Dispersions of magnetic nanoparticles in water/ionic liquid mixtures.

Nanoparticles (NPs) of iron oxide are dispersed in mixtures of water and ionic liquid, here ethylammonium nitrate (EAN), and the NP/NP and NP/solvent interactions are studied. They are analysed via small-angle X-ray scattering and dynamic light scattering coupled to forced Rayleigh scattering, from 22 °C to 80 °C. The NPs are well-dispersed as individual objects in the whole range of compositions and temperatures thanks to sufficient repulsion due to the organization of the solvents at the interface. The surface changes from hydrophilic to hydrophobic around a proportion of 50 vol% water : 50 vol% EAN, following the evolution of the bulk mixtures, which remain heterogeneous in the whole range of compositions.

Therapeutic drug monitoring in tuberculosis.

PURPOSE: Therapeutic drug monitoring (TDM) is a standard clinical procedure that uses the pharmacokinetic and pharmacodynamic parameters of the drug in the body to determine the optimal dose. The pharmacokinetic variability of the drug(s) is a significant contributor to poor treatment outcomes, including the development of acquired drug resistance. TDM aids in dose optimization and improves outcomes while lessening drug toxicity. TDM is used to manage patients with tuberculosis (TB) who exhibit a slow response to therapy, despite good compliance and drug-susceptible organisms. Additional indications include patients at risk of malabsorption or delayed absorption of TB drugs and patients with drug-drug interaction and drug toxicity, which confirm compliance with therapy. TDM usually requires two blood samples: the 2 h and the 6 h post-dose. This narrative review will discuss the pharmacokinetics and pharmacodynamics of TB drugs, determinants of poor response to therapy, indications of TDM, methods of performing TDM, and its interpretations. METHODS: This is a narrative review. We searched PubMed, Embase, and the CINAHL from inception to April 2024. We used the following search terms: tuberculosis, therapeutic drug monitoring, anti-TB drugs, pharmacokinetics, pharmacodynamics, limited sample strategies, diabetes and TB, HIV and TB, and multidrug-resistant TB. All types of articles were selected. RESULTS: TDM is beneficial in managing TB, especially in patients with slow responses, drug-resistance TB, recurrent TB, and comorbidities such as diabetes mellitus and human immunodeficiency virus infection. CONCLUSION: TDM is beneficial for improving outcomes, reducing the risk of acquired drug resistance, and avoiding side effects.

Exploring marine-derived bioactive compounds for dual inhibition of Pseudomonas aeruginosa LpxA and LpxD: integrated bioinformatics and cheminformatics approaches.

Pseudomonas aeruginosa can cause serious nosocomial infections. Targeting the biosynthesis of Lipid A, a major structural domain of lipopolysaccharide (LPS) in P. aeruginosa has emerged as a valuable strategy for developing novel therapeutic agents. The biosynthesis of Lipid A involves the activation of homolog enzymes including LpxA and LpxD. LpxA enzyme facilitates the transfer of R-3-hydroxydecanoic fatty acid to uridine diphosphate N-acetylglucosamine in the first step. While LPxD is accountable in third step, wherein R-3-hydroxydodecanoate is transferred to the 2' amine of UDP-3-O-(3-hydroxydecanoyl) utilizing an ACP donor. The exploration of LpxA and LpxD has been largely neglected, as no specific small-molecule inhibitors have been identified, thus far, except for peptide inhibitors. Here, we report the identification of potential dual inhibitors of the lipid A biosynthesis pathway that target both the LpxA and LpxD enzymes as novel antibiotic agents. Among the virtually screened 32,000 marine bioactive compounds Oscillatoxin A, NCI60_041046, and LTS0192263 exhibited optimal docking interactions with LpxA and LpxD, respectively. MD simulation and MMPBSA data showcased stable interactions between selected marine products and LpxA/LpxD. FMO analysis showed that Oscillatoxin A and NCI60_041046 are the most chemically active molecules. MEP analysis data highlighted the possible electrophilic and nucleophilic distribution zones present in the structure. In addition, these bioactive molecules showed acceptable ADMET profiles. These data confirmed that Oscillatoxin A, NCI60_041046, and LTS0192263 could serve as seeds for the development of potential therapeutics to combat P. aeruginosa infection.

Multifunctional Cell Regulation Activities of the Mussel Lectin SeviL: Induction of Macrophage Polarization toward the M1 Functional Phenotype.

SeviL, a galactoside-binding lectin previously isolated from the mussel Mytilisepta virgata, was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel ß-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.

Synthesis, Antimicrobial, Molecular Docking Against Bacterial and Fungal Proteins and In Silico Studies of Glucopyranoside Derivatives as Potent Antimicrobial Agents.

Carbohydrate derivatives play a crucial roles in biochemical and medicinal research, especially in the fields of chemistry and biochemistry. From this perspective, the present study was designed to explore the synthesis of methyl α-D-glucopyranoside derivatives (1-8), focusing on their efficacy against bacterial and fungal inhibition. The structure of the synthesized compounds was ascertained using FTIR, 1H-NMR, 13C-NMR, mass and elemental analyses. Antimicrobial screening revealed strong antifungal properties, with compound 7 exhibiting minimum inhibitory concentrations (MICs) ranging from 16-32 µg/L and minimum bactericidal concentrations (MBCs) ranging from 64-128 µg/L. Incorporating decanoyl acyl groups at C-2 and C-3 of (7) significantly improved the efficacy against bacteria and fungi. Structure-activity relationship (SAR) analysis indicated that adding nonanoyl and decanoyl groups to the ribose moiety enhanced potency against both bacterial and fungal strains. Computational methods, including molecular docking, density functional theory (DFT), Petra, Osiris, Molinspiration (POM) evaluation, and molecular dynamics (MD) simulations, were used to assess the efficacy of these derivatives. Compounds 6 and 7, which presented nonanoyl and decanoyl substituents, demonstrated greater efficacy. In addition, DFT studies identified compound 8 as possessing ideal electronic properties. Molecular docking revealed that compound 8 exhibits exceptional binding affinities to bacterial proteins, conferring potent antibacterial and antifungal activities. In addition, pharmacokinetic optimization via POM analysis highlighted compounds 1 and 2 as promising bioavailable drugs with minimal toxicity. Molecular dynamics simulations confirmed the stability of the 2-S. aureus complex, revealing the therapeutic potential of compounds 2 and 8. Future experiments are required to validate their efficacy for pharmaceutical development. The integration of in vitro and in silico methods, including DFT anchoring dynamics and molecular dynamics simulations, provides a solid framework for the advancement of effective anti-infective drugs.

Flavonoids as potential KRAS inhibitors: DFT, molecular docking, molecular dynamics simulation and ADMET analyses.

KRAS mutations linked with cancer. Flavonoids were docked against KRAS G12C and G12D receptors. Abyssinone III, alpha naphthoflavone, beta naphthoflavone, abyssinone I, abyssinone II and beta naphthoflavone, genistin, daidzin showed good docking scores against KRAS G12C and G12D receptors, respectively. The MD simulation data revealed that Rg, RMSD, RMSF, and SASA values were within acceptable limits. Alpha and beta naphthoflavone showed good binding energies with KRAS G12C and G12D receptors. DFT and MEP analysis highlighted the nucleophilic and electrophilic zones of best-docked flavonoids. A novel avenue for the control of KRAS G12C and G12D mutations is made possible by flavonoids.

In the present study, we computationally established the role of flavonoids as KRAS G12C and G12D inhibitors.Initially we selected 93 flavonoids and docked against 8AFB (KRAS G12C) and 7RT1 (KRAS G12D) using Sotorasib and MRTX 1133 as standards.A 100 ns MD simulation revealed that the radius of gyration, RMSD, RMSF, and SASA values were within acceptable limits and that there were a greater number of donors and acceptors for hydrogen bonds.In addition to the KRAS G12C 8AFB receptor, the maximum binding energy was shown by alpha Naphthoflavone (−26.471 kJ/mol), and for the KRAS G12D 7RT1 receptor, the maximum binding energy was shown by beta Naphthoflavone (−15.433 kJ/mol).FMO and MEP analysis data highlighted the best-docked flavonoids' potential areas for nucleophilic and electrophilic attacks.ADMET properties have been calculated and provide safe use and low toxicity for both aquatic and non-aquatic species.

Efficient Synthesis, Structural Characterization, Antibacterial Assessment, ADME-Tox Analysis, Molecular Docking and Molecular Dynamics Simulations of New Functionalized Isoxazoles.

This work describes the synthesis, characterization, and in vitro and in silico evaluation of the biological activity of new functionalized isoxazole derivatives. The structures of all new compounds were analyzed by IR and NMR spectroscopy. The structures of 4c and 4f were further confirmed by single crystal X-ray and their compositions unambiguously determined by mass spectrometry (MS). The antibacterial effect of the isoxazoles was assessed in vitro against Escherichia coli, Bacillus subtilis, and Staphylococcusaureus bacterial strains. Isoxazole 4a showed significant activity against E. coli and B. subtilis compared to the reference antibiotic drugs while 4d and 4f also exhibited some antibacterial effects. The molecular docking results indicate that the synthesized compounds exhibit strong interactions with the target proteins. Specifically, 4a displayed a better affinity for E. coli, S. aureus, and B. subtilis in comparison to the reference drugs. The molecular dynamics simulations performed on 4a strongly support the stability of the ligand-receptor complex when interacting with the active sites of proteins from E. coli, S. aureus, and B. subtilis. Lastly, the results of the Absorption, Distribution, Metabolism, Excretion and Toxicity Analysis (ADME-Tox) reveal that the molecules have promising pharmacokinetic properties, suggesting favorable druglike properties and potential therapeutic agents.

In vitro antimicrobial, anticancer evaluation, and in silico studies of mannopyranoside analogs against bacterial and fungal proteins: Acylation leads to improved antimicrobial activity.

Carbohydrate analogs are an important, well-established class of clinically useful medicinal agents that exhibit potent antimicrobial activity. Thus, we explored the various therapeutic potential of methyl α-D-mannopyranoside (MαDM) analogs, including their ability to synthesize and assess their antibacterial, antifungal, and anticancer properties; additionally, molecular docking, molecular dynamics simulation, and ADMET analysis were performed. The structure of the synthesized MαDM analogs was ascertained by spectroscopic techniques and physicochemical and elemental analysis. In vitro antimicrobial activity was assessed and revealed significant inhibitory effects, particularly against gram-negative bacteria along with the prediction of activity spectra for substances (PASS). Concurrently, MαDM analogs showed good results against antifungal pathogens and exhibited promising anticancer effects in vitro, demonstrating dose-dependent cytotoxicity against Ehrlich ascites carcinoma (EAC) cancer cells while sparing normal cells from compound 5, with an IC50 of 4511.65 µg/mL according to the MTT colorimetric assay. A structure-activity relationship (SAR) study revealed that hexose combined with the acyl chains of decanoyl (C-10) and benzenesulfonyl (C6H5SO2-) had synergistic effects on the bacteria and fungi that were examined. Molecular docking was performed against the Escherichia coli (6KZV) and Candida albicans (1EAG) proteins to acquire insights into the molecular interactions underlying the observed biological activities. The docking results were further supported by 100 ns molecular dynamics simulations, which provided a dynamic view of the stability and flexibility of complexes involving MαDM and its targets. In addition, ADMET analysis was used to evaluate the toxicological and pharmacokinetic profiles. Owing to their promising drug-like properties, these MαDM analogs exhibit potential as prospective therapeutic candidates for future development.

Unveiling potent Schiff base derivatives with selective xanthine oxidase inhibition: In silico and in vitro approach.

This research describes the synthesis by an environmentally-friendly method, microwave irradiation, development and analysis of three novel and one previously identified Schiff base derivative as a potential inhibitor of bovine xanthine oxidase (BXO), a key enzyme implicated in the progression of gout. Meticulous experimentation revealed that these compounds (10, 9, 4, and 7) have noteworthy inhibitory effects on BXO, with IC50 values ranging from 149.56 µM to 263.60 µM, indicating their good efficacy compared to that of the standard control. The validation of these results was further enhanced through comprehensive in silico studies, which revealed the pivotal interactions between the inhibitors and the catalytic sites of BXO, with a particular emphasis on the imine group (-C = N-) functionalities. Intriguingly, the compounds exhibiting the highest inhibition rates also showcase advantageous ADMET profiles, alongside encouraging initial assessments via PASS, hinting at their broad-spectrum potential. The implications of these findings are profound, suggesting that these Schiff base derivatives not only offer a new vantage point for the inhibition of BXO but also hold considerable promise as innovative therapeutic agents in the management and treatment of gout, marking a significant leap forward in the quest for more effective gout interventions.

Ion specific tuning of nanoparticle dispersion in an ionic liquid: a structural, thermoelectric and thermo-diffusive investigation.

Dispersions of charged maghemite nanoparticles (NPs) in EAN (ethylammonium nitrate) a reference Ionic Liquid (IL) are studied here using a number of static and dynamical experimental techniques; small angle scattering (SAS) of X-rays and of neutrons, dynamical light scattering and forced Rayleigh scattering. Particular insight is provided regarding the importance of tuning the ionic species present at the NP/IL interface. In this work we compare the effect of Li+, Na+ or Rb+ ions. Here, the nature of these species has a clear influence on the short-range spatial organisation of the ions at the interface and thus on the colloidal stability of the dispersions, governing both the NP/NP and NP/IL interactions, which are both evaluated here. The overall NP/NP interaction is either attractive or repulsive. It is characterised by determining, thanks to the SAS techniques, the second virial coefficient A2, which is found to be independent of temperature. The NP/IL interaction is featured by the dynamical effective charge ξeff0 of the NPs and by their entropy of transfer SNP (or equivalently their heat of transport ) determined here thanks to thermoelectric and thermodiffusive measurements. For repulsive systems, an activated process rules the temperature dependence of these two latter quantities.

Pharmacoinformatics and Breed-Based De Novo Hybridization Studies to Develop New Neuraminidase Inhibitors as Potential Anti-Influenza Agents.

Influenza represents a profoundly transmissible viral ailment primarily afflicting the respiratory system. Neuraminidase inhibitors constitute a class of antiviral therapeutics employed in the management of influenza. These inhibitors impede the liberation of the viral neuraminidase protein, thereby impeding viral dissemination from the infected cell to host cells. As such, neuraminidase has emerged as a pivotal target for mitigating influenza and its associated complications. Here, we apply a de novo hybridization approach based on a breed-centric methodology to elucidate novel neuraminidase inhibitors. The breed technique amalgamates established ligand frameworks with the shared target, neuraminidase, resulting in innovative inhibitor constructs. Molecular docking analysis revealed that the seven synthesized breed molecules (designated Breeds 1-7) formed more robust complexes with the neuraminidase receptor than conventional clinical neuraminidase inhibitors such as zanamivir, oseltamivir, and peramivir. Pharmacokinetic evaluations of the seven breed molecules (Breeds 1-7) demonstrated favorable bioavailability and optimal permeability, all falling within the specified parameters for human application. Molecular dynamics simulations spanning 100 nanoseconds corroborated the stability of these breed molecules within the active site of neuraminidase, shedding light on their structural dynamics. Binding energy assessments, which were conducted through MM-PBSA analysis, substantiated the enduring complexes formed by the seven types of molecules and the neuraminidase receptor. Last, the investigation employed a reaction-based enumeration technique to ascertain the synthetic pathways for the synthesis of the seven breed molecules.

Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson-Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis.

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: -9.9 kcal/mol), 6'-O-trans-para-coumaroyl geniposidic acid (dock score: -9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: -9.5 kcal/mol), Loganic acid 6'-O-beta-d-glucoside (dock score: -9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: -9.4), Loganic acid (dock score: -9.4 kcal/mol), and Amphicoside (dock score: -9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: -9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor's active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of -7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

Exploring Cinnamoyl-Substituted Mannopyranosides: Synthesis, Evaluation of Antimicrobial Properties, and Molecular Docking Studies Targeting H5N1 Influenza A Virus.

The pursuit of innovative combinations for the development of novel antimicrobial and antiviral medications has garnered worldwide interest among scientists in recent times. Monosaccharides and their glycosides, such as methyl α-d-mannopyranoside derivatives, play a significant role in the potential treatment of viral respiratory pathologies. This study was undertaken to investigate and assess the synthesis and spectral characterization of methyl α-d-mannopyranoside derivatives 2-6, incorporating various aliphatic and aromatic groups. The investigation encompassed comprehensive in vitro antimicrobial screening, examination of physicochemical properties, molecular docking analysis, molecular dynamics simulations, and pharmacokinetic predictions. A unimolar one-step cinnamoylation reaction was employed under controlled conditions to produce methyl 6-O-cinnamoyl-α-d-mannopyranoside 2, demonstrating selectivity at the C-6 position. This represented a pivotal step in the development of potential antimicrobial derivatives based on methyl α-d-mannopyranoside. Subsequently, four additional methyl 6-O-cinnamoyl-α-d-mannopyranoside derivatives were synthesized with reasonably high yields. The chemical structures of these novel analogs were confirmed through a thorough analysis of their physicochemical properties, elemental composition, and spectroscopic data. In vitro antimicrobial assays were conducted against six bacterial strains and two fungal strains, revealing promising antifungal properties of these methyl α-d-mannopyranoside derivatives in comparison to their antibacterial activity. Moreover, cytotoxicity testing revealed that the compounds are less toxic. Further supporting these findings, molecular docking studies were performed against the H5N1 influenza A virus, indicating significant binding affinities and nonbonding interactions with the target protein 6VMZ. Notably, compounds 4 (-7.2) and 6 (-7.0) exhibited the highest binding affinities. Additionally, a 100 ns molecular dynamics simulation was conducted to assess the stability of the complex formed between the receptor 6VMZ and methyl α-d-mannopyranoside derivatives under in silico physiological conditions. The results revealed a stable conformation and binding pattern within the stimulating environment. In silico pharmacokinetic and toxicity assessments of the synthesized molecules were performed using Osiris software (version 2.9.1). Compounds 4 and 6 demonstrated favorable computational and pharmacological activities, albeit with a low drug score, possibly attributed to their higher molecular weight and irritancy. In conclusion, this study showcases the synthesis and evaluation of methyl α-d-mannopyranoside derivatives as promising candidates for antimicrobial and antifungal agents. Molecular docking and dynamics simulations, along with pharmacological predictions, contribute to our understanding of their potential therapeutic utility, although further research may be warranted to address certain pharmacological aspects.

Marine-Derived Compounds as Potential Inhibitors of Hsp90 for Anticancer and Antimicrobial Drug Development: A Comprehensive In Silico Study.

Marine compounds constitute a diverse and invaluable resource for the discovery of bioactive substances with promising applications in the pharmaceutical development of anti-inflammatory and antibacterial agents. In this study, a comprehensive methodology was employed, encompassing pharmacophore modeling, virtual screening, in silico ADMET assessment (encompassing aspects of absorption, distribution, metabolism, excretion, and toxicity), and molecular dynamics simulations. These methods were applied to identify new inhibitors targeting the Hsp90 protein (heat shock protein 90), commencing with a diverse assembly of compounds sourced from marine origins. During the virtual screening phase, an extensive exploration was conducted on a dataset comprising 31,488 compounds sourced from the CMNPD database, characterized by a wide array of molecular structures. The principal objective was the development of structure-based pharmacophore models, a valuable approach when the pool of known ligands is limited. The pharmacophore model DDRRR was successfully constructed within the active sites of the Hsp90 crystal structure. Subsequent docking studies led to the identification of six compounds (CMNPD 22591, 9335, 10015, 360799, 15115, and 20988) demonstrating substantial binding affinities, each with values below -8.3 kcal/mol. In the realm of in silico ADMET predictions, five of these compounds exhibited favorable pharmacokinetic properties. Furthermore, molecular dynamics simulations and total binding energy calculations using MM-PBSA indicated that these marine-derived compounds formed exceptionally stable complexes with the Hsp90 receptor over a 100-nanosecond simulation period. These findings underscore the considerable potential of these novel marine compounds as promising candidates for anticancer and antimicrobial drug development.

Design, Synthesis, In Silico and POM Studies for the Identification of the Pharmacophore Sites of Benzylidene Derivatives.

Due to the uneven distribution of glycosidase enzyme expression across bacteria and fungi, glycoside derivatives of antimicrobial compounds provide prospective and promising antimicrobial materials. Therefore, herein, we report the synthesis and characterization of six novel methyl 4,6-O-benzylidene-α-d-glucopyranoside (MBG) derivatives (2-7). The structures were ascertained using spectroscopic techniques and elemental analyses. Antimicrobial tests (zone of inhibition, MIC and MBC) were carried out to determine their ability to inhibit the growth of different Gram-positive, Gram-negative bacteria and fungi. The highest antibacterial activity was recorded with compounds 4, 5, 6 and 7. The compounds with the most significant antifungal efficacy were 4, 5, 6 and 7. Based on the prediction of activity spectra for substances (PASS), compounds 4 and 7 have promising antimicrobial capacity. Molecular docking studies focused on fungal and bacterial proteins where derivatives 3 and 6 exhibited strong binding affinities. The molecular dynamics study revealed that the complexes formed by these derivatives with the proteins L,D-transpeptidase Ykud and endoglucanase from Aspergillus niger remained stable, both over time and in physiological conditions. Structure-activity relationships, including in vitro and in silico results, revealed that the acyl chains [lauroyl-(CH3(CH2)10CO-), cinnamoyl-(C6H5CH=CHCO-)], in combination with sugar, were found to have the most potential against human and fungal pathogens. Synthetic, antimicrobial and pharmacokinetic studies revealed that MBG derivatives have good potential for antimicrobial activity, developing a therapeutic target for bacteria and fungi. Furthermore, the Petra/Osiris/Molinspiration (POM) study clearly indicated the presence of an important (O1δ-----O2δ-) antifungal pharmacophore site. This site can also be explored as a potential antiviral moiety.

Repeat breeding: prevalence and potential causes in dairy cows at different milk pocket areas of Bangladesh.

The objective of this study was to figure out the prevalence and probable causes of repeat breeding (RB) in dairy cows. Hence, a cross-sectional study was conducted on randomly selected 265 dairy farms in Sirajganj, Bogura, Rangpur, Satkhira, and Munshiganj districts of Bangladesh from December 2018 to February 2019. Data were collected through a direct interview method using a survey questionnaire. The reproductive organs of repeat breeder cows were examined for pathological, infectious, and functional reasons, and genital tract abnormalities. Additionally, the influence of nutrition, season, and age on the frequency of RB was recorded. The prevalence of RB was 28% among the 3824 cows investigated. Among the total repeat breeder cases, 72.54% of RB cases were found in Holstein-Friesian crossbred, 23.90% in Jersey crossbred, 1.50% in Sahiwal crossbred, and 2.06% in indigenous cows. The prevalence of RB was significantly highest (P < 0.01) in Satkhira (44.35%) and lowest in the Munshiganj district (15.87%). Data indicated that a major proportion of cows significantly (P < 0.05) faced RB problems due to functional causes (34.18%), followed by pathological causes (28.01%), genital tract abnormalities (21.32%), and infectious causes (16.49%). Furthermore, the cows were remarkably (P < 0.001) affected in RB during the summer season and nutritional deficient diseases like milk fever (70%). Age (3-7 years) had a significant (P < 0.001) effect on the RB occurrence (90%) in crossbred cows. However, particular focus should be given to systematic breeding, balanced nutrition, artificial inseminator efficiency, and hygienic inseminating tools to reduce RB incidence in high-yielding crossbred cows.

Uridine Derivatives: Synthesis, Biological Evaluation, and In Silico Studies as Antimicrobial and Anticancer Agents.

Nucleoside analogs are frequently used in the control of viral infections and neoplastic diseases. However, relatively few studies have shown that nucleoside analogs have antibacterial and antifungal activities. In this study, a fused pyrimidine molecule, uridine, was modified with various aliphatic chains and aromatic groups to produce new derivatives as antimicrobial agents. All newly synthesized uridine derivatives were analyzed by spectral (NMR, FTIR, mass spectrometry), elemental, and physicochemical analyses. Prediction of activity spectra for substances (PASS) and in vitro biological evaluation against bacteria and fungi indicated promising antimicrobial capability of these uridine derivatives. The tested compounds were more effective against fungal phytopathogens than bacterial strains, as determined by their in vitro antimicrobial activity. Cytotoxicity testing indicated that the compounds were less toxic. In addition, antiproliferative activity against Ehrlich ascites carcinoma (EAC) cells was investigated, and compound 6 (2',3'-di-O-cinnamoyl-5'-O-palmitoyluridine) demonstrated promising anticancer activity. Their molecular docking against Escherichia coli (1RXF) and Salmonella typhi (3000) revealed notable binding affinities and nonbonding interactions in support of this finding. Stable conformation and binding patterns/energy were found in a stimulating 400 ns molecular dynamics (MD) simulation. Structure-activity relationship (SAR) investigation indicated that acyl chains, CH3(CH2)10CO-, (C6H5)3C-, and C2H5C6H4CO-, combined with deoxyribose, were most effective against the tested bacterial and fungal pathogens. Pharmacokinetic predictions were examined to determine their ADMET characteristics, and the results in silico were intriguing. Finally, the synthesized uridine derivatives demonstrated increased medicinal activity and high potential for future antimicrobial/anticancer agent(s).

Macromolecules: Synthesis, antimicrobial, POM analysis and computational approaches of some glucoside derivatives bearing acyl moieties.

Macromolecules i.e., carbohydrate derivatives are crucial to biochemical and medical research. Herein, we designed and synthesized eight methyl α-D-glucopyranoside (MGP) derivatives (2-8) in good yields following the regioselective direct acylation method. The structural configurations of the synthesized MGP derivatives were analyzed and verified using multiple physicochemical and spectroscopic techniques. Antimicrobial experiments revealed that almost all derivatives demonstrated noticeable antifungal and antibacterial efficacy. The synthesized derivatives showed minimum inhibitory concentration (MIC) values ranging from 0.75 µg/mL to 1.50 µg/mL and minimum bactericidal concentrations (MBCs) ranging from 8.00 µg/mL to 16.00 µg/mL. Compound 6 inhibited Ehrlich ascites carcinoma (EAC) cell proliferation by 10.36% with an IC50 of 2602.23 µg/mL in the MTT colorimetric assay. The obtained results were further rationalized by docking analysis of the synthesized derivatives against 4URO and 4XE3 receptors to explore the binding affinities and nonbonding interactions of MGP derivatives with target proteins. Compound 6 demonstrated the potential to bind with the target with the highest binding energy. In a stimulating environment, a molecular dynamics study showed that MGP derivatives have a stable conformation and binding pattern. The MGP derivatives were examined using POM (Petra/Osiris/Molinspiration) bioinformatics, and as a result, these derivatives showed good toxicity, bioavailability, and pharmacokinetics. Various antifungal/antiviral pharmacophore (Oδ-, O'δ-) sites were identified by using POM investigations, and compound 6 was further tested against other pathogenic fungi and viruses, such as Micron and Delta mutants of SARS-CoV-2.

Methyl ß-D-galactopyranoside esters as potential inhibitors for SARS-CoV-2 protease enzyme: synthesis, antimicrobial, PASS, molecular docking, molecular dynamics simulations and quantum computations.

Carbohydrate esters are significant in medicinal chemistry because of their efficacy for the synthesis of biologically active drugs. In the present study, methyl ß-D-galactopyranoside (MGP) was treated with various acyl halides to produce 6-O-acyl MGP esters by direct acylation method with an excellent yield. To obtain newer products for antimicrobial assessment studies, the 6-O-MGP esters were further modified into 2,3,4-tri-O-acyl MGP esters containing a wide variety of functionalities in a single molecular framework. The chemical structures of the newly synthesized compounds were elucidated by analyzing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) revealed that these MGP estes have promising antifungal functionality compared to their antibacterial activities. The antimicrobial tests demonstrated that the compounds 3 and 10 were the most potent against Bacillus subtilis and Escherichia coli strains, with the minimum inhibitory concentration (MIC) values ranging from 0.352 ± 0.02 to 0.703 ± 0.01 mg/ml and minimum bactericidal concentration (MBC) values ranging from 0.704 ± 0.02 to 1.408 ± 0.04 mg/ml. Density functional theory (DFT) at the B3LYP/3-21G level of theory was employed to enumerate, frontier orbital energy, enthalpy, free energy, electronic energy, MEP, dipole moment which evaluated the effect of certain groups (aliphatic and aromatic) on drug properties. They discovered that all esters were more thermodynamically stable than the parent molecule. Molecular docking is performed using AutoDock Vina to determine the binding affinities and interactions between the MGP esters and the SARS-CoV-2 main protease. The modified esters strongly interact with the prime Cys145, His41, MET165, GLY143, THR26, and ASN142 residues. The MGP esters' shape and ability to form multiple electrostatic and hydrogen bonds with the active site match other minor-groove binders' binding modes. The molecular dynamics simulation validates the molecular docking results. The pharmacokinetic characterization of the optimized inhibitor demonstrates that these MGP esters appear to be safer inhibitors and a combination of in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction and drug-likeness had promising results due to their improved kinetic properties. Structure activity relationships (SAR) study including in vitro and silico results revealed that the acyl chain, palmitoyl (C16) and 4-chlorobenzoyl (4.ClC6H4CO-) in combination with sugar were found the most potential activates against human and fungal pathogens. After all, our comprehensive computational and statistical analysis shows that these selected MGP esters can be used as potential inhibitors against the SARS-CoV-2.

Synthesis, antimicrobial, molecular docking and molecular dynamics studies of lauroyl thymidine analogs against SARS-CoV-2: POM study and identification of the pharmacophore sites.

Nucleoside precursors and nucleoside analogs occupy an important place in the treatment of viral respiratory pathologies, especially during the current COVID-19 pandemic. From this perspective, the present study has been designed to explore and evaluate the synthesis and spectral characterisation of 5́-O-(lauroyl) thymidine analogs 2-6 with different aliphatic and aromatic groups through comprehensive in vitro antimicrobial screening, cytotoxicity assessment, physicochemical aspects, molecular docking and molecular dynamics analysis, along with pharmacokinetic prediction. A unimolar one-step lauroylation of thymidine under controlled conditions furnished the 5́-O-(lauroyl) thymidine and indicated the selectivity at C-5́ position and the development of thymidine based potential antimicrobial analogs, which were further converted into four newer 3́-O-(acyl)-5́-O-(lauroyl) thymidine analogs in reasonably good yields. The chemical structures of the newly synthesised analogs were ascertained by analysing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi, along with the prediction of activity spectra for substances (PASS), indicated promising antibacterial functionality for these thymidine analogs compared to antifungal activity. In support of this observation, molecular docking experiments have been performed against the main protease of SARS-CoV-2, and significant binding affinities and non-bonding interactions were observed against the main protease (6LU7, 6Y84 and 7BQY), considering hydroxychloroquine (HCQ) as standard. Moreover, the 100 ns molecular dynamics simulation process was performed to monitor the behaviour of the complex structure formed by the main protease under in silico physiological conditions to examine its stability over time, and this revealed a stable conformation and binding pattern in a stimulating environment of thymidine analogs. Cytotoxicity determination confirmed that compounds were found less toxic. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. The POM analysis shows the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Overall, the current study should be of great help in the development of thymidine-based, novel, multiple drug-resistant antimicrobial and COVID-19 drugs.