Insights Into the Selective Imprinted Polymer of Voriconazole from Host-Guest Interaction Perspective

The incidence of fungal coinfections, such as Aspergillus spp., in patients with COVID-19 has been widely reported. Voriconazole is the first-line treatment for aspergillosis. A challenging sample preparation process is required to perform therapeutic drug monitoring of voriconazole. Recently, Molecularly Imprinted Polymers (MIP) have been shown to improve the separation selectivity for biological samples. Monomer selection in MIP is often performed by trial and error, without a design strategy. Therefore, this study aimed to construct a high-affinity MIP for voriconazole based on its interaction with functional monomers. All structures were optimized with B3LYP/6-311G++(d,p) and DFT-D3 dispersion correction method. Calculations of vacuum and solvated frequencies were carried out using a structure with maximum binding energy from molecular docking. The results showed that complex five was the most stable, exothermic, spontaneous, and enthalpy-driven among the complexes. In addition, there are nine intermolecular interactions and one moderate hydrogen bond in the QTAIM and NBO analysis, whereas hydrogen bonds, van der Waals interactions, and hydrophobic interactions were observed in the NCI-RDG analysis. The findings of this preliminary investigation showed that voriconazole possesses high stability when combined with functional monomers. It also provides information and assistance for further laboratory MIP synthesis.

Naphtho[2,1-b]furan derived triazole-pyrimidines as highly potential InhA and Cytochrome c peroxidase inhibitors: Synthesis, DFT calculations, drug-likeness profile, molecular docking and dynamic studies

Napthofuran and its fused heterocyclic derivatives evaluated with varied biological activity functional groups comprise an important class of compounds for new chemical entities. We here in reporting synthesis of new 3-(4-substituted phenyl)naphtho[1′,2′:4,5]furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidines 6(a-f). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and Mass. The DFT calculations were taken for the selected molecules using B3LYP hybrid functional with a 6–31+G (d, p) all-electron basis set using the Gaussian 09 package. The bioactivity predictions were evaluated for the synthesized compounds. The In vitro biological activities were reported for the all compounds 6(a-f). The compound 6a showed high activity of anti-TB and antioxidant activity with at MIC 1.6 μg/ml and at percentage of inhibition (72.54±0.21) at 10μg/ml respectively. The compound 6f (73.21±0.11) showed antioxidant activity better than standard drug BHA (71.32±0.13) at 10 μg/ml. Furthermore, the docking studies for the newly synthesized molecules were carried out by Auto dock software with proteins InhA (4TZK),Cytochrome c peroxidase (2 × 08) and protease (Mpro) of SARS-CoV-2 Omicron (PDB ID: 7TOB). All the compounds showed a strong binding affinity for the docked proteins. The outcome of docking results showed that compound 6ahad excellent binding energies -10.8, -9.4, and -9.0 kcal/mol with 4TZK, 2 × 08, and 7TOB respectively. Lastly, the protein stability, fluctuations of APO-Protein, protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified. © 2023

Fast-responsive and multi-applicable fluorescent turn-off chemodosimeter for monitoring hypochlorite: application to test strips, water samples, disinfectants and bioimaging

Due to the twin-demic of COVID-19 and flu virus, disinfectants containing ClO- have been widely used nowadays. Therefore, it is urgent to develop a sensor capable of efficiently detecting toxic hypochlorite. We present the invention and assessment of a fast-responsive and multi-applicable chemodosimeter sensor ETA (2-(2-((1E,2E)-3-(4-(dimethylamino)phenyl)allylidene)hydrazineyl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride) for monitoring ClO‑. In pure water, adding ClO- to ETA caused a turn-off fluorescence within 2 sec. These changes made it possible to quickly detect ClO- with a high level of selectivity. ETA displayed a low detection limit (0.68 μM) to ClO-. Using UV-vis titrations, ESI-MS and DFT calculations, we were able to demonstrate the detection mechanism, in which ETA was cleaved by ClO-. In particular, we established the possibility for reliable ClO- detection in environmental systems such as actual water samples, disinfectants, living cells, zebrafish and celery, in addition to confirming the practicality of ETA utilizing test strips.

Investigate the designing of eutectic mixture using DFT computation and evaluate their biological potency using molecular docking

Researchers are exploring the eutectic mixture because of their obvious great potential in various disciplines. Herein, authors have presented the DFT calculations, molecular docking and QSAR results for designed eutectic mixtures (EMs) using thiourea and resorcinol on taking different equivalent ratio. Authors have used Jakob et al. method to determine the melting temperature of the systems or EMs theoretically. Thermodynamic parameteres such as the free energy, enthalpy, and other energy of the EMs at room temperature are determined through DFT calculations using Gaussian. Authors have also calculated the physiochemical descriptors of various eutectic mixture based on DFT calculations. Further, molecular docking of the designed EMs is carried out to investigate their biological potential for inhibition of the Mpro of SARS-CoV-2. © 2023 Elsevier B.V.

Anti-SARS-CoV-2 Activity and Cytotoxicity of Amaryllidaceae Alkaloids from Hymenocallis littoralis.

The Amaryllidaceae species are well-known as a rich source of bioactive compounds in nature. Although Hymenocallis littoralis has been studied for decades, its polar components were rarely explored. The current phytochemical investigation of Amaryllidaceae alkaloids from H. littoralis led to the identification of three previously undescribed compounds: O-demethyl-norlycoramine (1), (-)-2-epi-pseudolycorine (2) and (+)-2-epi-pseudolycorine (3), together with eight known compounds: 6α-hydroxyhippeastidine (4), 6ß-hydroxyhippeastidine (5), lycorine (6), 2-epi-lycorine (7), zephyranthine (8), ungeremine (9), pancratistatin (10) and 9-O-demethyl-7-O-methyllycorenine (11). Among the eight previously reported compounds, five were isolated from H. littoralis for the first time (compounds 4, 5, 7, 8, and 9). Compounds 1, 4, 5, 7, 8, and 11 exhibited weak anti-SARS-CoV-2 activity (EC50 = 40-77 µM) at non-cytotoxic concentrations. Assessment of cytotoxicity on the Vero-E6 cell line revealed lycorine and pancratistatin as cytotoxic substances with CC50 values of 1.2 µM and 0.13 µM, respectively. The preliminary structure-activity relationship for the lycorine-type alkaloids in this study was further investigated, and as a result ring C appears to play a crucial role in their anti-SARS-CoV-2 activity.

DFT calculations, molecular docking, in vitro antimicrobial and antidiabetic studies of green synthesized Schiff bases: as Covid-19 inhibitor.

In this investigation, we synthesized Schiff bases 2-(2-methoxyphenoxy)-N-(4-methylbenzylidene)ethanamine, N-(4-methoxybenzylidene)-2-(2-methoxyphenoxy)ethanamine and 2-(2-methoxyphenoxy)-N-(4-nitrobenzylidene)ethanamine from 2-(2-methoxyphenoxy)ethanamine and various aromatic aldehydes by the environmentally friendly sonication method. The B3LYP method with a 6-311++G (d, p) basis set was used in the DFT calculation to obtain the optimized structure of the Schiff base MPEA-NIT. The compounds were tested in vitro for inhibition of bacterial growth (disc well method) and inhibition of α-amylase (starch-iodine method). The compounds tested showed inhibitory activities. In addition, they were subjected to PASS analysis, drug likeness, and bioactivity score predictions using online software. To confirm the experimental findings, molecular docking analyses of synthesized compounds on α-amylase (PDB ID: 1SMD), tRNA threonylcarbamoyladenosine (PDB ID: 5MVR), glycosyl transferase (PDB ID: 6D9T), and peptididoglycan D,D-transpeptidase (PDB ID: 6HZQ) were performed. The emergence of a new coronavirus epidemic necessitates the development of antiviral medications (SARS-CoV-2). Docking active site interactions were investigated to predict compounds' activity against COVID-19 by binding with the SARS-CoV-2 (PDB ID: 6Y84).Communicated by Ramaswamy H. Sarma.

Biological efficacy of novel metal complexes of Nitazoxanide: Synthesis, characterization, anti-COVID-19, antioxidant, antibacterial and anticancer activity studies.

It has been repeatedly reported that nitazoxanide (NTZ) exhibits a wide range of antiviral activities against various viral infections and has shown antimicrobial properties against anaerobic bacteria, helminths and protozoa. To improve these properties, three novel metal complexes were synthesized. The bidentate characteristic of the NTZ ligand was characterized by different spectroscopic techniques, including Fourier transform infrared (FT-IR), thermogravimetric, nuclear magnetic resonance (NMR) and UV - visible spectroscopy. The geometries of the formed compounds were evaluated by density functional theory, and the results revealed that NTZ-Ru(III) has an octahedral geometry, while NTZ-Au(III) and NTZ-Ag(I) complexes have distorted square planar structures. Binding between the metal complexes and calf thymus DNA (Ct-DNA) has been studied via absorption spectra. Moreover, human albumen serum (HAS) titration has been carried out to test their susceptibility to interact with a major target molecule via absorption and fluorescence spectroscopic techniques. Several in vitro bioassays were performed to evaluate the biological activity, antibacterial potency against E. coli, antioxidant activity and cytotoxicity of the ligand and the obtained complexes. The results showed that complexes Ru(III) and Au(III) have the highest radical scavenging percentage while the Ag(I) demonstrated the greatest antibacterial activity. Moreover, the metal complexes presented potentially effective against E. coli. Furthermore, compared with NTZ-Ag and the free ligand, the in vitro cytotoxicity assay showed that both NTZ-Ru(III) and NTZ-Au(III) exhibited significant anticancer activity against HeLa cells. The efficiency of the novel compounds as antivirals was tested by molecular docking with two COVID-19 receptors to obtain all interaction details.

Computational investigation of natural compounds as potential main protease (Mpro) inhibitors for SARS-CoV-2 virus.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly impacting human lives, overburdening the healthcare system and weakening global economies. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. The SARS-CoV-2 Main protease (Mpro) is considered an appealing target because of its role in replication in host cells. We curated a set of 7809 natural compounds by combining the collections of five databases viz Dr Duke's Phytochemical and Ethnobotanical database, IMPPAT, PhytoHub, AromaDb and Zinc. We applied a rigorous computational approach to identify lead molecules from our curated compound set using docking, dynamic simulations, the free energy of binding and DFT calculations. Theaflavin and ginkgetin have emerged as better molecules with a similar inhibition profile in both SARS-CoV-2 and Omicron variants.

Fabrication, DFT Calculation, and Molecular Docking of Two Fe(III) Imine Chelates as Anti-COVID-19 and Pharmaceutical Drug Candidate.

Two tetradentate dibasic chelating Schiff base iron (III) chelates were prepared from the reaction of 2,2'-((1E,1'E)-(1,2-phenylenebis(azanylylidene))bis(methanylylidene))bis(4-bromophenol) (PDBS) and 2,2'-((1E,1'E)-((4-chloro-1,2-phenylene)bis(azanylylidene))-bis(methanylylidene))bis(4-bromophenol) (CPBS) with Fe3+ ions. The prepared complexes were fully characterized with spectral and physicochemical tools such as IR, NMR, CHN analysis, TGA, UV-visible spectra, and magnetic moment measurements. Moreover, geometry optimizations for the synthesized ligands and complexes were conducted using the Gaussian09 program through the DFT approach, to find the best structures and key parameters. The prepared compounds were tested as antimicrobial agents against selected strains of bacteria and fungi. The results suggests that the CPBSFe complex has the highest activity, which is close to the reference. An MTT assay was used to screen the newly synthesized compounds against a variety of cell lines, including colon cancer cells, hepatic cellular carcinoma cells, and breast carcinoma cells. The results are expressed by IC50 value, in which the 48 µg/mL value of the CPBSFe complex indicates its success as a potential anticancer agent. The antioxidant behavior of the two imine chelates was studied by DPPH assay. All the tested imine complexes show potent antioxidant activity compared to the standard Vitamin C. Furthermore, the in vitro assay and the mechanism of binding and interaction efficiency of the tested samples with the receptor of COVID-19 core protease viral protein (PDB ID: 6lu7) and the receptor of Gram-negative bacteria (Escherichia coli, PDB ID: 1fj4) were investigated using molecular docking experiments.

Synthesis, characterized, QSAR studies and molecular docking of some phosphonates as COVID-19 inhibitors.

The global coronavirus (COVID-19) outbreak has prompted scientists to discover a cure for the disease. So far, phosphorus-based drugs have been proposed. These drugs have good inhibitory activity against the main protease (Mpro). Hence, in order to introduce a group of inhibitors the coronavirus, 51 compounds containing different mono, bis, and tetra phosphonates as Remdesivir derivatives, 32 of which are new, were synthesized and characterized by 31P, 13C, and 1H NMR and IR spectroscopy. Their biological activities were also investigated by Molecular Docking, QSAR, and Pharmacophore. Van der Waals, hydrogen bonding, and hydrophobic interactions were studied for all compounds as well as binding energy (△G, Kcal/mole) and the inhibitory constant Ki (µM) obtained by Molecular Docking. The results showed that the topology of the ligands and the change of the different groups attached to them can be effective in the placement position in the active site of the enzyme (Glu 166 and Gln 189). And bisphosphonates have a high interaction tendency with Mpro COVID-19. Compound L24 was identified as the best inhibitor with the -6.38 kcal/mol binding energy. The quantitative structure-activity relationship (QSAR) findings demonstrated that the polarity and topology of molecules in all phosphonate derivatives were important parameters affecting the effecting on the binding energy and inhibitory ability of compounds. The DFT and pharmacophore results are in good accordance with those of QSAR and molecular docking. This study can be helpful to gain a better understanding of the interactions between the Mpro of virus and its inhibitors in order to attain drugs with more effect on coronavirus (COVID-19).

Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives.

Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained by cyclocondensation of 5,6-diaminouracils 1a-c with different oxazolones in glacial acetic acid. Moreover, 5,6-diaminouracils 1a-e were reacted with oxazolones 2a-c in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives 6-13. Furthermore, Schiff base of compounds 14-16 were obtained by condensing 5,6-diaminouracils 1a,b,e with 4-dimethylaminobenzaldehyde in acetic acid. The structural identity of the resulting compounds was resolved by IR, 1H-, 13C-NMR and Mass spectral analyses. The novel synthesized compounds were screened for their antifungal and antibacterial activities. Compounds 3, 6, 13 and 16 displayed the highest activity against Escherichia coli as revealed from the IC50 values (1.8-1.9 µg/mL). The compound 16 displayed a significant antifungal activity against Candia albicans (0.82 µg/mL), Aspergillus flavus (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds 3, 12, 13 and 16 exhibited a strong deformation to the cellular entities, by interfering with the cell membrane components, causing cytosol leakage, cellular shrinkage and irregularity to the cell shape. In addition, docking study for the most promising antimicrobial tested compounds depicted high binding affinity against acyl carrier protein domain from a fungal type I polyketide synthase (ACP), and Baumannii penicillin- binding protein (PBP). Moreover, compound 12 showed high drug- likeness, and excellent pharmacokinetics, which needs to be in focus for further antimicrobial drug development. The most promising antimicrobial compounds underwent theoretical investigation using DFT calculation.

Advancing insights on ß-cyclodextrin inclusion complexes with SSRIs through lens of X-ray diffraction and DFT calculation.

Depression-the global crisis hastened by the coronavirus outbreak, can be efficaciously treated by the selective serotonin reuptake inhibitors (SSRIs). Cyclodextrin (CD) inclusion complexation is a method of choice for reducing side effects and improving bioavailability of drugs. Here, we investigate in-depth the ß-CD encapsulation of sertraline (STL) HCl (1) and fluoxetine (FXT) HCl (2) by single-crystal X-ray diffraction and DFT complete-geometry optimization, in comparison to the reported complex of paroxetine (PXT) base. X-ray analysis unveiled the 2:2 ß-CD-STL/FXT complexes with two drug molecules inserting their halogen-containing aromatic ring in the ß-CD dimeric cavity, which are stabilized by the interplay of intermolecular O2-H⋯N1-H⋯O3 H-bonds, C3/C5-H⋯π and halogen⋯halogen interactions. Similarly, the 1:1 ß-CD-tricyclic-antidepressant (TCA) complexes have an exclusive inclusion mode of the aromatic ring, which is maintained by C3/C5-H⋯π interactions. By contrast, the 2:1 ß-CD-PXT complex has a total inclusion that is stabilized by host-guest O6-H⋯N1-H⋯O5 H-bonds and C3-H⋯π interactions. The inherent stabilization energies of 1 and 2 evaluated using DFT calculation suggested that the improved thermodynamic stabilities via CD encapsulation facilitates the reduction of drug side effects. Moreover, the SSRI conformational flexibilities are thoroughly discussed for understanding of their pharmacoactivity.

Distinctive Supramolecular Features of ß-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation.

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the ß-CD-TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the ß-CD-TCA stability spectrum based on binding constants (Kas) in solution, ß-CD-protriptyline (PRT) 1-most stable and ß-CD-maprotiline (MPL) 2-least stable. X-ray crystallography unveiled that in the ß-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C-H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH2-CH2- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round ß-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔEstbs), although the complex stability orders based on Kas and ΔEstbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the ß-CD cavity, suggesting the potential application of CDs for efficient drug delivery.