Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study.

Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.

Synergistic effect of new pyrimidine derivative with oxacilin against methicillin-resistant Staphylococcus aureus.

Aim: This work aimed to synthesize a new pyrimidine PYB01 with potential application against antimicrobial resistance.Materials & methods: PYB01 was synthesized through condensation reaction between 3a and 3b. The antimicrobial evaluation was carried out using the microdilution method in Mueller-Hinton Agar and in silico predictions using different software.Results: PYB01 has moderate antibiotic activity and high capacity to efficiently modulate antibiotic resistance in Staphylococcus aureus. In silico evaluations demonstrated that PYB01 is probably an allosteric inhibitor of Protein Binding Penicilin 2a and modulates the action of oxacillin by decreasing the minimum inhibitory concentration by 64-times. PYB01 demonstrate a good pharmacokinetic profile and toxicological.Conclusion: PYB01 has great potential to go further in investigating its use against antimicrobial resistance.

[Box: see text].

Kaempferol as a novel inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly become a global health pandemic. Among the viral proteins, RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as a promising target against SARS-CoV-2 infection. Dietary bioactive compounds represent an important source of evolutionarily optimized molecules with antiviral properties against SARS-CoV-2 RdRp. We investigated the inhibitory potential effects of different phytochemicals against SARS-CoV-2 RdRp, including andrographolide, kaempferol, resveratrol, and silibinin. Unlike the other investigated compounds, kaempferol exhibited a significant dose-dependent in vitro inhibition of SARS-CoV-2 RdRp activity. To assess the binding interactions and stability of the SARS-CoV-2 RdRp-kaempferol complex, we performed in silico techniques, including molecular docking, quantum chemical calculation, and molecular dynamics simulations. We found strong binding affinities and stability between kaempferol and SARS-CoV-2 RdRp variants (Wuhan and Omicron). These findings provide valuable insights into the antiviral properties of kaempferol as a stable inhibitor of SARS-CoV-2 RdRp.Communicated by Ramaswamy H. Sarma.

Cheminformatics-based analysis identified (Z)-2-(2,5-dimethoxy benzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one as an inhibitor of Marburg replication by interacting with NP.

The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family, a non-segmented negative-strand RNA virus. This article represents the computer-aided drug design (CADD) approach for identifying drug-like compounds that prevent the MARV virus disease by inhibiting nucleoprotein, which is responsible for their replication. This study used a wide range of in silico drug design techniques to identify potential drugs. Out of 368 natural compounds, 202 compounds passed ADMET, and molecular docking identified the top two molecules (CID: 1804018 and 5280520) with a high binding affinity of -6.77 and -6.672 kcal/mol, respectively. Both compounds showed interactions with the common amino acid residues SER_216, ARG_215, TYR_135, CYS_195, and ILE_108, which indicates that lead compounds and control ligands interact in the common active site/catalytic site of the protein. The negative binding free energies of CID: 1804018 and 5280520 were -66.01 and -31.29 kcal/mol, respectively. Two lead compounds were re-evaluated using MD modeling techniques, which confirmed CID: 1804018 as the most stable when complexed with the target protein. PC3 of the (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) was 8.74 %, whereas PC3 of the 2'-Hydroxydaidzein (CID: 5280520) was 11.25 %. In this study, (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) unveiled the significant stability of the proteins' binding site in ADMET, Molecular docking, MM-GBSA and MD simulation analysis studies, which also showed a high negative binding free energy value, confirming as the best drug candidate which is found in Angelica archangelica which may potentially inhibit the replication of MARV nucleoprotein.

A Series of Novel 1-H-isoindole-1,3(2H)-dione Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: In Silico, Synthesis and In Vitro Studies.

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 µM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 µM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.

De novo Antineoplastic Drug Design to Suppress Head, Neck and Oral Cancer using Theoretical Organic and Biochemistry via Comprehensive Molecular Docking and Dynamics.

OBJECTIVE: A de novo antineoplastic drug was planned to suppress and modulate the Head, Neck, and Oral Cancer. METHODS: Using the computational software tools including molecular docking, molecular dynamics (MD), and post-molecular dynamics bond contact analyses, it has been shown that the new drug called ''Innovative Head, Neck, and Oral Cancer Suppressor'', or simply abbreviated as "IHNOCS" is very effective in terms of suppressing and co-modulating TGF-ß and KRTAP2-3 together. RESULT: The drug suppresses the KRTAP2-3 protein activity while also holding onto TGF-ß and modulating it to slow down and halt the metastasis. CONCLUSION: We have effectively created a novel medication using principles of theoretical chemistry, biochemistry, pharmaceutical chemistry and organic chemistry and organic chemistry to inhibit Head, Neck, and Oral Cancer. This medication should further undergo experimental testing in various stages, including in vitro, in vivo, and human clinical phases. It exhibits significant effectiveness in inhibiting the progression of cancer by simultaneously targeting TGF-ß and KRTAP2-3, thereby impeding metastasis and suppressing the disease.

Computational discovery of AKT serine/threonine kinase 1 inhibitors through shape screening for rheumatoid arthritis intervention.

Rheumatoid Arthritis (RA) is a chronic, symmetrical inflammatory autoimmune disorder characterized by painful, swollen synovitis and joint erosions, which can cause damage to bone and cartilage and be associated with progressive disability. Despite expanded treatment options, some patients still experience inadequate response or intolerable adverse effects. Consequently, the treatment options for RA remain quite limited. The enzyme AKT1 is crucial in designing drugs for various human diseases, supporting cellular functions like proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. Therefore, AKT serine/threonine kinase 1 is considered crucial for targeting therapeutic strategies aimed at mitigating RA mechanisms. In this context, directing efforts toward AKT1 represents an innovative approach to developing new anti-arthritis medications. The primary objective of this research is to prioritize AKT1 inhibitors using computational techniques such as molecular modeling and dynamics simulation (MDS) and shape-based virtual screening (SBVS). A combined SBVS approach was employed to predict potent inhibitors against AKT1 by screening a pool of compounds sourced from the ChemDiv and IMPPAT databases. From the SBVS results, only the top three compounds, ChemDiv_7266, ChemDiv_2796, and ChemDiv_9468, were subjected to stability analysis based on their high binding affinity and favorable ADME/Tox properties. The SBVS findings have revealed that critical residues, including Glu17, Gly37, Glu85, and Arg273, significantly contribute to the successful binding of the highest-ranked lead compounds at the active site of AKT1. This insight helps to understand the specific binding mechanism of these leads in inhibiting RA, facilitating the rational design of more effective therapeutic agents.

Identification of bio-active secondary metabolites from Actinobacteria as potential drug targets against Porphyromonas gingivalis in oral squamous cell carcinoma using molecular docking and dynamics study.

Chronic periodontitis caused by the bacteria Porphyromonas gingivalis is thought to be a risk factor for the advancement of oral squamous cell carcinoma (OSCC). Virulence factors of P. gingivalis include gingipains, outer membrane surface lipoproteins, and fimbriae contribute to the activation of oncogenic pathways in OSCC by up-regulating different cytokines. Gingipains (Arg and Lys) proteases have an important role in the activation of proMMP-9, which promotes cellular invasion and metastatic ability of OSCC. Thus gingipains and MMP-9 were actively investigated as potential therapeutic targets in OSCC therapy. Various natural bioactive compounds from Actinobacteria have been explored for their anticancer potential in a variety of cancers, but very few studies have been reported in OSCC. Therefore, the current study is focused to identify potential actinobacterial compounds that can be considered as a therapeutic target against gingipains and inflammatory proteins in OSCC through high-throughput virtual screening, Molecular Docking (MD), and Molecular Dynamics Simulation (MDS) approaches. A total of 179 bioactive secondary metabolites of Actinobacteria were explored for their binding affinity against six virulence proteins of P. gingivalis. The Molecular Docking studies revealed that among 179 metabolites screened, Actinosporin G showed a highly acceptable binding affinity of -7.9 kcal/mol with RgpB (1CVR), and exhibited multi-protein targeting and drug-likeness property and passed level of toxicity. Comprehensive docking interaction of the best top-ranked Actinosporin G with OSCC-related protein targets illustrated high binding affinity towards MMP-9 and JAK-1 proteins among all targeted receptor proteins. The molecular dynamic (MD) simulation has been executed for the metabolite Actinosporin G for both bacterial gingipain (RgpB) and MMP-9 & JAK-1 showed stable intermolecular binding with both hydrogen and hydrophobic interactions. In conclusion, this work suggests that the bioactive secondary metabolite of Actinosporin G from Actinobacteria genera may serve as a promising therapy for P. gingivalis-induced OSCC. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00209-0.

Probing the anti-Aß42 aggregation and protective effects of prenylated xanthone against Aß42-induced toxicity in transgenic Caenorhabditis elegans model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-ß (Aß) protein aggregates, leading to synaptic dysfunction and neuronal cell death. In this study, we used a comprehensive approach encompassing in vitro assays, computational analyses, and an in vivo Caenorhabditis elegans model to evaluate the inhibitory effects of various xanthones, focusing on Garcinone D (GD), on Aß42 oligomer formation. Dot blot analysis revealed concentration-dependent responses among xanthones, with GD consistently inhibiting Aß42 oligomer formation at low concentrations (0.1 and 0.5 µM, inhibitions of 84.66 ± 2.25% and 85.06 ± 6.57%, respectively). Molecular docking and dynamics simulations provided insights into the molecular interactions between xanthones and Aß42, highlighting the disruption of key residues involved in Aß42 aggregation. The neuroprotective potential of GD was established using transgenic C. elegans GMC101, with substantial delays in paralysis reported at higher concentrations. Our findings show that GD is a potent suppressor of Aß42 oligomer formation, suggesting its potential as a therapeutic candidate for AD. The concentration-dependent effects observed in both in vitro and in vivo models underscore the need for nuanced dose-response assessments. These findings contribute novel insights into the therapeutic landscape of xanthones against AD, emphasizing the multifaceted potential of GD for further translational endeavors in neurodegenerative disorder research.

GC-MS analysis, pharmacokinetic properties, molecular docking and dynamics simulation of bioactives from Curcumis maderaspatanus to target oral cancer.

Oral cancer (OC) which is the most predominant malignant epithelial neoplasm in the oral cavity, is the 8th commonest type of cancer globally. Natural products are excellent sources of functionally active compounds and essential nutrients that play an important role in cancer therapeutics. Using the structure-based virtual screening, drug-likeness, toxicity, and molecular dynamics simulation, the current study focused on the evaluation of anticancer activity of bioactive compounds from Curcumis maderaspatanus. AURKA, CDK1, and VEGFR-2 proteins which play a crucial role in the development and progression of oral cancer was selected as targets and 216 phytochemicals along with a known reference inhibitor were docked against these target proteins. Based on the docking score, it was found that phytochemicals namely 3-Benzoyl-2,4(1H,3H)-Pyrimidinedione (- 8.0 kcal/mol), 1-Cyclohexylethanol, trifluoroacetate (- 6.3 kcal/mol), and Alpha-Curcumene (- 8.9 kcal/mol) interacts with AURKA, CDK1, and VEGFR-2 with highest binding affinity. The molecular dynamics simulation demonstrated that the best docked complexes exhibited excellent structural stability in terms of RMSD, RSMF, SASA and Rg for a period of 100 ns. Altogether, our computational analysis reveals that the bioactives from C. maderaspatanus could emerge as efficacious drug candidates in oral cancer therapy. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00177-x.

In silico screening of selective ATP mimicking inhibitors targeting the Plasmodium falciparum Grp94.

Plasmodium falciparum parasites export more than 400 proteins to remodel the host cell environment and increase its chances of surviving and reproducing. The endoplasmic reticulum (ER) plays a central role in protein export by facilitating protein sorting and folding. The ER resident member of the Hsp90 family, glucose-regulated protein 94 (Grp94), is a molecular chaperone that facilitates the proper folding of client proteins in the ER lumen. In P. falciparum, Grp94 (PfGrp94) is essential for parasite survival, rendering it a promising anti-malarial drug target. Despite this, its druggability has not been fully explored. Consequently, this study sought to identify small molecule inhibitors targeting the PfGrp94. Potential small molecule inhibitors of PfGrp94 were designed and screened using in silico studies. Molecular docking studies indicate that two novel compounds, Compound S and Compound Z selectively bind to PfGrp94 over its human homologues. Comparatively, Compound Z had a higher affinity for PfGrp94 than Compound S. Further interrogation of the inhibitor binding using molecular dynamics (MD) analysis confirmed that Compound Z formed stable binding poses within the ATP-binding pocket of the PfGrp94 N-terminal domain (NTD) during the 250 ns simulation run. PfGrp94 interacted with Compound Z through hydrogen bonding and hydrophobic interactions with residues Asp 148, Asn 106, Gly 152, Ile 151 and Lys 113. Based on the findings of this study, Compound Z could serve as a competitive and selective inhibitor of PfGrp94 and may be useful as a starting point for the development of a potential drug for malaria.Communicated by Ramaswamy H. Sarma.

Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches.

In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α-amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques and elemental analysis. The obtained results were compared to those of the reference drug, acarbose (IC50 = 296.6 ± 0.825 µM for α-amylase & IC50 = 780.4 ± 0.346 µM for α-glucosidase). Among the title compounds, 5d exhibited impressive α-amylase and α-glucosidase inhibitory activity with IC50 values of 30.39 ± 1.52 µM and 65.1 ± 3.11 µM, respectively, followed by 5h (IC50 = 46.65 ± 2.3 µM; IC50 = 85.16 ± 4.25 µM) and 5f (IC50 = 55.71 ± 2.78 µM; IC50 = 106.77 ± 5.31 µM). Mechanistic studies revealed that the most potent derivative 5d bearing the chloro substituent attached to the oxoindolin-3-ylidene core, and acarbose, are a competitive inhibitors of α-amylase and α-glucosidase, respectively. Structure activity relationship (SAR) was examined to guide further structural optimization of the most appropriate substituent(s). Moreover, drug-likeness qualities and ADMET prediction of the most active analogue, 5d was also performed. Subsequently, 5d was subjected to molecular docking and dynamic simulation during the progression of 120 ns analysis to check the essential ligand-receptor patterns, and to estimate its stability. In silico studies were found in good agreement with the in vitro enzymatic inhibitions results. In conclusion, we demonstrated that most potent compound 5d could be exploited as dual potential inhibitor of α-amylase and α-glucosidase for possible management of diabetes.

Novel hydrazone schiff's base derivatives of polyhydroquinoline: synthesis, in vitro prolyl oligopeptidase inhibitory activity and their Molecular docking study.

This research work reports the synthesis of new derivatives of the hydrazone Schiff bases (1-17) based on polyhydroquinoline nucleus through multistep reactions. HR-ESIMS,1H- and 13C-NMR spectroscopy were used to structurally infer all of the synthesized compounds and lastly evaluated for prolyl oligopeptidase inhibitory activity. All the prepared products displayed good to excellent inhibitory activity when compared with standard z-prolyl-prolinal. Three derivatives 3, 15 and 14 showed excellent inhibition with IC50 values 3.21 ± 0.15 to 5.67 ± 0.18 µM, while the remaining 12 compounds showed significant activity. Docking studies indicated a good correlation with the biochemical potency of compounds estimated in the in-vitro test and showed the potency of compounds 3, 15 and 14. The MD simulation results confirmed the stability of the most potent inhibitors 3, 15 and 14 at 250 ns using the parameters RMSD, RMSF, Rg and number of hydrogen bonds. The RMSD values indicate the stability of the protein backbone in complex with the inhibitors over the simulation time. The RMSF values of the binding site residues indicate that the potent inhibitors contributed to stabilizing these regions of the protein, through formed stable interactions with the protein. The Rg. analysis assesses the overall size and compactness of the complexes. The maintenance of stable hydrogen bonds suggests the existence of favorable binding interactions. SASA analysis suggests that they maintained stable conformations without large-scale exposure to the solvent. These results indicate that the ligand-protein interactions are stable and could be exploited to design new drugs for disease treatment.Communicated by Ramaswamy H. Sarma.

Synthesis, X-ray crystallography, computational investigation on quinoxaline derivatives as potent against adenosine receptor A2AAR.

Quinoxaline represents one of the most important classes of heterocyclic compounds, which have exhibited a wide range of biological activities and industrial importance in many different fields. In this regard, we have synthetized two new quinoxaline derivatives. Their structures were confirmed by single-crystal X-ray analysis. The compounds show potent activity against adenosine receptors A2AAR based on structural activity relationship studies. Further molecular docking, molecular dynamics, ADMET analysis, and DFT (density functional theory) calculations were performed to understand the titled compound's future drug candidacy. DFT computations confirmed the good stability of the synthesized compounds, as evidenced by the optimized molecular geometry, HOMO-LUMO energy gap, and intermolecular interactions. NBO analysis confirmed intermolecular interactions mediated by lone pair, bonding, and anti-bonding orbitals. All DFT findings were consistent with experimental results, indicating that the synthesized molecules are highly stable. These findings suggest that the synthesized compounds are promising candidates for further development as drugs for the treatment of A2AAR-related diseases.Communicated by Ramaswamy H. Sarma.

XRD/DFT, Hirshfeld surface analysis and molecular modelling simulations for unfolding reactivity of newly synthesized vanillin derivatives: excellent optical, NLO and protein binding efficiency.

New vanillin derivatives, namely, ethyl (4-formyl-2-methoxyphenoxy)acetate (2a) and 2-(4-formyl-2-methoxyphenoxy)-N-phenylacetamide (2b), respectively, were synthesized and characterized by NMR (1H and 13C), IR, mass spectra and confirmed by single-crystal X-ray analysis. Hirshfeld surface (HS) analysis was performed to probe intra- and intermolecular interactions and surface reactivity. 2D fingerprint plots (FP) were used to study the nature and percentage contribution of intermolecular interactions leading to the formation of the crystal unit. Density functional theory (DFT) simulations were used to obtain the electronic structure and reactivity of the new molecules. Natural population analysis (NPA) and frontier molecular orbital (FMO) calculations reveal significant charge transfer and a reduced HOMO-LUMO gap up to 4.34 eV for 2b. Bader's quantum theory of atoms in molecules (QTAIM) study is utilized to understand the surface topological and bonding nature of 2a and 2b. The performed molecular electrostatic potential (MESP) and density of states (DOS) study further suggest sites likely to be attractive to incoming reagents. At the same time, hyperpolarizability (ßo) is used to characterize the nonlinear optical properties, and TD-DFT study shows the excitation energy and absorption behavior. In silico studies were performed, including docking, binding free energies (MMBGSA) and molecular dynamics simulations. Compounds 2a and 2b were docked with RdRp of SARS-Cov-2, and the MMBGSA for 2a and 2b were -30.70 and -28.47 kcal/mol, respectively, while MD simulation showed the stability of protein-ligand complexes.Communicated by Ramaswamy H. Sarma.

Inhibition of NS2B-NS3 protease from all four serotypes of dengue virus by punicalagin, punicalin and ellagic acid identified from Punica granatum.

Despite a major threat to the public health in tropical and subtropical regions, dengue virus (DENV) infections are untreatable. Therefore, efforts are needed to investigate cost-effective therapeutic agents that could cure DENV infections in future. The NS2B-NS3 protease encoded by the genome of DENV is considered a critical target for the development of anti-dengue drugs. The objective of the current study was to find out a specific inhibitor of the NS2B-NS3 proteases from all four serotypes of DENV. To begin with, nine plant extracts with a medicinal history were evaluated for their role in inhibiting the NS2B-NS3 proteases by Fluorescence Resonance Energy Transfer (FRET) assay. Among the tested extracts, Punica granatum was found to be the most effective one. The metabolic profiling of this extract revealed the presence of several active compounds, including ellagic acid, punicalin and punicalagin, which are well-established antiviral agents. Further evaluation of IC50 values of these three antiviral molecules revealed punicalagin as the most potent anti-NS2B-NS3 protease drug with IC50 of 0.91 ± 0.10, 0.75 ± 0.05, 0.42 ± 0.03, 1.80 ± 0.16 µM against proteases from serotypes 1, 2, 3 and 4, respectively. The docking studies demonstrated that these compounds interacted at the active site of the enzyme, mainly with His and Ser residues. Molecular dynamics simulations analysis also showed the structural stability of the NS2B-NS3 proteases in the presence of punicalagin. In summary, this study concludes that the punicalagin can act as an effective inhibitor against NS2B-NS3 proteases from all four serotypes of DENV.Communicated by Ramaswamy H. Sarma.

Synthesis, antimicrobial properties and in silico evaluation of coumarin derivatives mediated by 1,4-dibromobutane.

In this study, monobrominated coumarins (5-6) and bis-coumarins (7-9) were synthesized from 3-carboxylic coumarin and 7-hydroxy-4-methyl coumarin using 1,4-dibromobutane as a binding agent, according to the synthesis procedures described in the literature. Amongst these coumarins, three are new compounds: monobrominated coumarin 5 and bis-coumarins 7 and 9. The structures of the synthesized coumarins were confirmed by FTIR, NMR and HRMS-ESI. In vitro antimicrobial evaluation of these coumarins against strains of twelve bacteria and four fungi revealed their bactericidal and fungicidal properties, with increased antibacterial activity for monocoumarins and improved antifungal activity for bis-coumarins. It was also found that the antibacterial activity was enhanced by the etheric bond, Br atom and alkyl chain and reduced by the ester bonds at position 3 of the pyrone ring or an additional coumarin unit, while the antifungal activity was reinforced by ester bonds and deactivated by the Br atom. For the first time, the in silico investigations of such coumarins were carried out and it was observed that they are less toxic, suitable for oral administration with good permeability through cell membrane, are able to circulate freely in the bloodstream and cross Blood-Brain-Barriers. Moreover, their molecular docking in DNA indicated stable coumarin-DNA complexes with good scores. The results of molecular dynamics simulations performed for 200 ns revealed the rigidity and stability of bis-coumarins (7-9) in the DNA binding pocket and predict that they are potent binders.Communicated by Ramaswamy H. Sarma.

Insights into the crystal structure investigation and virtual screening approach of quinoxaline derivatives as potent against c-Jun N-terminal kinases 1.

Quinoxaline derivatives are an important class of heterocyclic compounds in which N replaces one or more carbon atoms of the naphthalene ring and exhibit a wide spectrum of biological activities and therapeutic applications. As a result, we were encouraged to explore a new synthetic approach to quinoxaline derivatives. In this work, we synthesized two new derivatives namely, ethyl 4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (2) and 3-oxo-3,4-dihydroquinoxaline-2-carbohydrazide (3) respectively. Their structures were confirmed by single-crystal X-ray analysis. Hirshfeld surface (HS) analysis is performed to understand the nature and magnitude of intermolecular interactions in the crystal packing. Density functional theory using the wb97xd/def2-TZVP method was chosen to explore their reactivity, electronic stability and optical properties. Charge transfer (CT) and orbital energies were analyzed via natural population analysis (NPA), and frontier molecular orbital (FMO) theory. The calculated excellent static hyperpolarizability (ßo) indicates nonlinear optical (NLO) properties for 2 and 3. Both compounds show potent activity against c-Jun N-terminal kinases 1 (JNK 1) based on structural activity relationship studies, further subjected to molecular docking, molecular dynamics and ADMET analysis to understand their potential as drug candidates.Communicated by Ramaswamy H. Sarma.

Natural flavonoids as promising 6-phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments.

The primary strategy in the fight against cancer is to screen compounds that may be effective on different types of cancer. Compounds from plants seem to be a good source. The present study investigated the inhibitory effects of some flavonoids on the 6-phosphogluconate dehydrogenase (6-PGD) enzyme. We determined that quercetin, myricetin, fisetin, morin, apigenin, and baicalein exhibited powerful inhibition effects with IC50 values between 4.08 and 21.26 µM, while luteolin, kaempferol, apiin, galangin, and baicalin showed moderate effects with IC50 values between 54.15 and 138.91 µM. Quercetin competitively inhibited the binding of NADP and 6-phosphogluconate to the 6-PGD enzyme with Ki values of 0.527 ± 0.251 and 0.374 ± 0.138 µM, respectively. We calculated Ki values using the Cheng-Prusoff equation as between 0.44 and 14.88 µM. The possible interaction details of polyphenols with the active site of 6-PGD were analyzed with docking software. In silico and in vitro studies indicated that the -OH groups on the A and C ring of flavonoids bind to the enzyme's active site via hydrogen bonding, while the -OH groups on the C ring contributed significantly to the increase in the inhibitory potentials of the molecules. Molecular dynamic simulations tested the stability of the 6-PGD-quercetin complex during 100 ns. These phytochemicals were suitable for drug use when optimized with absorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria. The effects of the studied compounds on cancer cell lines of potential targets were demonstrated by network analysis. In conclusion, this study suggests that flavonoids found to be potent inhibitors could serve as leading candidates to treat many cancers via 6-PGD inhibition.

Tailored horseshoe-shaped nicotinonitrile scaffold as dual promising c-Met and Pim-1 inhibitors: Design, synthesis, SAR and in silico study.

For the horseshoe tactic to succeed in inhibiting c-Met and Pim-1, the nicotinonitrile derivatives (2a-n) were produced in high quantities by coupling acetyl phenylpyrazole (1) with the proper aldehydes and ethyl cyanoacetate under basic conditions. Consistent basic and spectroscopic data (NMR, IR, Mass, and HPLC) supported the new products' structural findings. With IC50 potency in nanomolar ranges, these compounds had effectively repressed them, particularly compounds 2d and 2 h, with IC50 values below 200 nM. The most potent compounds (2d and 2 h) were tested for their antitumor effects against prostate (PC-3), colon (HCT-116), and breast (MDA-MB-231) and were evaluated in comparison to the anticancer drug tivantinib using the MTT assay. Similar to tivantinib, these compounds showed good antiproliferative properties against the HCT-116 tumor cells while having low cytotoxicity towards healthy fetal colon (FHC) cells. In the HCT-116 cell line, their ability to trigger the apoptotic cascade was also investigated by looking at the level of Bax and Bcl-2 as well as the activation of the proteolytic caspase cascade. When HCT-116 cells were exposed to compounds 2d and 2 h in comparison to the control, active caspase-3 levels increased. The HCT-116 cell line also upregulated Bcl-2 protein levels and downregulated Bax levels. Additionally, when treated with compound 2d, the HCT-116 cell cycle was primarily stopped at the S phase. Compared to the control, compound 2d treatment significantly inhibited the protein expression levels of c-Met and Pim-1 kinases in the treated HCT-116 cells. Thorough molecular modeling analyses, such as molecular docking and dynamic simulation, were performed to ascertain the binding mechanism and stability of the target compounds.