Simple approach to thieno[3,2-d]pyrimidines as new scaffolds of antimicrobial activities

6-(4-Chlorophenyl)-spiro[cyclohexane-1,2-thieno[3,2-d][1,3]oxazin]-4(1H)-one (1) was synthesized and used as a starting material for the synthesis of a novel series of spiro compounds having biologically active sulfonamide (2a-e) and 3-(4-acetylphenyl)-6-(4-chlorophenyl)-1H-spiro[cyclohexane-1,2-thieno[3,2-d]pyrimidine-4(3H)-one (3). Compound 2a was used as a key intermediate for the synthesis of sulfonyl carbothioamide derivatives (4a-c). Also, compound 3 was used as an intermediate for the synthesis of 3H-spiro[cyclohexane-1,2-thieno[3,2-d]pyrimidin]-3-yl]phenyl}-2-imino-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine-3-carbonitrile derivatives (5a-e), 3H-spiro[cyclohexane-1,2-thieno[3,2-d]pyrimidin]-3-yl]phenyl}-2-oxo-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine-3-carbonitrile derivatives (6a-e), and 4-[(2Z)-3-substituted-arylprop-2-enoyl]phenyl-1H-spiro[cyclohexane-1,2-thieno[3,2-d]pyrimidine derivatives (7a-e). Cyclocondensation of 7a-e with hydrazine hydrate produced 6-(4-chlorophenyl)-3-[4-(5-substituted aryl-4,5-dihydro-1H-pyrazol-3-yl)phenyl]-1H-spiro[cyclohexane-1,2-thieno-[3,2-d]pyrimidin]-4(3H)-ones (8a-e), but with hydroxylamine hydrochloride afforded the corresponding isoxazoline derivatives (9a-e). Also, cyclocondensation by thiourea afforded 2-thioxo-1,2-dihydropyrimidin-4-yl)-phenyl-spiro-{cyclohexanethieno[3,2-d]pyrimidin}-4-one derivatives (10a-e). The new compounds were investigated for antimicrobial activity. Compounds 2c, 8b, c, 9b and 10b were the most potent ones against both Gram-negative and Gram-positive bacteria. Compound 8c exhibited higher antifungal activity towards the examined fungi with MIC of 1–2 µmol mL–1 compared to ketoconazole (MIC 2–3 µmol mL–1)

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds

Application of codon usage and context analysis in genes up- or down-regulated in neurodegeneration and cancer to combat comorbidities

IntroductionNeurodegeneration and cancer present in comorbidities with inverse effects due to the expression of genes and pathways acting in opposition. Identifying and studying the genes simultaneously up or downregulated during morbidities helps curb both ailments together.MethodsThis study examines four genes. Three of these (Amyloid Beta Precursor Protein (APP), Cyclin D1 (CCND1), and Cyclin E2 (CCNE2) are upregulated, and one protein phosphatase 2 phosphatase activator (PTPA) is simultaneously downregulated in both disorders. We investigated molecular patterns, codon usage, codon usage bias, nucleotide bias in the third codon position, preferred codons, preferred codon pairs, rare codons, and codon context.ResultsParity analysis revealed that T is preferred over A, and G is preferred over C in the third codon position, suggesting composition plays no role in nucleotide bias in both the upregulated and downregulated gene sets and that mutational forces are stronger in upregulated gene sets than in downregulated ones. Transcript length influenced the overall %A composition and codon bias, and the codon AGG exerted the strongest influence on codon usage in both the upregulated and downregulated gene sets. Codons ending in G/C were preferred for 16 amino acids, and glutamic acid-, aspartic acid-, leucine-, valine-, and phenylalanine-initiated codon pairs were preferred in all genes. Codons CTA (Leu), GTA (Val), CAA (Gln), and CGT (Arg) were underrepresented in all examined genes.DiscussionUsing advanced gene editing tools such as CRISPR/Cas or any other gene augmentation technique, these recoded genes may be introduced into the human body to optimize gene expression levels to augment neurodegeneration and cancer therapeutic regimens simultaneously

In-silico studies to recognize repurposing therapeutics toward arginase-I inhibitors as a potential onco-immunomodulators

Rudolf Virchow was the first person to point out the important link between immune function and cancer. He did this by noticing that leukocytes were often found in tumors. Overexpression of arginase 1 (ARG1) and inducible nitric oxide synthase (iNOS) in myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) depletes both intracellular and extracellular arginine. TCR signalling is slowed as a result, and the same types of cells produce reactive oxygen and nitrogen species (ROS and RNS), which aggravates the situation. Human arginase I is a double-stranded manganese metalloenzyme that helps L-arginine break down into L-ornithine and urea. Thus, a quantitative structure-activity relationship (QSAR) analysis was performed to unearth the unrecognised structural aspects crucial for arginase-I inhibition. In this work, a balanced QSAR model with good prediction performance and clear mechanistic interpretation was developed using a dataset of 149 molecules encompassing a broad range of structural scaffolds and compositions. The model was made to meet OECD standards, and all of its validation parameters have values that are higher than the minimum requirements (R2tr = 0.89, Q2LMO = 0.86, and R2ex = 0.85). The present QSAR study linked structural factors to arginase-I inhibitory action, including the proximity of lipophilic atoms to the molecule’s centre of mass (within 3A), the position of the donor to the ring nitrogen (exactly 3 bonds away), and the surface area ratio. As OAT-1746 and two others are the only arginase-I inhibitors in development at the time, we have performed a QSAR-based virtual screening with 1650 FDA compounds taken from the zinc database. In this screening, 112 potential hit compounds were found to have a PIC50 value of less than 10 nm against the arginase-I receptor. The created QSAR model’s application domain was evaluated in relation to the most active hit molecules identified using QSAR-based virtual screening, utilising a training set of 149 compounds and a prediction set of 112 hit molecules. As shown in the Williams plot, the top hit molecule, ZINC000252286875, has a low leverage value of HAT i/i h* = 0.140, placing it towards the boundary of the usable range. Furthermore, one of 112 hit molecules with a docking score of −10.891 kcal/mol (PIC50 = 10.023 M) was isolated from a study of arginase-I using molecular docking. Protonated ZINC000252286875-linked arginase-1 showed 2.9 RMSD, whereas non-protonated had 1.8. RMSD plots illustrate protein stability in protonated and non-protonated ZINC000252286875-bound states. Protonated-ZINC000252286875-bound proteins contain 25 Rg. The non-protonated protein-ligand combination exhibits a 25.2-Rg, indicating compactness. Protonated and non-protonated ZINC000252286875 stabilised protein targets in binding cavities posthumously. Significant root mean square fluctuations (RMSF) were seen in the arginase-1 protein at a small number of residues for a time function of 500 ns in both the protonated and unprotonated states. Protonated and non-protonated ligands interacted with proteins throughout the simulation. ZINC000252286875 bound Lys64, Asp124, Ala171, Arg222, Asp232, and Gly250. Aspartic acid residue 232 exhibited 200% ionic contact. 500-ns simulations-maintained ions. Salt bridges for ZINC000252286875 aided docking. ZINC000252286875 created six ionic bonds with Lys68, Asp117, His126, Ala171, Lys224, and Asp232 residues. Asp117, His126, and Lys224 showed 200% ionic interactions. In protonated and deprotonated states, GbindvdW, GbindLipo, and GbindCoulomb energies played crucial role. Moreover, ZINC000252286875 meets all of the ADMET standards to serve as a drug. As a result, the current analyses were successful in locating a novel and potent hit molecule that inhibits arginase-I effectively at nanomolar concentrations. The results of this investigation can be used to develop brand-new arginase I inhibitors as an alternative immune-modulating cancer therapy

Target specific inhibition of West Nile virus envelope glycoprotein and methyltransferase using phytocompounds: an in silico strategy leveraging molecular docking and dynamics simulation

Mosquitoes are the primary vector for West Nile virus, a flavivirus. The virus’s ability to infiltrate and establish itself in increasing numbers of nations has made it a persistent threat to public health worldwide. Despite the widespread occurrence of this potentially fatal disease, no effective treatment options are currently on the market. As a result, there is an immediate need for the research and development of novel pharmaceuticals. To begin, molecular docking was performed on two possible West Nile virus target proteins using a panel of twelve natural chemicals, including Apigenin, Resveratrol, Hesperetin, Fungisterol, Lucidone, Ganoderic acid, Curcumin, Kaempferol, Cholic acid, Chlorogenic acid, Pinocembrin, and Sanguinarine. West Nile virus methyltransferase (PDB ID: 2OY0) binding affinities varied from −7.4 to −8.3 kcal/mol, whereas West Nile virus envelope glycoprotein affinities ranged from −6.2 to −8.1 kcal/mol (PDB ID: 2I69). Second, substances with larger molecular weights are less likely to be unhappy with the Lipinski rule. Hence, additional research was carried out without regard to molecular weight. In addition, compounds 01, 02, 03, 05, 06, 07, 08, 09, 10 and 11 are more soluble in water than compound 04 is. Besides, based on maximum binding affinity, best three compounds (Apigenin, Curcumin, and Ganoderic Acid) has been carried out molecular dynamic simulation (MDs) at 100 ns to determine their stability. The MDs data is also reported that these mentioned molecules are highly stable. Finally, advanced principal component analysis (PCA), dynamics cross-correlation matrices (DCCM) analysis, binding free energy and dynamic cross correlation matrix (DCCM) theoretical study is also included to established mentioned phytochemical as a potential drug candidate. Research has indicated that the aforementioned natural substances may be an effective tool in the battle against the dangerous West Nile virus. This study aims to locate a bioactive natural component that might be used as a pharmaceutical

Design, Synthesis and Evaluation of Novel Antimicrobial Polymers Based on the Inclusion of Polyethylene Glycol/TiO₂ Nanocomposites in Cyclodextrin as Drug Carriers for Sulfaguanidine

Polymers and their composites have recently attracted attention in both pharmaceutical and biomedical applications. Polyethylene glycol (PEG) is a versatile polymer extensively used in medicine. Herein, three novel PEG-based polymers that are pseudopolyrotaxane (PEG/α-CD) (1), titania–nanocomposite (PEG/TiO2NPs) (2), and pseudopolyrotaxane–titania–nanocomposite (PEG/α-CD/TiO2NPs) (3), were synthesized and characterized. The chemical structure, surface morphology, and optical properties of the newly materials were examined by FT-IR, 1H-NMR, SEM, and UV–Vis., respectively. The prepared polymers were used as drug carriers of sulfaguanidine as PEG/α-CD/Drug (4), PEG/TiO2NPs/Drug (5), and PEG/α-CD/TiO2NPs/Drug (6). The influence of these drug-carrying formulations on the physical and chemical characteristics of sulfaguanidine including pharmacokinetic response, solubility, and tissue penetration was explored. Evaluation of the antibacterial and antibiofilm effect of sulfaguanidine was tested before and after loading onto the prepared polymers against some Gram-negative and positive bacteria (E. coli, Pseudomonas aeruginosa, and Staphylococcus aureus (MRSA)), as well. The results of this work turned out to be very promising as they confirmed that loading sulfaguanidine to the newly designed polymers not only showed superior antibacterial and antibiofilm efficacy compared to the pure drug, but also modified the properties of the sulfaguanidine drug itself

Exploring the Antimicrobial and Pharmacological Potential of NF22 as a Potent Inhibitor of <i>E. coli</i> DNA Gyrase: An In Vitro and In Silico Study

Toward the search for novel antimicrobial agents to control pathogenic E. coli-associated infections, a series of novel norfloxacin derivatives were screened for antimicrobial activities. The norfloxacin derivative, 1-ethyl-6-fluoro-7-(4-(2-(2-(3-hydroxybenzylidene)hydrazinyl)-2-oxoethyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (NF22) demonstrated excellent antibacterial activities against E. coli ATCC 25922 (MIC = 0.0625 μg/mL) and MDR E. coli 1–3 (MIC = 1, 2 and 1 µg/mL). The time-kill kinetic studies have demonstrated that the NF22 was advantageous over norfloxacin and ciprofloxacin in killing the control and MDR E. coli strains. The checkerboard assay showed that NF22 in combination with tetracycline had a synergistic effect against the E. coli strains. The experimental findings are supported by molecular modeling studies on DNA gyrase, explaining the interactions involved for compound NF22, compared to norfloxacin and ciprofloxacin. Further, the compound was also evaluated for various pharmacokinetics (absorption, metabolism, distribution, toxicity and excretion) as well as drug-likeness properties. Our data have highlighted the potential of norfloxacin by restoring its efficacy against E. coli which could lead to the development of new antimicrobial agents

QSAR and Pharmacophore Modeling of Nitrogen Heterocycles as Potent Human N-Myristoyltransferase (Hs-NMT) Inhibitors

N-myristoyltransferase (NMT) is an important eukaryotic monomeric enzyme which has emerged as an attractive target for developing a drug for cancer, leishmaniasis, ischemia-reperfusion injury, malaria, inflammation, etc. In the present work, statistically robust machine leaning models (QSAR (Quantitative Structure–Activity Relationship) approach) for Human NMT (Hs-NMT) inhibitory has been performed for a dataset of 309 Nitrogen heterocycles screened for NMT inhibitory activity. Hundreds of QSAR models were derived. Of these, the model 1 and 2 were chosen as they not only fulfil the recommended values for a good number of validation parameters (e.g., R2 = 0.77–0.79, Q2LMO = 0.75–0.76, CCCex = 0.86–0.87, Q2-F3 = 0.74–0.76, etc.) but also provide useful insights into the structural features that sway the Hs-NMT inhibitory activity of Nitrogen heterocycles. That is, they have an acceptable equipoise of descriptive and predictive qualities as per Organisation for Economic Co-operation and Development (OECD) guidelines. The developed QSAR models identified a good number of molecular descriptors like solvent accessible surface area of all atoms having specific partial charge, absolute surface area of Carbon atoms, etc. as important features to be considered in future optimizations. In addition, pharmacophore modeling has been performed to get additional insight into the pharmacophoric features, which provided additional results

Halloysite nanotubes-enhanced epoxy acrylate latex emulsion as a novel anticorrosive protective coating for metal surface in 3.5% NaCl solution

Corrosion is a major problem that can lead to the degradation of metal structures. In this study, we developed a novel corrosion-protective coating for metal substrates based on a modified epoxy acrylate formulation reinforced with halloysite nanotubes (HNTs). Epoxy acrylate oligomers were first synthesized through the acrylation of epoxy using acrylic acid, followed by copolymerization with butyl methacrylate/vinyl acetate monomers to produce grafted epoxy acrylates (GEA). HNTs were then incorporated into the polymeric dispersion at weight loadings of 1%, 1.5%, and 2%. The corrosion resistance and waterproofing properties of the coatings were evaluated. The results showed that steel samples coated with HNTs-modified GEA showed no signs of rusting even after 16 days of immersion in a corrosive solution, whereas those coated with GEA alone showed rusting after only 9 days. These results demonstrate the effectiveness of HNTs-modified GEA coatings in protecting steel surfaces against corrosion. The coatings are also water-resistant and can be easily applied. This work provides a new approach to developing corrosion-protective coatings for metal substrates