which are essential for DNA replication, DNA repair, and cellular signalling pathways, which are dysregulated in cervical cancer cells, leading to uncontrolled growth. We have used the multisampling algorithms for screening using HTVS, SP, and XP docking; identified 6- oxidopamine HBr (C8H12BrNO3), which is used to create a model of Parkinson's disease in animals, and obtained the docking score ranging from -5.057 to -8.871 Kcal/mol. The poses were filtered with MM\GBSA score ranging from -21.67 to -27.63 Kcal/mol. We performed QM-based DFT and pharmacokinetics studies and compared them with the standard values, suggesting that the compound can be used in cervical cancer proteins. The P-L complex's interaction fingerprints have resulted in the most interacting residues, 4THR, 4SER, and 4LYS, showing the compound's interaction pattern. Further, the stability of 6-oxidopamine HBr in complex with each protein was evaluated with 100ns MD simulation in the SPC water model in a neutralised state to analyse the deviation, fluctuations, and intermolecular interactions that have proven the compound to have a better inhibitory effect against each protein and that it can be used for cervical cancer; however, experimental validation is suggested before human use.

Synthesis and DFT-optimized structures of hydrazonal-based compound: Biological activity and molecular docking

Distinctive quinolinyl hydrazonal-based compound was synthesized by an azo-coupling reaction of an enaminonitrile (piperidinylacrylonitrile) with the diazonium salt of 8-aminoquinoline. The synthesized compound was characterized by different spectroscopic methods and displayed distinctive solvatochromism. The possible tautomeric transformation of the arylhydrazonal was studied using DFT quantum chemical calculations revealing that the E→Z tautomerization was a spontaneous exothermic process and its equilibrium constant (Keq) was high with positive power. Thus, the Z-tautomer is more favorable than E-tautomer. This study looks at arylhydrazonal's multiple biological actions, showing its substantial promise in antibacterial, antifungal, anticancer, and enzyme inhibition applications. The arylhydrazonal exhibited concentration-dependent strong antibacterial action against Gram-positive and negative bacteria. Moreover, it showed a comparable concentration-dependent antifungal efficiency against C. albicans and A. fumigatus, and close to fluconazole's potency against A. fumigatus. The arylhydrazonal exhibits significant anticancer action, targeting skin and breast cancer cells, suggesting lesser harm to normal cells. In comparison with acetazolamide (AZA), It inhibited carbonic anhydrase isozymes IX and XII with substantial potency against CA-XII. Molecular docking investigations demonstrated the compound's interactions with proteins such 1D2S, 1AS0, 4WW8, and 5Fl4, revealing different binding energies, RMSD values, and stable configurations via hydrogen bonding and π-H stacking interactions. These results highlight the compound's potential as a therapeutic agent in a variety of clinical applications, calling for more study into its development and clinical usage.

Abstract 4937: Potential therapeutic targets with anti-inflammatory activity spectrum(COX-2/PGE2) of compounds associated with anti-cancer activityagainst oral and colorectal cancers

Abstract Introduction: COX-2 and PGE2 are prevalent inflammatory cytokines that exert influence on several cancer-related pathways throughout the gastrointestinal tract, spanning from oral cancers to colorectal cancers. One of the tactics being developed for the treatment of oral and colorectal malignancies is the identification of drugs that can selectively target receptors associated with COX-2 and PGE2. Materials and Methods: The objective was to identify potential therapeutic targets for oral cancer and colorectal cancer, specifically focusing on drugs that act as inhibitors or antagonists of the COX2/PGE2 pathway and its related receptor. A method for systematic data mining was created with a total of 32 targets associated with the COX-2/PGE2 pathway which were identified using the KEGG database. These targets were shown to be linked to both the oral cancer pathway and the colorectal cancer pathway. The compounds of interest were obtained from the Chembl25 database and their similarity was assessed using the Tanimoto similarity index, which was generated based on the Morgan fingerprints. The study employed molecular docking techniques to examine the interaction between the chosen drugs and the anticipated targets. A systematic data mining approach and computational methodology were devised utilizing the KNIME platform. Results: A total of 16,900 compounds were extracted for a set of 32 targets. Following the implementation of rule-based filters, the number of compounds was reduced to 13,800. The compounds that have a similarity index greater than 0.7 were chosen for inclusion in final analysis. Among various targets examined, empirical evidence was found to support the inhibition of expected target for PI-3 kinase-mTOR, GSK-3CD1, GSK3-AKT and PI3kinase-AKT pair. However, no evidence was found to support the inhibition of GSK3-Ikappa B-kinase. In order to examine the likelihood of the compound's interaction with anticipated target, molecular docking was employed to explore the interaction of one inhibitor compound for each pair. This investigation was conducted in contrast to the existing inhibitor compound and the subsequent findings were analyzed and discussed. Conclusion: The implemented data mining technique has demonstrated a notable decrease in the duration needed for comparable investigations, enabling the execution of experiments including numerous targets and a substantial number of ligands within a cumulative timeframe of 30 minutes. The findings of this study have the potential to be utilized in the identification of targets and the discovery of lead compounds for the purpose of managing oral as well as colorectal malignancies. Citation Format: Saravanan Sampoornam Pape. Potential therapeutic targets with anti-inflammatory activity spectrum(COX-2/PGE2) of compounds associated with anti-cancer activityagainst oral and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4937.

Targeting yeast topoisomerase II by imidazo and triazoloacridinone derivatives resulting in their antifungal activity

Fungal pathogens are considered as serious factors for deadly diseases and are a case of medical concern. Invasive fungal infections also complicate the clinical course of COVID-19, leading to a significant increase in mortality. Furthermore, fungal strains' multidrug resistance has increased the demand for antifungals with a different mechanism of action. The present study aimed to identify antifungal compounds targeting yeast topoisomerase II (yTOPOII) derived from well-known human topoisomerase II (hTOPOII) poisons C-1305 and C-1311. Two sets of derivatives: triazoloacridinones (IKE1-8) and imidazoacridinones (IKE9-14) were synthetized and evaluated with a specific emphasis on the molecular mechanism of action. Our results indicated that their effectiveness as enzyme inhibitors was not solely due to intercalation ability but also as a result of influence on catalytic activity by the formation of covalent complexes between plasmid DNA and yTOPOII. Lysine conjunction increased the strength of the compound's interaction with DNA and improved penetration into the fungal cells. Triazoloacridinone derivatives in contrast to starting compound C-1305 exhibited moderate antifungal activity and at least twice lower cytotoxicity. Importantly, compounds (IKE5-8) were not substrates for multidrug ABC transporters whereas a derivative conjugated with lysine (IKE7), showed the ability to overcome C. glabrata fluconazole-resistance (MIC 32–64 µg mL−1).

Synthesis, biological evaluation and molecular docking studies of novel 1,3,4-thiadiazoles as potential anticancer agents and human carbonic anhydrase inhibitors.

Thiosemicarbazide and also 1,3,4-thiadiazole derivatives have been garnering substantial attention from researchers worldwide due to their expansive range of biological activities, encompassing antimicrobial, anti-inflammatory, and anticancer properties. Herein, we embarked on a comprehensive investigation in this study, introducing a novel series of thiosemicarbazides (3a-3i) and their corresponding 1,3,4-thiadiazole (4a-4i) derivatives. The compounds were meticulously designed, synthesized, and subjected to meticulous characterization using various spectroscopic methods such as FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. Afterward, their potential anti-proliferative effectiveness was assessed using MTT assay against two cancer cell lines (U87 and HeLa) and normal fibroblast cells (L929). Among the compounds, 4d showed the highest cytotoxic activity against U87 and 4i against HeLa. Compound 3b exhibited selective cytotoxic activity against both cancer cells. Among the molecules with selective activity against the U87 cell line; 3a, 3b, 4d and 4e were further evaluated by caspase-3 activity levels, Bax and Bcl-2 protein expression, and total oxidant status assay. Besides, carbonic anhydrase IX activity studies were also performed in order to understand the underlying mechanism of action. The results indicated that compound 4e showed higher efficacy than standard acetazolamide (IC50 = 0.58 ± 0.02 µM) with an IC50 value of 0.03 ± 0.01 µM. Furthermore, molecular docking studies were carried out using carbonic anhydrase IX crystals to determine the compound's interactions with the enzyme's active sites. This comprehensive investigation sheds light on the intricate interplay between molecular structure and biological activity, providing valuable insights into the therapeutic potential of these compounds.

Derivative of 7-hydroxycoumarin has antifungal potential against Candida species and low cytotoxicity against human cells: In silico studies and biological evaluation

This study investigates the antifungal and cytotoxic properties of 7-(pentyloxy)-2H-chromen-2-one. Through molecular docking and dynamics simulations, we explored the compound's interactions with fungal cell protein targets. Notably, it exhibited strong affinities for 1,3β-glucan synthase, squalene epoxidase, δ-14-sterol reductase, 14-α-demethylase, and thymidylate synthase, with binding energies ranging from -100.39 to -73.15 kcal/mol. Molecular dynamics simulations confirmed its stable binding at active targets. The MIC and MFC values ranged from 67.16 μM (15.6 μg/mL) to 537.28 μM (125.0 μg/mL). The compound displayed promising antifungal effects, inhibiting fungal growth for at least 24 hours. Fungal plasma membrane function alteration likely contributed to these antifungal mechanisms. Additionally, the combination of the compound with nystatin, fluconazole, and caspofungin showed indifferent effects on antifungal activity. Cytotoxicity assessment in human keratinocyte cells (HaCaT) revealed an IC50 of 100 μM, which was approximately 1.5 times higher than the MIC for C. krusei. Thus, the compound exhibited strongly in silico and in vitro antifungal activity with low cytotoxicity in HaCaT cells. These findings support its potential as a candidate for further development as an antifungal compound.

Identification and Study of the Action Mechanism of Small Compound That Inhibits Replication of Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is known to cause annual epidemics of respiratory infections; however, the lack of specific treatment options for this disease poses a challenge. In light of this, there has been a concerted effort to identify small molecules that can effectively combat RSV. This article focuses on the mechanism of action of compound K142, which was identified as a primary screening leader in the earlier stages of the project. The research conducted demonstrates that K142 significantly reduces the intensity of virus penetration into the cells, as well as the formation of syncytia from infected cells. These findings show that the compound's interaction with the surface proteins of RSV is a key factor in its antiviral activity. Furthermore, pharmacological modeling supports that K142 effectively interacts with the F-protein. However, in vivo studies have shown only weak antiviral activity against RSV infection, with a slight decrease in viral load observed in lung tissues. As a result, there is a need to enhance the bioavailability or antiviral properties of this compound. Based on these findings, we hypothesize that further modifications of the compound under study could potentially increase its antiviral activity.

Numerical Analysis of Spray Characteristics With Methane and Nanoparticles Under Various Injection Velocities

Abstract Utilization of numerical simulations has been increased rapidly to test many innovative concepts in the field of advanced fuel technologies. Implementation of chemical compound's interaction is viable option by numerical tools. Hence in this current study, the numerical simulation has been performed to evaluate the effect of spray velocities on the mass fraction of various compounds. The conceptual numerical domain has been constructed with mixture of two inlets such as air and CH4 using ansys-cfd. In addition to the CH4, the nanoparticles were injected in the same inlet using the volume of fluid method. The fuel was injected at different velocities varied from 100 m/s to 175 m/s, under the intervals of 25 m/s. Here two sections of the domains are created, one for the oxidizers and another for the CH4 with nanoparticles. Throughout the entire trial runs, the nanoparticle concentration has been maintained constant. A series of the pictorial contours have been captured to understand the influence of the fuel impinging characteristics and reaction rates in the combustion chamber. The results revealed that CH4 injection enhances the vortices formation inside the combustion chamber. Furthermore, turbulence intensity inside the chamber is high which delays the reaction time and leads to the higher combustion indeed.

Potential Cytotoxic Activity of Methanol Extract, Ethyl Acetate, and n-Hexane Fraction from Clitoria ternatea L. on MCF-7 Breast Cancer Cell Line and Molecular Docking Study to P53

Breast cancer is a condition where the cells in breast tissue lose control and multiply uncontrollably. In this study, MCF-7 breast cancer cells were tested for cytotoxic activity using the MTT assay and the active compound's interaction with the p53 protein was tested in silico. The most active fraction was found to be the ethyl acetate fraction, with an IC50 value of 1.730 μg/mL and a selectivity index of 2.485. However, the selectivity index was less than 3, and Vero cells showed changes in morphology with the addition of the ethyl acetate fraction. GC-MS was used to identify 19 compounds in the ethyl acetate fraction, and in-silico tests were performed on 5 potential anticancer compounds. Lipinski's Rule of Five test showed that only 3 of these compounds could undergo molecular docking. The results indicated that Anethole compound can interact with p53 protein, while Cinnamaldehyde, (E)- can interact with p21 protein.

Antiviral Activitiy of Curcumin, Demethoxycurcumin, Bisdemethoxycurcumin and Cyclocurcumin compounds of Curcuma longa against NSP3 on SARS-CoV-2

SARS-CoV-2 genome encodes two large polyproteins (pp), pp1a and pp1ab which are cleaved and transformed into a mature form by a protease, non-structural protein 3 (NSP3). NSP3 is encoded by open reading frame (ORF) 1a/b. Curcuma longa (C. longa) or turmeric has been documented to have antiviral effects. The aim of this study was to assess the viral activities of C. longa against SARS-CoV-2 focusing on its potency to inhibit viral replication by targeting NSP3. PubChem databases were used to obtain the metabolic profile of C. longa. The compound's interaction with nucleocapsid was analyzed using molecular docking with Molegro Virtual Docker. Bioinformatics analysis based on rerank score presents all compounds of C. longa have higher binding affinity than the native ligand with cyclocurcumin as the lowest score (-128.38 kcal/mol). This anti-viral activity was hypothesized from the similarity of hydrogen bonds with amino acid residues Ser 128 and Asn 40 as key residues present in Ribavirin. This study reveals that C. longa is the potential to be developed as an antiviral agent through replication inhibition in SARS-CoV-2 targeting its replication mediated by NSP3.Keywords: C. longa, Non-Structural Protein 3, COVID-19.

Design, synthesis, biological activity evaluation and in silico studies of new nicotinohydrazide derivatives as multi-targeted inhibitors for Alzheimer's disease

A new series of 6‑chloro-N'-(substituted benzylidene)nicotinohydrazide were synthesized via condensation reactions between the corresponding hydrazides and aldehydes. All compounds were tested for their AChE and BuChE inhibitory activity. Compounds P5, P7, P9, P10 and P12 exhibited significant AChE inhibition potencies. Among them, compound P5 having para nitro substituent was found to be the most effective derivative against AChE with an IC50 value of 0.027 ± 0.001 µM. After that, the BACE-1 and beta-amyloid plaque inhibitory potencies of selected compounds P5, P7, P9, P10 and P12 were evaluated. Among them, compound P5 displayed the highest inhibition rate against the BACE-1 enzyme and beta-amyloid plaque. Molecular docking studies were carried out using both AChE and BACE-1 crystals to determine the compound's interactions with the enzyme's active sites. Furthermore, we evaluated the ADMET properties of compounds and their blood–brain barrier (BBB) permeation was also found to be high.

Half-Lantern Cyclometalated Platinum(II) Complexes as Anticancer Agents: Molecular Docking, Apoptosis, Cell Cycle Analysis, and Cytotoxic Activity Evaluations.

In the design of modern metal-based anticancer drugs, platinum-based complexes have gained growing interest. In this study, the anticancer activity of half-lantern cyclometalated Pt(II)‒Pt(II) complexes was evaluated using MTT, apoptosis, cell cycle analysis, and DNA binding studies. The cytotoxicity of Pt(II)‒Pt(II) complexes were evaluated against different cancer cell lines, such as human lung (A549), breast (MCF-7, and MDA-MB-231), ovarian (SKOV-3), and colon (HT-29) as well as normal breast (MCF-10A), and human lung fibroblast (MRC-5) cells using MTT assay. BioLegend's PE Annexin, V Apoptosis Detection Kit with 7AAD, was applied to assess the apoptotic effects of 1A and 1B compound against MCF-7 and A549 cell lines. Cell cycle analysis was determined using the flow cytometry method. The interaction of compounds with four different DNA structures with PDB codes (1BNA, 1LU5, 3CO3, and 198D) has been investigated by molecular docking. To achieve binding to DNA experimentally, the electrophoresis mobility shift assay and comet assay were applied. In the evaluation of cytotoxic effects, 1A showed the highest cytotoxicity among the studied compounds, and it showed higher potency with more selectivity against normal cell lines than cisplatin. This compound had IC50 of 7.24, 2.21, 1.18, 2.71, 10.65, 18.32, and 49.21 μM against A549, SKOV3, HT29, MCF-7, MDA-MB-231, MRC-5, and MCF-10A, respectively, whereas cisplatin had IC50 of 9.75, 19.02, 107.23, 15.20, 18.09, 14.36, and 24.21 μm, respectively, on the same cell lines. In order to check the DNA binding activity of 1A, and 1B, electrophoretic mobility was also conducted, which indicated that the binding of these compounds led to a slight change in electrophoretic mobility to DNA. The migration of chromosomal DNA from the nucleus in the form of a tail or comet was executed in the comet assay of 1A on MCF-7. Examination of apoptosis of 1A and 1B on the MCF-7 cancer cell line showed that it could increase induction of apoptosis in this cancerous cell in a concentration-dependent manner. Investigating the effect of 1A using cell cycle analysis on MCF-7 cancer cell line showed that this complex affects stage G1 and S of the cell cycle. 1A has the potential to play a significant role in future biopharmaceutical studies.

Design, synthesis, biological activity, molecular docking, and molecular dynamics of novel benzimidazole derivatives as potential AChE/MAO-B dual inhibitors.

To develop new acetylcholinesterase (AChE)-monoamine oxidase-B (MAO-B) dual inhibitors against Alzheimer's disease, the benzimidazole ring, which has a propargyl side chain with previously proven selective MAO-B inhibitory activity, was used as the main structure. Moreover, like donepezil, it was thought that the enzyme AChE would provide π-π interactions with the peripheral anionic side in this structure. Piperazine derivatives were chosen for the cationic active site. The synthesis of the compounds was carried out in five steps. The structures of the compounds were determined using 1 H-NMR (nuclear magnetic resonance), 13 C-NMR, and high-resolution mass spectrometry spectroscopic methods. First, the in vitro AChE, butyrylcholinesterase (BChE), MAO-A, and MAO-B inhibitory potentials of the obtained compounds were investigated. As a result of activity tests, compounds 5b, 5e, 5g, and 5h showed inhibitory activity against AChE; compounds 5e and 5g showed inhibitory activity against MAO-B. None of the compounds showed inhibitory activity against BChE or MAO-A. Compounds 5e and 5g showed dual inhibition. Among these compounds, compound 5g had inhibition potential similar to that of donepezil and selegiline. For compound 5g, further kinetic studies and Aβ-plaque inhibitory potentials were investigated using in vitro methods. Molecular docking studies were performed using both AChE and hMAO-B crystals to elucidate the compound's interactions with the enzyme active site. The binding modes of the compound on AChE were fully elucidated by molecular dynamics studies.

Hydration of Aromatic Heterocycles as an Adversary of π-Stacking.

Hydration is one of the key players in the protein–ligand binding process. It not only influences the binding process per se, but also the drug’s absorption, distribution, metabolism, and excretion properties. To gain insights into the hydration of aromatic cores, the solvation thermodynamics of 40 aromatic mono- and bicyclic systems, frequently occurring in medicinal chemistry, are investigated. Thermodynamics is analyzed with two different methods: grid inhomogeneous solvation theory (GIST) and thermodynamic integration (TI). Our results agree well with previously published experimental and computational solvation free energies. The influence of adding heteroatoms to aromatic systems and how the position of these heteroatoms impacts the compound’s interactions with water is studied. The solvation free energies of these heteroaromatics are highly correlated to their gas phase interaction energies with benzene: compounds showing a high interaction energy also have a high solvation free energy value. Therefore, replacing a compound with one having a higher gas phase interaction energy might not result in the expected improvement in affinity. The desolvation costs counteract the higher stacking interactions, hence weakening or even inverting the expected gain in binding free energy.