Active Site Of Enzyme Research Articles

Comprehensive Chemical Analysis of the Methyl 3-Nitrogen-2,3-Dideoxysaccharides Derivatives with d-ribo-Configuration: Synthesis, Reactivity of HIV-1 Reverse Transcriptase Inhibitors.

This study extends previous research, particularly focusing on patented scientific objects No. ID: PL 240 353 B1, investigating the physicochemical properties of the methyl 3-azido- and 3-amino-2,3-dideoxysaccharides with a nucleoside scaffold similar to 3'-azidothymidine (AZT). The study utilizes multiwavelength spectrophotometric and potentiometric methods to evaluate the ionization of the saccharide units in aqueous solutions. pKa values, obtained from two independent methods, reveal significant sugar ionization effects on UV spectra with varying pH levels. Stability constants for divalent metal ion complexes (Cu2+ and Ni2+) with the saccharide isomers indicate that complex stoichiometries and stabilities are highly dependent on the configuration of sugar ring substituents. Spectrophotometric results show a descending order of CT-DNA-binding affinity: BRNH2OMe > BRN3OMe > ARN3OMe > ARNH2OMe, suggesting varied interaction strengths. Molecular docking of models of synthesized O-glycosides confirmed their potential as reverse transcriptase inhibitors. Among the derivatives tested, the compound BRN3OMe displays the highest interaction with the enzyme active site residues and DNA, suggesting it may possess the greatest efficacy. Our reported results highlight the promising inhibitory properties of novel O-glycosides against HIV reverse transcriptase, supporting their potential development as antiviral agents.

Antilipase and antioxidant activities of topiramate-phenolic acid conjugates: Computational modelling, synthesis, and in-vitro investigations.

A series of ten topiramate-phenolic acid conjugates (T1-T10) were synthesized, and evaluated for their pancreatic lipase inhibitory and antioxidant potentials. The design of the compounds reflected the structural attributes extracted from robust QSAR models developed for predicting the pancreatic lipase inhibition potency. Conjugate T4 competitively inhibited pancreatic lipase with IC50 value of 8.96μM, comparable to the standard drug, orlistat (IC50=11.68μM). Molecular docking of T4 into the active site of human PL (PDB ID: 1LPB) revealed strong binding score of -11.54kcal/mol. Molecular dynamics simulation of T4 complexed with pancreatic lipase, confirmed the role of phenolic acid core in stabilizing the ligand through hydrophobic interactions (maximum observed RMSD=3.77Å). Additionally, T4 with its LUMO (-0.20254) and HOMO (0.30502) values, abstracted from DFT studies, depicts considerable promise in the pursuit of selecting an effective enzyme inhibitor binding to the enzyme's active site and disrupting its catalytic function. The conjugation of topiramate with phenolic acids has imparted potential antioxidant properties to the synthesized conjugates especially T3, T4 and T5. Conclusively, with good safety profile as predicted from in silico ADMET studies, potent pancreatic lipase inhibition and free radical quenching, T4 stands taller as promising anti-obesity drug candidate.

Engineering high-activity crosslinked enzyme aggregates via SpyCatcher/SpyTag-mediated self-assembly.

Crosslinked Enzyme Aggregates (CLEAs) are favored for their operational stability and recyclability. However, the traditional CLEAs preparation may distort the enzyme's active site and reduce activity. Therefore, we developed a universally applicable crosslinked SpyCatcher scaffold system designed for the facile preparation of CLEAs. Four lysine residues were introduced to the N-terminus of SpyCatcher to enhance the crosslinking selectivity with glutaraldehyde. This scaffold subsequently enables the assembly of enzymes through the specific binding affinity between SpyTag and SpyCatcher. By precipitating SpyCatcher with (NH4)2SO4 at a 1:2 (v/v) ratio at 4°C for 1h, followed by crosslinking with glutaraldehyde at 25°C and 100rpm for 3h, the SpyCatcher scaffold achieved a crosslinking efficiency exceeding 90%. Utilizing this approach for the immobilization of SpyTaged enzymes to construct xylanase-CLEAs (X-CLEAs) and cellulase-CLEAs (C-CLEAs) highlighted the accurate construction the enzyme complex. Furthermore, C-CLEAs retained approximately 90% activity after 3cycles and over 50% activity after 10cycles, demonstrating good operational stability and reusability. C-CLEAs achieved a 1.6-fold more reducing sugars in corn stover hydrolysis compared to free enzymes. This suggests that the close proximity within CLEAs provided an advantage for the enzymatic cascade reaction, highlighting the potential application of CLEAs in various fields.

Purification, characterization, optimization, and docking simulation of alkaline protease produced by Brevibacillus agri SAR25 using fish wastes as a substrate.

Recycling of protein-rich environmental wastes and obtaining more valuable products from these recycled products is a topic of interest for researchers. This study aims to produce, purify, and characterize the physicochemical and structural properties of the protease enzyme produced from Brevibacillus agri SAR25 using salmon fish waste as substrate and also to evaluate the effect of protease on the chicken feather, enzyme-ligand interactions, and active site surface area. The production of protease was optimum on 50g/L fish waste, pH8, 40°C, 96h, and 150rpm. The alkaline protease was isolated using three-phase partitioning (TPP), a straightforward and efficient one-step method for purifying enzymes in industrial applications. TPP achieved a purification efficiency of 115% with a 3.1-fold increase in concentration. As a result, the molecular weight of the purified protease was determined to be 50kDa under optimal conditions of pH9 and 45°C. The 3D structure of the alkaline protease enzyme with the determined ligands was predicted by homology modeling using UCSF Chimera 1.17.3 software. Tween-20 ligand showed the best binding affinity by hydrogen bonding with amino acids 106A, Asn 133A, Gly 198, Asn 226, Glu 232 and hydrophobic interaction with His 135, Leu 283 in the active site of the alkaline protease enzyme, thus leading to the discovery of new semisynthetic enzymes of salmon fish waste. The activity and stability of Brevibacillus agri SAR25 alkaline protease over a wide range of temperatures and pH, and its relatively high stability in the presence of various metal ions, organic solvents, and surfactants indicate that it can be used as a biocatalyst for different industrial applications. This could lead to the creation of new enzymes made from recycled biological materials.

Anilino-1,4-naphthoquinones as potent mushroom tyrosinase inhibitors: in vitro and in silico studies

Tyrosinase, a pivotal enzyme in melanin synthesis, is a primary target for the development of depigmenting agents. In this work, in vitro and in silico techniques were employed to identify novel tyrosinase inhibitors from a set of 12 anilino-1,4-naphthoquinone derivatives. Results from the mushroom tyrosinase activity assay indicated that, among the 12 derivatives, three compounds (1, 5, and 10) demonstrated the most significant inhibitory activity against mushroom tyrosinase, surpassing the effectiveness of the kojic acid. Molecular docking revealed that all studied derivatives interacted with copper ions and amino acid residues at the enzyme active site. Molecular dynamics simulations provided insights into the stability of enzyme–inhibitor complexes, in which compounds 1, 5, and particularly 10 displayed greater stability, atomic contacts, and structural compactness than kojic acid. Drug likeness prediction further strengthens the potential of anilino-1,4-naphthoquinones as promising candidates for the development of novel tyrosinase inhibitors for the treatment of hyperpigmentation disorders.

In Silico Study Highlighting the Interactions Between the Active Sites of Steroidogenic Enzymes and Endocrine Disruptors Found in Daily Use Products

In Silico Study Highlighting the Interactions Between the Active Sites of Steroidogenic Enzymes and Endocrine Disruptors Found in Daily Use Products

Preservative effects and mechanism of condensed tannins from Cercis chinensis Bunge leaves on fresh-cut lotus root.

This study aimed to investigate the potential of condensed tannins isolated from Cercis chinensis Bunge leaves as natural preservatives for fruits and vegetables. The research demonstrated that C. chinensis leaves condensed tannins (CLCT) significantly delay the browning process and reduce nutritional loss in fresh-cut lotus roots. Prodelphinidins were identified as the primary component of CLCT through electrospray ionization mass spectrometry and high-performance liquid chromatography analyses, with minor proportions of procyanidins and high levels of galloylation. The structural units predominantly consisted of (epi)gallocatechin. CLCT exhibited substantial inhibitory activity against tyrosinase, which may involve interactions with copper ions at the enzyme's active site and alterations in enzyme conformation, resulting in reversible inhibition. Additionally, CLCT displayed remarkable antioxidant and antibacterial properties, effectively scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'- azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radicals and significantly inhibiting the growth of Pseudomonas aeruginosa and Staphylococcus aureus. Overall, the potential of CLCT as a natural preservative and tyrosinase inhibitor underscores its promising application in preserving fruits and vegetables.

Network pharmacology-integrated molecular modeling analysis of Aquilaria malaccensis L. (agarwood) essential oil phytocompounds.

A network pharmacology approach was used to construct comprehensive pharmacological networks, elucidating the interactions between agarwood compounds and key biological targets associated with cancer pathways. We have employed a combination of network pharmacology, molecular docking and molecular dynamics to unravel agarwood plants' active components and potential mechanisms. Reported 23 molecules were collected from the agarwood plants and considered to identify molecular targets. Further, we identified ten potent targets related to cancer through network pharmacology analysis. The key targets include EGFR, JUN, TP53, SRC, MAPK3, ACTB, GAPDH, AKT1, MYC and CTNNB1. The biological processes include the negative regulation of fibroblast proliferation, metabolic, oxidative, and more. Subsequently, molecular docking results have indicated that 7-isopropenyl-1, 4a-dimethyl-4, 4a, 5,6,7,8-hexahydro-3 H-naphthalen-2-one showed an excellent binding affinity for all ten targets. This is the first study; we employed a novel integrated approach that combines network pharmacology, molecular docking and molecular dynamics simulation (MDS). The GO and KEGG, pathway enrichment analyses, shed light on biological processes relevant to cancer treatment. Moreover, molecular docking studies results indicated that the molecule 7-isopropenyl-1,4a-dimethyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one exhibited strong binding affinity among all ten cancer targets, with a docking score ranging from - 9.9 to - 6.7kcal/mol and found to have hydrogen bond interaction with Lys168, Ser322, Thr336 and Ala946 residues. MDS sheds light on the stability of their binding, the longevity of their interactions, and their overall effect on the enzyme's active site throughout the simulation. The current work signifies the initial report using bioinformatics approaches to assess the anticancer properties of compounds derived from the agarwood plant.

Bixa orellana (Bixaceae) seeds as a potential source of bioactive compounds for modulating postprandial hyperglycemia.

α-Amylase (α-AMY) and α-glucosidase (α-GLU) inhibitors are important for controlling postprandial hyperglycemia (PHG). Bixa orellana (annatto) reported inhibitory activity against these enzymes because of its bioactive compound content. However, an understanding of its inhibitory mechanisms and metabolic profile is necessary to establish its therapeutic potential. The present study aimed to elucidate the inhibitory mechanisms of B. orellana extract (BOE) on α-AMY and α-GLU, identify and quantify its bioactive compounds using metabolomics (untargeted and targeted) analyses, and evaluate their interactions through in silico approaches. BOE exhibited IC50 values of 37.75 and 47.06 mg mL-1 for α-AMY and α-GLU, respectively, indicating mixed and competitive inhibition types. Thirty-six putative compounds were identified by untargeted metabolomics, mainly fatty acids (dethiobiotin, occidentalol, palmitic acid, norbixin, among others). The most significant biosynthetic pathways included secondary metabolites (unclassified), unsaturated fatty acids, phenylpropanoids and flavonoid metabolism. Eighteen compounds were identified and quantified by the targeted analysis, such as l-phenylalanine, gallic acid, protocatechuic acid and naringenin. In silico studies highlighted xanthoangelol, norbixin, myricetin and 26-hydroxybrassinolide as key compounds with the highest binding affinities to enzyme active sites. BOE effectively inhibited α-AMY and α-GLU, with gallic acid, naringenin, xanthoangelol, norbixin and 26-hydroxybrassinolide identified as key bioactive contributors. These findings provide molecular evidence of the inhibitory mechanisms of BOE and support its potential for PHG management and diabetes control. © 2024 Society of Chemical Industry.

Molecular modeling, synthesis and biological evaluation of caffeic acid based Dihydrofolate reductase inhibitors

Dihydrofolate reductase (DHFR) is an enzyme that plays a crucial role in folate metabolism, which is essential for cell growth and division. DHFR has been identified as a molecular target for numerous diseases due to its significance in various biological processes. DHFR inhibitors can disrupt folate metabolism by inhibiting DHFR, leading to the inhibition of cell growth. So, a series of caffeic acid derivatives were designed, synthesized, characterized and evaluated for their in vitro ability to inhibit DHFR, as well as their antimicrobial and anticancer properties. Among all synthesized compounds, compound CE11 exhibited the highest DHFR inhibitory activity, with an IC50 value of 0.048 µM, which is approximately four times more potent than methotrexate. Compound CE11 exhibited similar docking performance to methotrexate, binding to the same site and engaging key residues such as Glh30, Phe31, Phe34, and Ser59. It also fit snugly in the hydrophobic pocket of modeled protein. Moreover, substantial hydrophobic interactions were noted between the ligand and the hydrophobic amino acid residues of DHFR. This effectively secured the derivative within the restricted substrate cavity. Furthermore, compound CE11 demonstrated a significant anticancer activity against MCF-7 breast cancer cell line, with an IC50 value of 5.37 ± 0.16 µM. Compounds CE3 and CE15 displayed better antibacterial activity compared to trimethoprim and comparable to ampicillin against the gram-positive bacteria S. aureus. Moreover, compounds CE3 and CE15 have shown better antibacterial activity than standard trimethoprim, ampicillin and tetracycline against the gram-negative bacteria, particularly P. aeruginosa and E. coli. Molecular docking analysis of CE3 revealed that it firmly entrapped into the active site of enzyme through hydrophobic interaction with hydrophobic residues. Additionally, it forms hydrogen bonds with important amino acid residues Ala7, Asn18, and Thr121 with excellent docking score and binding energy (-9.9, -71.77 kcal/mol). These interactions might be contributed to the significant DHFR inhibition and antimicrobial activity. The generated model holds potential value in facilitating the development of a novel category of DHFR inhibitors as anticancer and antimicrobial agents.

Two highly selected mutations in the tandemly duplicated CYP6P4a and CYP6P4b genes drive pyrethroid resistance in Anopheles funestus in West Africa

BackgroundGaining a comprehensive understanding of the genetic mechanisms underlying insecticide resistance in malaria vectors is crucial for optimising the effectiveness of insecticide-based vector control methods and developing diagnostic tools for resistance management. Considering the heterogeneity of metabolic resistance in major malaria vectors, the implementation of tailored resistance management strategies is essential for successful vector control. Here, we provide evidence demonstrating that two highly selected mutations in CYP6P4a and CYP6P4b are driving pyrethroid insecticide resistance in the major malaria vector Anopheles funestus, in West Africa.ResultsContinent-wide polymorphism survey revealed escalated signatures of directional selection of both genes between 2014 and 2021. In vitro insecticide metabolism assays with recombinant enzymes from both genes showed that mutant alleles under selection exhibit higher metabolic efficiency than their wild-type counterparts. Using the GAL4-UAS expression system, transgenic Drosophila flies overexpressing mutant alleles exhibited increased resistance to pyrethroids. These findings were consistent with in silico predictions which highlighted changes in enzyme active site architecture that enhance the affinity of mutant alleles for type I and II pyrethroids. Furthermore, we designed two DNA-based assays for the detection of CYP6P4a-M220I and CYP6P4b-D284E mutations, showing their current confinement to West Africa. Genotype/phenotype correlation analyses revealed that these markers are strongly associated with resistance to types I and II pyrethroids and combine to drastically reduce killing effects of pyrethroid bed nets.ConclusionsOverall, this study demonstrated that CYP6P4a and CYP6P4b contribute to pyrethroid resistance in An. funestus and provided two additional insecticide resistance molecular diagnostic tools that would contribute to monitoring and better management of resistance.

Synthesis and molecular docking analysis of novel hydrazone and thiosemicarbazide derivatives incorporating a pyrimidine ring: exploring neuroprotective activity

The increasing global prevalence of Alzheimer’s disease necessitates the development of novel therapeutic approaches. Neurodegenerative diseases are associated with increased oxidative stress and levels of cholinesterase enzymes. Hence, the development of cholinesterase inhibitors and antioxidants may provide neuroprotective effects. Our study focused on the synthesis of a new series of hydrazone and thiosemicarbazide derivatives bearing a pyrimidine ring. The compounds of structures were characterized by FT-IR, 1H NMR, 13C NMR, and HR-MS spectroscopic methods. Compounds 3a and 4f were determined using COSY and HSQC spectra. Compared to the standard drug galantamine (IC50 = 4.82 ± 0.75 µM), compound 3d exhibited remarkable inhibitory activity against AChE (IC50 values of 20.15 ± 0.44 µM). This compound was more effective against BChE (IC50 = 36.42 ± 0.73 µM) than galantamine (IC50 = 45.54 ± 0.18 µM). Antioxidant assays revealed the robust antioxidant activity of compound 3d. Furthermore, docking studies have shown that the active site of enzymes interacts strongly with electron donors through hydrogen bonds, while the aromatic ring structure plays an active role in π interactions.

A Novel Platform Featuring Nanomagnetic Ligand Fishing Based on Fixed-Orientation Immobilized Magnetic Beads for Screening Potential Cyclooxygenase-2 Inhibitors from Panax notoginseng Leaves.

A novel screening platform based on an Fe3O4@C@PDA-Ni2+@COX-2 ligand fishing combination with high-performance liquid chromatography-mass spectrometry was first designed, synthesized, and employed to screen and identify COX-2 inhibitors from Panax notoginseng leaves. The obtained magnetic nanoparticles exhibit outstanding preconcentration ability that allows for controlling the enzyme orientation to avoid enzyme active site blocking, conformational changes, or denaturing during immobilization. The as-prepared Fe3O4@C@PDA-Ni2+@COX-2 composite was carefully characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectrometry (FT-IR), Xray powder diffraction (XRD), thermal gravimetric analyzer (TGA), vibrating sample magnetometer (VSM), and Zeta potential analysis. The analytical parameters influencing the magnetic solid-phase fishing efficiency were optimized by univariate and multivariate methods (Box-Behnken design) by testing a positive control and celecoxib with active and inactive COX-2. Under the optimized ligand fishing conditions, twelve potential COX-2 inhibitors were screened and characterized in Panax notoginseng leaves. The results indicate that the proposed method provides a simple, feasible, selective, and effective platform for the efficient screening and identification of active compounds from Chinese herbal medicine. It has guiding significance for the synthesis and development of novel anti-inflammatory drugs, and provides a reference for the efficient discovery of anti-inflammatory drugs or lead compounds from the complex system of Chinese herbal medicine.

Synthesis of Some Novel 4-bromobenzoic Acid Clubbed Hydrazone Schiff Base Derivatives as Potent α-amylase Inhibitors: In vitro and In silico Studies

Aims: Synthesis of novel 4-bromobenzoic acid-based hydrazone-Schiff base derivatives and to screen them for their α-amylase inhibitory activity. Objective: The biological activities of hydrazone-Schiff base compounds encouraged us to evaluate the synthesized derivatives (4-32) for in-vitro inhibition activity against the α-amylase enzyme. Methods: In current research work twenty-nine Schiff base derivatives (4-32) of 4-bromobenzoic acid were synthesized in worthy yields by treating various replaced aldehydes with 4- bromobenzohydrazide using methanol solvent in catalytic quantity of acetic acid. The products were structurally described through the support of several spectroscopic methods (EI-MS and 1HNMR) and finally evaluated against α-amylase enzyme. Results: All the made derivatives exhibited worthy inhibition potential from IC50 = 0.21 ± 0.01 to 5.50 ± 0.01 μM when equated to the usual acarbose drug having IC50 = 1.34 ± 0.01 μM. Compound 21 (IC50 = 0.21 ± 0.01 μM) was established as the most active inhibitor among the series better than standard. The structure-activity relationship study showed that the alteration in the activity of the produced products might be due to the attached position and nature of the substituents. Furthermore, in-silico study supported the effects of groups attached on the binding interaction with α-amylase enzyme. Conclusion: A series of substituted hydrazone Schiff bases based on 4-bromobenzoic acid were produced, confirmed the structures by EI-MS and 1H-NMR spectroscopic methods and lastly tested for their in-vitro α-amylase inhibitory potential. Among the series, twenty-four products indicated brilliant inhibition potential having IC50 values from 0.21 ± 0.01 to 1.30 ± 0.01 μM. The structure-activity relationship study showed that the alteration in the activity of the synthesized products might be due to the attached position and nature of the substituents. On the other hand, in silico studies advocated that the synthesized Schiff base derivatives have prevalent interactions of binding within the active site of the α-amylase enzyme, and because of their various attached substituent, their conformation is altered in the active site of the enzyme. The current study recognized a number of lead candidates derived from 4-bromobenzoic acid. Additional investigation of the synthesized derivatives for coming research to get novel α-amylase inhibitors.

Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide.

Designing new compounds from existing chemotherapeutic drugs to enhance inhibitory effects on tumor cells while overcoming multidrug resistance is one of the important strategies for new drug discovery in medicinal chemistry. A new series of urea and thiourea derivatives based on Lenalidomide as potential anticancer agents have been designed and synthesized. In vitro anticancer activity assay against Caki cancer cells and HUVEC endothelial cells revealed that 1-(4-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl]urea (11) exhibited the highest anticancer activity and selectivity in the series with IC50 values of 9.88 and 179.03 µM, respectively. Among the compounds, 11 showed significant HDAC1 inhibiton of 68.02 ± 2.44% at 10 µM concentration. TGF-β, Bax, Bcl-2 protein levels and scratch assay were analyzed in Caki cells. As a result, compound 11 induced apoptosis in Caki cells. In this study, it has been demonstrated that compound 11 can be a lead compound for further detailed investigation in renal cancer treatment. Through molecular docking studies, it was determined that the most active compound, 11, forms stable interactions with key residues in the enzyme's active site, particularly engaging in hydrogen bonds with GLY149 and coordinating with the zinc ion in the HDAC1 active site. These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.

Identification of the arachidonic acid 5-lipoxygenase and its function in the immunity of Apostichopus japonicus.

A number of studies have been demonstrated that arachidonate 5-lipoxygenase (ALOX-5) plays a role in regulating a range of physiological and pathological processes through the catalysis of leukotriene formation from arachidonic acid (ARA). The coding sequence of ALOX-5 from Apostichopus japonicus (Aj-ALOX-5) was successfully amplified, resulting in a 2028 bp ORF sequence that encodes 674 amino acids. A comparison of the amino acid sequence with those of other 5-lipoxygenases revealed that Aj-ALOX-5 has the N-terminal "PLAT domain" and C-terminal "lipoxygenase structural domain" characteristic of this enzyme family. The enzyme activity sites and Ca2⁺-binding sites exhibited high levels of conservation. The phylogenetic tree also indicated that Aj-ALOX-5 was closely related to starfish 5-lipoxygenase. The recombinant Aj-ALOX-5 (rAj-ALOX-5) was obtained through the exogenous expression of an engineered bacterium and purified using Ni2+-NTA. rAj-ALOX-5 was observed to catalyze ARA to produce 5-HPETE and LTA4, which indicated that the Aj-ALOX-5 protein belonged to the 5-lipoxygenase family. qRT-PCR demonstrated that Aj-ALOX-5 is widely distributed in tissues. Furthermore, the Aj-ALOX-5 mRNA and the production of 5-HETE were found to be significantly up-regulated in response to stress induced by Vibrio splendidus. Inhibition of Aj-ALOX-5 expression by the optimal caffeic acid resulted in a significant increase in mortality rates of sea cucumbers. Further investigation revealed that the production of 5-HPETE and NF-κB I was also significantly suppressed. It can be hypothesized that Aj-ALOX-5 plays an important role in the immune response of sea cucumbers by mediating the NF-κB I pathway.

Synthesis and characterization of novel Schiff base ligands and their Cu (II), Zn (II), Co (II), and Ni (II) complexes: DNA binding, antibacterial activity, and docking studies

In this paper, we describe the process of synthesizing and characterizing of cu (II), Ni (II), Co (II) and Zn (II) coordination compounds of 4,4’-((1E,1’E) -((4chloro-1,2phenylene) bis(azanylylidine)bis (methanylylidine)) bis (naphthalene-2-ol) [CAMD] Schiff base. Elemental analysis, molar conductance, spectral data (FT-IR, 1H NMR & 13C NMR, UV-visible, EPR, XRD and mass spectra), and thermogravimetric analysis (TGA) were used to establish their formation and validate their structures. All the complexes obtained as monomeric structure and the metal center moieties are four-coordinated with square planar geometry, according to the spectral analysis. Thermogravimetric analysis (TGA) was castoff to consider the decomposition of the complexes and Schiff base ligand. Herein, the calf thymus DNA (CT DNA) binding Goldfeather#12#kinships of complexes have been examined by UV–visible spectroscopy. All complexes interact with DNA through an intercalating way. In a series of dilution experiments with Kanamycin and Fluconazole as standards, the ligand and its metallic complexes (1-4) demonstrated antimicrobial activity against a variety of bacterial and fungal species, including Gram-positive (Staphylococcus aureus, Pseudomonas aeruginosa) and Gram-negative (Escherichia coli, Bacillus Subtilis, Salmonella Typhi), as well as fungal infections, as well as fungal infections, as well as fungal infections, as well as fungal infections, yeast infections, and yeast infections. The preliminary in vitro antimicrobial screening revealed that the newly synthesised Schiff base inhibits bacterial and fungal growth significantly, compared to standard drugs. Additionally in silico studies of molecular docking were also done for Schiff base ligand and its multiplexes in the active site of DNA Gyrase enzyme (PDB code:6TCK), demonstrating strong hydrogen bonding interactions of drug targets and can be used as antibacterial drugs angainst pathogens. The performance of complexes closely matched the reactivity order seen in in-vitro studies. Overall, the complexes are intriguing candidates for antimicrobial development. We intend to use these compounds in a therapeutic context. Synthesized substances were determined to be non-toxic after undergoing ADME/T analysis to assess their drug-likeness.

New 4-methanesulfonyloxy benzohydrazide derivatives as potential antioxidant and carbonic anhydrase I and II inhibitors: synthesis, characterization, molecular docking, dynamics & ADME studies

As an archetypal molecule, hydrazides have a crucial vital role in numerous applications, so hydrazide-related inhibitors, especially sulfur-enriched, are favored. In the present work, we designed, synthesized and characterized fifteen novel benzohydrazide derivatives containing 4-methanesulfonyloxy and arylidene building blocks with a four-step synthesis pathway. The inhibitory potential of the compounds was assessed using human carbonic anhydrases I and II (hCA I and II) isozymes and the results were compared to those of the standard inhibitor, acetazolamide (AZA). The antioxidant activity profiles for all compounds were also examined using various bioanalytical methods and the results were compared with the standards. The hCA I and II were the best inhibited by compounds 5f, 5g, and 5i with inhibition constants IC50 in the range 20.45–51.43 nM (AZA: IC50=218.38) for hCA I and 33.54–42.45 nM (AZA: IC50=44.39) for hCA II. Structure-activity relationships were also discussed and discovered that hCA I and II inhibition was unaffected by the presence of an electron-withdrawing or releasing group. This effectiveness was the only result of the sort of substituted group(s), which was located at the reagent. Molecular docking and dynamics simulations showed that compounds 5f, 5g, and 5i have strong and stable interactions with key amino acids and zinc ions in the active sites of enzymes, which supports their ability to block enzyme activity. In silico ADME studies predicted favorable drug-like properties and high human oral absorption for all synthesized compounds. In silico ADME studies predicted favorable drug-like properties and high human oral absorption for all synthesized compounds. These findings highlight the multifunctional potential of the synthesized benzohydrazide derivatives as hCA I and II inhibitors and antioxidants, paving the way for their further development and optimization for therapeutic applications.

Insights into the Mechanism of a Vanadium Bromoperoxidase from the Marine Macro‐Algae Corallina pilulifera for Biocatalytic Halogenation

AbstractVanadium haloperoxidases have been studied to understand their mechanism and halide specificity. Crystal structures of vanadium bromoperoxidase enzyme complexes from Corallina piluifera, with vanadate and bromide and with phosphate and chloride, show significant displacement of loop residues 336–338 upon halogen binding. This shows a “closed position” of Leu337 locking the bromide ion in a hydrophobic environment favoring the vanadium peroxide reaction with the halogen by retaining the resulting hypobromite in the enzyme active site. The bound cofactor exists as a mixture of free vanadate and histidine553‐vanadate adduct. A mutant enzyme Arg397Trp also has been crystallized with bound phosphate and its structure determined with and without the bound bromide ion. The precise positions of the bromine have been determined using its anomalous signal. The bromide binding site in the mutant enzyme is displaced by 2.5 Å resulting in a mixed population of the “open” and the “closed” forms of Leu337. This allows additional chloroperoxidase activity due to re‐positioning of the halogen ion 0.6 Å closer to the vanadate ion. These studies support the application of vanadium haloperoxidase enzymes for selective halogenation of important drug molecules.

Therapeutic Potential of Rare Sesterterpenoids from Aspergillus Variecolor Strain SDG and Docking Studies.

Ethyl acetate extract of the cultures of the soil-derived filamentous fungus, Aspergillus variecolor SDG strain from Nallamala forest resulted in the isolation of extremely rare sesterterpenoids, stellatic acid (1) and andilesin C (2). We report a thorough chemical characterization of these compounds using various spectroscopic techniques and evaluation of their in vitro preclinical therapeutic potential. Stellatic acid exhibits potent antioxidant activity with an IC50 of 38 μg/mL and significant anticancer activity against HeLa, HepG2, MCF7, and A549 cancer cell lines with an IC50 of 7-12 μM. On the other hand, andilesin C displayed moderate cytotoxicity against DU145 and B16F10 cancer cell lines but lacked antioxidant activity. Furthermore, the potential hypoglycemic property of stellatic acid was evaluated by measuring its inhibitory effect against α-glucosidase. It exhibited tenfold potency against yeast α-glucosidase (IC50 101.73 μg/mL) than mammalian α-glucosidase (IC50 1000.00 μg/mL). Docking studies were also performed to suggest the interaction mode of stellatic acid in the α-glucosidase enzyme active site. Notably, yeast α-glucosidase shows a higher affinity towards stellatic acid than mammalian α-glucosidase (3TOP). Thus, the in vitro preclinical study of stellatic acid suggests its potential efficacy in therapeutic drug development.