Docking Studies Research Articles

Farnesyl pyrophosphate synthase inhibitors with antiosteoporosis efficacy in ovariectomized rats: A mixed binding approach beyond bisphosphonates

The primary focus of bisphosphonate medications is on targeting human farnesyl pyrophosphate synthase (hFPPS), an essential regulator of mammalian isoprenoids. Yet, these drugs encounter limitations due to their restricted "druglike" properties and their effectiveness primarily in treating skeletal disorders. In this study, we synthesized novel non-bisphosphonate compounds, using 4,4'-(ethane-1,2-diylbis(oxy))bis(3-methoxybenzaldehyde) (1) as a starting compound, with the aim of targeting hFPPS through a mixed binding approach. Among the various compounds tested, compounds 4a and 4b exhibited significant inhibition of hFPPS activity, with IC50 values of 1.108 and 1.24 μM, respectively. Docking studies further revealed that both compounds bound within the allylic binding site and near the isopentenyl diphosphate (IPP) site within the hFPPS pocket. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 4a to confirm the formation of a stable complex with hFPPS. In an in vivo study conducted on ovariectomized rats, various biochemical markers including osteocalcin, estradiol, osteoprotegerin, bone mineral content, and density were negatively impacted, while levels of bone specific alkaline phosphatase, receptor activator of nuclear factor kappa-Β ligand, serum/urinary calcium, and phosphate increased. Notably, compound 4a exhibited antiresorptive properties similar to zoledronate, effectively restoring most of the perturbed biochemical estimations. These findings suggest the potential of compound 4a, a non-bisphosphonate compound, as alternative therapeutic agents for combating osteoporosis.

Structural, Computational, Docking and Biological Studies of a Triaminopyrimidine Caspase-1 Inhibitor

In order to more fully characterize the binding properties and activities of a potent, low nanomolar IC50 (half maximal inhibitory concentration) inhibitor of caspase-1, CK-1-41, a series of experiments were designed to probe its structure and function. To accomplish this, larger quantities of the molecule were synthesized in an efficient manner using a microwave method, in only 30 min. The structure of the inhibitor was determined by X-ray crystallography in its neutral and protonated form yielding useful structural information. The protonation site in the X-ray structure was found to be the trialkylamine basic site, but nuclear magnetic resonance (NMR) H/D exchange experiments shows that protonation at the triaminopyrimidine sp[2] C is also accessible in solution. Density Functional Theory (DFT) calculations were performed and supported the experimental H/D exchange results. Docking studies with several protonated forms of the inhibitor with caspase-1 revealed the compound binds favorably in an allosteric site, with the strongest binding from the protonated form where the proton is bound to the sp[2] C. Due to the involvement of caspase-1 in inflammatory cancers, CK-1-41 was screened against a panel of cancer cell lines displaying modest activity against some of the cell lines tested. These studies further clarify the structure and biological function of the representative member of the triaminopyrimidine inhibitors of caspase-1.

Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers

Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC50 = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC50 = 14.86 μM HePG-2, 8.04 μM PC-3 and 12.90 μM MCF-7) and 17 (IC50 = 9.98 μM HePG-2, 33.66 μM PC-3 and 14.62 μM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC50 = 0.161 and 1.06 μM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC50 = 0.487 and 0.364 μM, respectively, while compound 17 showed IC50 = 0.164 and 0.452 μM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands.

Molecular structure, spectroscopic (FT-IR, NMR and UV-Vis), electronic properties, molecular docking, and molecular dynamics studies on novel thiazolidinone derivative: A potent breast cancer drug

This study details the synthesis, characterization, and comprehensive computational analysis of a novel (R)-camphor-based thiazolidinone derivative. The structural integrity of the synthesized compound was confirmed using 1H- and 13C-NMR spectroscopy as well as HRMS. Theoretical vibrational modes were successfully assigned and matched well with the observed FT-IR spectrum. Simulated NMR values were in excellent agreement with experimental chemical shifts, showing maximum deviations of less than 1.5 ppm for 1H and 4 ppm for 13C. UV-vis spectroscopy revealed n→π* and π→π* transitions in thiazolidinone, with intermolecular charge transfer (ICT) corroborated by Frontier Molecular Orbital (FMO), density of states (DOS), and Natural Bond Orbital (NBO) analyses. Molecular docking studies indicated that thiazolidinone exhibited strong inhibitory activity against the breast cancer target protein 6HQO, which was further validated by molecular dynamics simulations, confirming the stability and accuracy of the docking results.

Synthesis, COX-2 inhibition, anti-inflammatory activity, molecular docking, and histopathological studies of new pyridazine derivatives

Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1β. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.

Synthesis, molecular docking, molecular dynamics and ADMET prediction studies of novel (S)-Verbenone-Arylidene -Isoxazoline Hybrids

The main objective of this work was to develop novel hybrid compounds from naturally occurring (S)-Verbenone. This last was used as a starting material to prepare new isoxazoline-verbenone-arylidene hybrids in two steps. All targeted compounds as well as their intermediates were fully characterized by 1H-, 13C-NMR and HRMS spectroscopic techniques. Then, a DFT study was carried out to understand the reactivity between the verbenone-arylidene as a source of two dipolarophiles with nitrile oxides. Finally, in silico molecular docking method was carried out to analyze the interactions of the prepared compounds with EGFR and Bcl-2 proteins. Moreover, the best-docked protein-ligand complexes was assessed using molecular dynamic simulation.

Exploration of Berberine Against Ulcerative Colitis via TLR4/NF-κB/HIF-1α Pathway by Bioinformatics and Experimental Validation.

This study aimed to delineate the molecular processes underlying the therapeutic effects of berberine on UC by employing network pharmacology tactics, molecular docking, and dynamic simulations supported by empirical validations both in vivo and in vitro. We systematically screened potential targets and relevant pathways affected by berberine for UC treatment from comprehensive databases, including GeneCards, DisGeNET, and GEO. Molecular docking and simulation protocols were used to assess the interaction stability between berberine and its principal targets. The predictions were validated using both a DSS-induced UC mouse model and a lipopolysaccharide (LPS)-stimulated NCM460 cellular inflammation model. Network pharmacology analysis revealed the regulatory effect of the TLR4/NF-κB/HIF-1α pathway in the ameliorative action of berberine in UC. Docking and simulation studies predicted the high-affinity interactions of berberine with pivotal targets: TLR4, NF-κB, HIF-1α, and the HIF inhibitor KC7F2. Moreover, in vivo analyses demonstrated that berberine attenuates clinical severity, as reflected by decreased disease activity index (DAI) scores, reduced weight loss, and mitigated intestinal inflammation in DSS-challenged mice. These outcomes include suppression of the proinflammatory cytokines IL-6 and TNF-α and downregulation of TLR4/NF-κB/HIF-1α mRNA and protein levels. Correspondingly, in vitro findings indicate that berberine decreases cellular inflammatory injury and suppresses TLR4/NF-κB/HIF-1α signaling, with notable effectiveness similar to that of the HIF-1α inhibitor KC7F2. Through network pharmacology analysis and experimental substantiation, this study confirmed that berberine enhances UC treatment outcomes by inhibiting the TLR4/NF-κB/HIF-1α axis, thereby mitigating inflammatory reactions and improving colonic pathology.

A SIMULATION APPROACH FOR NOVEL 1,3,4 THIADIAZOLE ACETAMIDE MOIETIES AS POTENT ANTIMYCOBACTERIAL AGENTS

Objective: To design novel series of 1,3,4 thiadiazoles and to evaluate their anti-mycobacterial potency via In silico modeling. Methods: In silico modeling comprising of Lipinski rule evaluation, ADMET prediction, Molecular docking and Simulation studies aimed to identify potent 1,3,4 thiadiazoles. Results: The various physiochemical parameters and molecular descriptors of the proposed 1,3,4 thiadiazoles were predicted. And they exhibited good binding score compared with standard drug INH. The simulation studies showed minimal fluctuation of the ligand receptor complexes. Conclusion: The MD simulation and binding affinity of designed 1,3,4 thiadiazoles proved their efficiency as InhA inhibitors. The potency of the selected derivatives can be confirmed by further in vitro and in vivo experiments.

Synthesis, biological screening, and binding mode analysis of some N-substituted tetrahydroquinoline analogs as apoptosis inducers and anticancer agents

One of the most common malignancies in the world is lung cancer. Lung cancer involves mutations in many different genes, however, EGFR, KRAS, PTEN, and PIK3CA involvement is more frequent. The lack of effective drugs and drug resistance are major issues and obstacles associated with the current treatment of lung cancer. Seven novel tetrahydroquinoline analogs were synthesized and screened against a range of cancer cell lines in this study. Among these, 17f (IC50=0.082µM) was shown to be the most potent when compared to the standard drug 5-Flurouracil (5FU) (IC50=0.28µM). Moreover, flow cytometry analysis was carried out to ascertain the nature of programmed cell death. This provides conclusive evidence of late apoptosis in all synthesized compounds when contrasted with the standard drug (5FU) and control. After comparing all of the outputs, additional binding mode analysis was carried out to determine the potential mechanism of its anticancer activity. Molecular docking and MD simulation studies were carried out, and the results show that all of the synthesized compounds 17-a-f (17f docking score -10.5 Kcal/mol) have a better binding affinity towards mTOR (PDB id: 4JT6) than both the standard drug 5FU and the co-crystal ligand X6K (docking score: -7.6 Kcal/mol). Despite the aforementioned information, strong hit compounds from this series may eventually be developed to become lead mTOR inhibitors for the treatment of lung cancer.

Magnetic ligand fishing protocol combined with HPLC-FT-ICR-MS for screening potential α-Glucosidase inhibitors from UCG and in silico analysis

Uremic Clearance Granule (UCG) is a traditional Chinese medicines (TCMs) that has been recognized as potentially effective treatment for diabetic nephropathy (DN). However, the chemical composition and the hypoglycemic ingredients of UCG remain unclear. In this experiment, a magnetic ligand fishing protocol combined with HPLC coupled Fourier transform ion cyclotron resonance mass spectrometry (HPLC-FT-ICR-MS) technology was developed to screen and identify α-Glucosidase inhibitors from UCG. First, constituents of UCG was identified by HPLC-FT-ICR-MS. Next, α-Glucosidase coated Fe3O4@SiO2@NH2 (Fe3O4@SiO2@NH2@α-Glucosidase) nano composites was synthesized. The essential parameters (concentration of Glutaraldehyde (GA), ratio of Fe3O4@SiO2@NH2 to enzyme, crosslinking time and immobilization time) were optimized to obtain maximum enzyme activity and the performance of immobilized enzyme was compared with that of free enzyme. The α-Glucosidase inhibitory activities were then evaluated using autodock and the 4-Nitrophenyl-α-D-glucopyranoside (pNPG) method. As a result, 142 compounds were identified were identified by comparing the retention time, molecular ions and fragmentation behaviors with the reference compounds or the in-house database. 20 possible α-Glucosidase activity inhibitory components were identified using HPLC-FT-ICR-MS. Molecular docking and inhibition studies showed that 4 compuunds including Limonexic acid, Sanggenol A, Glabrone, Matrine were more likely to stronger α-Glucosidase inhibitory activities than acarbose. In conclusion, the proposed approach, which combined highly specific screening with HPLC-FT-ICR-MS, provided a powerful platform for discovering bioactive components from multi-component and multi-target traditional Chinese medicines (TCMs).

“Deciphering the Potential Therapeutic Effects of Hydnocarpus wightianus Seed Extracts using in vitro and in silico approaches”

Phytocompounds possess the potential to treat a broad spectrum of disorders due to their remarkable bioactivity. Naturally occurring compound possess lower toxicity profiles, which make them attractive targets for drug development. Hydnocarpus wightianus seeds were extracted using ethanol, acetone, and hexane solvents. Evaluated for phytochemicals screening and other therapeutic characteristics such as free radicals scavenging, anti α-amylase, anti α-glucosidase, and anti-bacterial activities, ethanolic extract exhibited noteworthy antibacterial characteristics, and demonstrated considerable antioxidant, and anti-diabetic effects. Ethanolic extracts IC50 value ranges for Dpph, α-amylase and α-glucosidase was found to be 77.299±3.381μg/mL, 165.56±2.56μg/mL, and 136.58±5.82μg/mL. The ethanolic extract showed effective against Methicillin resistant Staphylococcus aureus (26 mm zone of inhibition at 100 μL concentration). Molecular docking investigations revealed the phytoconstituents inhibitory mechanisms against diabetic, free radicals, and bacterial activity. Docking score for phytocompounds against targeted protein varies from -7.2 to -5.1 kcal/mol. The bioactive compounds present in the ethanolic extract identified by Gas chromatography/Mass spectrometry analysis, followed by molecular docking and molecular dynamic simulation studies to further explore the phytoconstituents inhibitory mechanism of α-glucosidase, radical scavenging, and bacterial activity. Phytocompound electronic structure and possible pharmacological actions were revealed through the use of Density Functional Theory (DFT) analysis. Computational and in vitro studies revealed that these identified compounds have anti-diabetic, anti-oxidant, and anti-bacterial activities against antibiotic-resistant strain of Staphylococcus aureus.

Exploring Squalene's Impact on Epidermal Thickening and Collagen Production: Molecular Docking Insights

Background:: Aging is a progressive deterioration characterized by the gradual buildup of physiological alterations as time passes. The aging phenomenon encompasses various interconnected systems within the body, such as the skin, bones, cartilage, and hair. Objective and Methods: In this study, based on the appropriate properties of squalene, including antioxidant, anti-inflammatory, and skin repair properties, a molecular docking study was designed for the drug squalene and proteins related to the dermis and epidermis pathway and collagen production (including Col3A1, Col1A2, FBN1, Decorin, and HAS2). Results and Discussion:: The docking results indicated that the interaction of squalene with hyaluronan synthetase 2 (HAS2) possessed the highest negative binding free energy value of -10.90 KCal/mol, followed by decorin with a value of -9.99 KCal/mol. Also, the inhibition constant values of squalene- HAS2 and squalene-decorin complexes were equal to 1.61 and 7.51 μM, respectively. It has been stated that decorin (as a small proteoglycan) and HAS2 are involved in controlling the assembly of skin fibrils and the biosynthesis of glucosaminoglycans, respectively. Conclusion:: Considering that proteoglycans and glucosaminoglycans play a role in the skin aging process, squalene may be used as an anti-aging agent to induce these pathways and for different purposes. Squalene may be used as a potential agent alone or in combination with other compounds in tissue engineering scaffolds for cosmetic, anti-aging, wound healing, and tissue repair applications.

Synthesis and characterization of sulfonamide appended rigid phenyl-based and non-rigid 1,4-benzodioxan-based ring systems and their Pt(II) complexes towards potential therapeutic targets

Two novel non-rigid; 1,4-benzodioxan (bzd) based and rigid; 4-methylbiphenyl (4-Mebip) based di-(2-picolyl)amine derived sulfonamide ligands, and their cis-dichloroplatinum(II) complexes have been synthesized. The ligands; L1: N(SO2)(bzd)dpa and L2: N(SO2)(4-Mebip)dpa were synthesized via N-sulfonylation of di-(2-picolyl)amine in good yield. Their platinum(II) complexes; C1: [PtCl2(N(SO2)(bzd)dpa)], C2: [PtCl2(N(SO2)(4-Mebip)dpa)]·CH3CN were synthesized and characterized by 1H NMR, FTIR, UV–Vis and fluorescence spectroscopies. Structural studies revealed that the L1 and L2 ligands coordinate Pt(II) in a bidentate mode in C1 and C2 complexes, forming an eight-membered chelate ring. Interestingly, L1 possesses two conformations because the dioxan ring exists with a 95:5 occupancy ratio. The L2 ligand crystal undergoes a phase transition to triclinic form with twinning at 90 K whereas, at 150 K, the ligand exists in a monoclinic system; the populations of the two orientations for one pyridine substituent are approximately 78:22. The 1H NMR spectra of both Pt complexes obtained in DMSO‑d6 revealed two doublets (exo-CH2 and endo-CH2) for the magnetically inequivalent methylene protons, in contrast to their uncoordinated ligands, which show a singlet peak for the methylene protons. The NCI-H292 (non-small cell lung cancer cells) and MRC-5 (human normal lung fibroblast cells) were used to examine the in vitro cytotoxic activity of all synthesized compounds. All tested compounds demonstrated notable cytotoxicity against NCI-H292 cells, with the most pronounced cytotoxic effect being displayed by [PtCl2(N(SO2)(4-Mebip)dpa)]·CH3CN (C2). Docking studies strengthen in vivo antiproliferation activity where specific interactions with AKT1, BAX, STK-11, and BCL-2 were explored. Further predictions revealed that the compounds have inhibitory effects on COX-2 and PDE10A proteins.

A classic prescription alleviates inflammation in CUMS model mice via modulating MYDGF/MAP4K4/NF-κB signaling pathway, verified through UPLC-HRMS and proteomics analysis

BackgroundXiaoyaosan (XYS), a renowned classical traditional Chinese medicinal formula utilized in addressing major depressive disorder (MDD), has garnered significant acclaim for its remarkable efficacy in clinical application. The onset of major depressive disorder (MDD) often correlates with chronic unpredictable mild stress (CUMS), a pivotal instigating factor in its development.Aim of the study: This study aims to clarify the potential anti-inflammatory mechanisms of XYS in treating CUMS model mice. Materials and methodsUtilizing cutting-edge ultra high-performance liquid chromatography - high-resolution mass spectrometry (UPLC-HRMS), the active constituents of XYS were discerned, while employing proteomics analysis to delve into the potential mechanisms of its efficacy. Molecular docking studies, alongside subsequent in vivo experiments utilizing CUMS model mice, were conducted to corroborate the findings derived from the proteomics analysis. ResultsIn vivo experiments demonstrated that XYS not only markedly ameliorated behavioral markers but also attenuated serum inflammatory markers and suppressed IL-6 and TNF-α expression within the brains of CUMS model mice. Proteomics analysis suggested that the pivotal anti-inflammatory mechanism of XYS against CUMS-induced damage might involve modulation of the MAPK signaling pathway. Utilizing UPLC-HRMS, the active constituents of XYS were successfully identified, while molecular docking investigations explored interactions between XYS and MYDGF, PKC, MAP4K4, P-p65, p65, P-IKBα, and IKBα. The findings revealed XYS's regulatory influence on the MYDGF/MAP4K4/NF-κB signaling cascade. ConclusionsThis study is the first to our knowledge to demonstrate that XYS can alleviate inflammation in CUMS model mice by modulating the MYDGF/MAP4K4/NF-κB signaling pathway.

Anti-bacterial compounds from Indian curry-leaf tree Murraya koenigii have potential to inhibit carbapenem-resistant Streptococcus pneumoniae

Problems consideredSpike in the mortality rates due to pneumococcal infections post-COVID-19 has raised clinical concerns globally. β-lactam antibiotic-susceptibility in the causative organism, Streptococcus pneumoniae has been compromised due to non-synonymous single nucleotide polymorphisms (nsSNPs) in different penicillin-binding protein (PBP) targets. Carbapenem-resistant S. pneumoniae strains have further constricted the pharmacologically safe therapeutic options. MethodsIn-house sequenced whole genomes of meropenem and cefotaxime resistant Indian and global isolates were used to retrieve parent and mutant proteins. Anti-bacterial phtytochemicals (ABPs) from Indian curry-leaf tree Murraya koenigii were identified using database-mining. ABPs were screeened based on pharmacokinetics, and toxicity profiles. Site-specific molecular docking studies revealed ABPs‘ affinity towards the targets as compared to control drug meropenem. Coarse-grained and normal-mode molecular dynamics simulation further asserted the interactive stability of the chosen compounds. ResultsFrom the whole genomes (n = 28) of meropenem and cefotaxime resistant (MIC ≥0.5 μg/ml) Indian and global isolates, ∼50 nsSNPs in the active-site regions of PBP1A, PBP2B and PBP2X were identified. Based on pharmacological safety and high drug-likeliness, 10 ABPs were funnelled down from 226 ABPs in M. koenigii. A pyrano-carbazole alkaloid koenine was further prioritized as the most efficient candidate based on consistently high binding affinity (binding energies −7.7 to −8.9 kcal/mol), low inhibition constant (0.69–3.5 μM) and low structural fluctuations (<1.1 Å), against mutant targets as compared to meropenem. ConclusionThe study encourages experimental validation of koenine against pneumococci and also promotes the use of similar phytochemical resources for evaluation against emerging drug-resistant pathogens harbouring mutant targets.

Unveiling the Antimicrobial, Anti-Biofilm, and Anti-Quorum-Sensing Potential of Paederia foetida Linn. Leaf Extract against Staphylococcus aureus: An Integrated In Vitro–In Silico Investigation

Antimicrobial resistance poses a global health threat, with Staphylococcus aureus emerging as a notorious pathogen capable of forming stubborn biofilms and regulating virulence through quorum sensing (QS). In the quest for novel therapeutic strategies, this groundbreaking study unveils the therapeutic potential of Paederia foetida Linn., an Asian medicinal plant containing various bioactive compounds, contributing to its antimicrobial activities, in the battle against S. aureus. Through a comprehensive approach, we investigated the effect of ethanolic P. foetida leaf extract on S. aureus biofilms, QS, and antimicrobial activity. The extract exhibited promising inhibitory effects against S. aureus including the biofilm-forming strain and MRSA. Real-time PCR analysis revealed significant downregulation of key virulence and biofilm genes, suggesting interference with QS. Biofilm assays quantified the extract’s ability to disrupt and prevent biofilm formation. LC-MS/MS analysis identified quercetin and kaempferol glycosides as potential bioactive constituents, while molecular docking studies explored their binding to the QS transcriptional regulator SarA. Computational ADMET predictions highlighted favorable intestinal absorption but potential P-glycoprotein interactions limiting oral bioavailability. While promising anti-virulence effects were demonstrated, the high molecular weights and excessive hydrogen bond donors/acceptors of the flavonoid glycosides raise concerns regarding drug-likeness and permeability. This integrated study offers valuable insights for developing novel anti-virulence strategies to combat antimicrobial resistance.

Cholinesterase inhibitors for the treatment of Alzheimer’s disorder: Synthesis, biological analysis and molecular modelling studies of iso-quinoline derivatives

The most difficult issue nowadays is Alzheimer’s, particularly in developing nations. Targeting the associated enzymes is most efficient way for new drug development. We synthesized isoquinoline analogues (1–13) against acetylcholinesterase and butyrylcholinesterase. With respect to acetylcholinesterase, the range of inhibitory activity (IC50) for each analogue was 0.10 ± 0.05 to 11.10 ± 0.30 μM, and for butyrylcholinesterase, it was 0.30 ± 0.05 to 20.30 ± 0.40 μM. Compounds 2, 7, 9, 11, 12, and 13 showed excellent inhibition, with IC50 values of 2.30 ± 0.10, 0.30 ± 0.05, 2.70 ± 0.10, 1.05 ± 0.10, 1.40 ± 0.10, and 2.70 ± 0.10 μM, respectively. The butyrylcholinesterase activity of all analogues was good. Structure activity relationship (SAR) has been established for all newly synthesized derivatives. Molecular docking studies were carried out to understand the binding interactions with enzyme active sites.

Synthesis and Anticancer Activity of Novel Indole Derivatives as Dual EGFR/SRC Kinase Inhibitors.

Recent studies showed that the cooperation between c-SRC and EGFR is responsible for more aggressive phenotype in diverse tumors, including glioblastomas and carcinomas of the colon, breast, and lung. Studies show that combination of SRC and EGFR inhibitors can induce apoptosis and delay the acquired resistance to chemotherapy. Therefore, such combination may lead to a new therapeutic strategy for the treatment of EGFR-mutant lung cancer. Osimertinib was developed as a third-generation EGFR-TKI to combat the toxicity of EGFR mutant inhibitors. Due to the resistance and adverse reaction of osimertinib and other kinase inhibitors, 12 novel compounds structurally similar to osimertinib were designed and synthesized. Recent studies showed that the cooperation between c-SRC and EGFR is responsible for more aggressive phenotype in diverse tumors, including glioblastomas and carcinomas of the colon, breast, and lung. Studies show that combination of SRC and EGFR inhibitors can induce apoptosis and delay the acquired resistance to chemotherapy. Therefore, such combination may lead to a new therapeutic strategy for the treatment of EGFR-mutant lung cancer. Osimertinib was developed as a third-generation EGFR-TKI to combat the toxicity of EGFR mutant inhibitors. Due to the resistance and adverse reaction of osimertinib and other kinase inhibitors, 12 novel compounds structurally similar to osimertinib were designed and synthesized. Compounds were synthesized by developing novel original synthesis methods and receptor interactions were evaluated through a molecular docking study. To evaluate their inhibitory activities against EGFR and SRC kinase, in vitro enzyme assays were used. Anticancer potencies were determined using lung, breast, prostate (A549, MCF6, PC3) cancer cell lines. Compounds were also tested against normal (HEK293) cell line to evaluate their cyctotoxic effects. Although, none of compounds showed stronger inhibition compared to osimertinib in the EGFR enzyme inhibition studies, compound 16 showed the highest efficacy with an IC50 of 1.026 μM. It also presented potent activity against SRC kinase with an IC50 of 0.002 μM. Among the tested compounds, the urea containing derivatives 6-11 exhibited a strong inhibition profile (80.12-89.68%) against SRC kinase in comparison to the reference compound dasatinib (93.26%). Most of the compounds caused more than 50% of cell death in breast, lung and prostate cancer cell lines and weak toxicity for normal cells in comparison to reference compounds osimertinib, dasatinib and cisplatin. Compound 16 showed strong cytotoxicity on lung and prostate cancer cells. Treatment of prostate cancer cell lines with the most active compound, 16, significantly increased the caspase-3 (8-fold), caspase-8 (6-fold) and Bax (5.7-fold) levels and decreased the Bcl-2 level (2.3-fold) compared to the control group. These findings revealed that the compound 16 strongly induces apoptosis in the prostate cancer cell lines. Overall kinase inhibition, cytotoxicity and apoptosis assays presented that compound 16 has dual inhibitory activity against SRC and EGFR kinases while maintaining low toxicity against normal cells. Other compounds also showed considerable activity profiles in kinase and cell culture assays.

Synthesis, in vitro β-glucuronidase inhibition of benzoxazole bearing thiosemicarbazide derivatives along with in silico molecular docking study

This study was aimed to design and synthesize hybrid analogues of benzoxazole bearing thiosemicarbazide analogues 1–15 as promising β-Glucuronidase inhibitory activity using D-saccharic acid 1,4-lactone as the reference inhibitor. The newly afforded benzoxazole-thiosemicarbazide compounds 1–15 displayed a broad range of inhibitory potential with IC50 values ranging from 20.58 ± 2.46 to 87.89 ± 8.43 μM, as compared to D-saccharic acid 1,4-lactone (IC50 = 59.5 ± 5.36 μM). Among the synthesized series, the compounds 14, 2, and 5 demonstrated outstanding β-Glucuronidase inhibitory potential with IC50 values of 20.58 ± 2.46, 25.24 ± 2.34 and 24.53 ± 2.53 μM respectively. Further, the precise structures of synthesized analogues were confirmed using 1H NMR, 13C NMR and HREIMS. Additionally, the molecular docking approach was employed to correlate the in vitro β-Glucuronidase inhibitory activity well with in silico study and result obtained corroborated that active analogues established several key interactions with the active sites of β-Glucuronidase enzyme.

Interdisciplinary Insights into (1'R,3S,3'R)-1'-(4-chlorobenzoyl)-5',6',7',7a'-tetrahydro-1'H dispiro[indoline-3,2'-pyrrolizine-3',3''-indoline]-2,2''-dione: Structural, Electronic, and Molecular Dynamics Perspectives

In the field of heterocyclic compounds, the spiro-pyrrolidine and oxindole ring systems are highly esteemed due to their distinctive structural scaffold that is present in numerous pharmacologically significant alkaloids. Interdisciplinary research has been increasingly important in recent years for deciphering the intricate characteristics and behaviors of novel organic compounds. The current work uses quantum chemical computational techniques to study the structural stability and nonlinear optical (NLO) activity of 1'R,3S,3'R)-1'-(4-chlorobenzoyl)-5',6',7',7a'-tetrahydro-1'H dispiro[indoline-3,2'-pyrrolizine-3',3''-indoline]-2,2''-dione (DSOIP-Cl). The study combines molecular biology, computational chemistry, and theoretical chemistry knowledge to create a comprehensive picture of this fascinating organic compound. This study employed the density functional theory (DFT) B3LYP method to compute the electronic properties and molecular geometry. The basis set for the computations was 6-311++G(d,p). The IEFPCM solvation method is used to investigate the behavior of the head compound in different solvents. Understanding the interaction between organic compounds and the solvent phase is crucial because the majority of interactions in biological systems occur in solution. UV-Vis spectral analysis of the molecule in different solvents is performed using the TD-DFT method. The compound exhibits more excellent absorption in polar solvents such as water, while its absorption is lower in the gaseous phase. Assessing NLO properties revealed optoelectronics applications. DSOIP-Cl has 5.25 times the first-order hyperpolarizability of urea. Different solvents have higher dipole moments and first-order hyperpolarizability than gases. To identify the inter- and intramolecular charge transfer interactions, intermolecular hydrogen bonding, and hyperconjugative interactions that stabilize the structure, natural bond orbital (NBO) analysis is performed. A stabilization energy of 9.99 kcal/mol is obtained for π(C32-C33) → σ*(C33-C34) due to strong intramolecular hyperconjugative interactions. Frontier molecular orbital (FMO) analysis helps determine the global reactivity parameters and the charge transfer interaction. The van der Waals interaction and steric effect within the molecule are identified using RDG analysis. The pharmacokinetic properties, adherence to drug-likeness criteria, and easily controllable synthesis process were evaluated through ADME analysis, establishing it as an up-and-coming candidate for subsequent drug development. Ultimately, to determine the biological activity and the ability of the title compound to inhibit aldose reductase, a series of computational techniques are employed, including molecular docking study, molecular dynamic (MD) simulation, and MM-PBSA binding energy calculations. -7.86 kcal/mol was reported as the docking score. Hydrophobic interactions play an essential role in the efficiency of protein-ligand binding. The remarkable energetic contribution of DSOIP-Cl to the MM-PBSA binding dynamics highlights its unique association with the AR protein, with a binding energy of -79.81 kJ/mol.