Multiple spectroscopic and computational studies on binding interaction of 2-phenylamino-4-phenoxyquinoline derivatives with bovine serum albumin.

Binding characteristics of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 4-(2',6'-dimethyl-4'-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (1) and 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (2), to bovine serum albumin (BSA) under simulative physiological conditions were investigated by multiple spectroscopic and computational methods. The experimental results demonstrated that (1) and (2) bound to BSA at site III (subdomain IB), and quenched BSA fluorescence through a static quenching process. The binding interaction of (1) or (2) to BSA forms stable complexes with the binding constants (Kb) at the level of 104 L/mol and the number of binding site was determined to be 1 for both systems, indicating that new synthesized compounds occupied one site in BSA with moderate binding affinities. Based on the analysis of the thermodynamic parameters, it can be indicated that the main binding forces for interaction between BSA and both compounds were hydrogen bonding and van der Waals force. Synchronous fluorescence results revealed that the interaction of two compounds with BSA led to modifications in the microenvironment surrounding tryptophan residue of BSA. Circular dichroism spectra demonstrated alterations in the secondary structure of BSA induced by (1) and (2). Moreover, the experimental data of molecular docking and molecular dynamics (MD) simulations supported the results obtained from multiple spectroscopic techniques, confirming the binding interactions between both compounds and BSA.

Allicin and Capsaicin Ameliorated Hypercholesterolemia by Upregulating LDLR and Downregulating PCSK9 Expression in HepG2 Cells.

Hypercholesterolemia is a common cause of cardiovascular diseases (CVDs). Although allicin and capsaicin possess hypolipidemic effects through several molecular mechanisms, their effects on LDLR and PCSK9 expression are still unknown. This study aimed to investigate the effects of allicin and capsaicin on LDLR and PCSK9 expression in HepG2 cells. The effects of allicin and capsaicin on cell viability were evaluated by MTT assay and trypan blue exclusion assay. Low-density lipoprotein receptor (LDLR) levels and LDL uptake were determined by flow cytometry and confocal laser scanning microscopy (CLSM), respectively. RT-qPCR and Western blot analyses were performed to evaluate the expression of PCSK9, LDLR, SREBP-2, and HNF1α. ELISA was used to measure PCSK9 levels in culture media. Allicin and capsaicin increased the protein expression levels of LDLR via activation of the transcription factor SREBP2. However, allicin and capsaicin decreased the expression of PCSK9 protein and the secretion of PCSK9 in culture media via the suppression of HNF1α. Moreover, allicin and capsaicin increased LDL uptake into HepG2 cells. The efficacies of the hypolipidemic effects of allicin (200 µM) and capsaicin (200 µM) were comparable to that of atorvastatin (10 µM) in this study. In conclusion, allicin and capsaicin possessed hypolipidemic effects via the upregulation of LDLR and downregulation of PCSK9 expression, thereby enhancing LDL uptake into HepG2 cells. This indicates that allicin and capsaicin should be used as potent supplements to ameliorate hypercholesterolemia.

One-Pot and Green Preparation of Phyllanthus emblica Extract/Silver Nanoparticles/Polyvinylpyrrolidone Spray-On Dressing.

A spray-on wound dressing has many benefits, including easy and quick administration to broad and uneven wounds, better interface with the wound site, adhesion without additional dressing, and multiple applications in a portable package. By limiting direct contact with the wound site, such a design can prevent wound damage during treatment. This study revealed a simple, one-pot synthesis of spray-on wound dressing relying on polyvinylpyrrolidone solution incorporating silver nanoparticles as a broad-spectrum antibacterial agent and wound-healing antioxidant Phyllanthus emblica extract. Silver nanoparticles were synthesized in situ using Phyllanthus emblica extract as a biogenic reducing agent. Polyvinylpyrrolidone was employed as a film-forming agent to create an adhesive hydrogel-based dressing matrix to provide moisture and establish a shielding barrier for the wound bed as well as to regulate the release of fruit extract. In vitro tests revealed that the produced dressing film had a controlled release of the fruit extract, high antioxidant activity, and a good antibacterial action against S. aureus, P. aeruginosa, E. coli, and MRSA. Additionally, a biocompatibility study has shown that both human fibroblasts and keratinocytes are unaffected by the dressing film. Based on established findings, the current spray-on solution might be a potential option for antibacterial wound dressing.

Computational Screening of Phenylamino-Phenoxy-Quinoline Derivatives against the Main Protease of SARS-CoV-2 Using Molecular Docking and the ONIOM Method.

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from -7.06 to -10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.

Structural Basis of 2-Phenylamino-4-phenoxyquinoline Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.

New target molecules, namely, 2-phenylamino-4-phenoxyquinoline derivatives, were designed using a molecular hybridization approach, which was accomplished by fusing the pharmacophore structures of three currently available drugs: nevirapine, efavirenz, and rilpivirine. The discovery of disubstituted quinoline indicated that the pyridinylamino substituent at the 2-position of quinoline plays an important role in its inhibitory activity against HIV-1 RT. The highly potent HIV-1 RT inhibitors, namely, 4-(2',6'-dimethyl-4'-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6b) and 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6d) exhibited half-maximal inhibitory concentrations (IC50) of 1.93 and 1.22 µM, respectively, which are similar to that of nevirapine (IC50 = 1.05 µM). The molecular docking results for these two compounds showed that both compounds interacted with Lys101, His235, and Pro236 residues through hydrogen bonding and interacted with Tyr188, Trp229, and Tyr318 residues through π-π stacking in HIV-1 RT. Interestingly, 6b was highly cytotoxic against MOLT-3 (acute lymphoblastic leukemia), HeLA (cervical carcinoma), and HL-60 (promyeloblast) cells with IC50 values of 12.7 ± 1.1, 25.7 ± 0.8, and 20.5 ± 2.1 µM, respectively. However, 6b and 6d had very low and no cytotoxicity, respectively, to-ward normal embryonic lung (MRC-5) cells. Therefore, the synthesis and biological evaluation of 2-phenylamino-4-phenoxyquinoline derivatives can serve as an excellent basis for the development of highly effective anti-HIV-1 and anticancer agents in the near future.

Zingiber cassumunar Roxb. Essential Oil-Loaded Electrospun Poly(lactic acid)/Poly(ethylene oxide) Fiber Blend Membrane for Antibacterial Wound Dressing Application.

The essential oil from Zingiber cassumunar Roxb. (Plai) has long been used in Thai herbal remedies to treat inflammation, pains, sprains, and wounds. It was therefore loaded into an electrospun fibrous membrane for use as an analgesic and antibacterial dressing for wound care. The polymer blend between poly(lactic acid) and poly(ethylene oxide) was selected as the material of choice because its wettability can be easily tuned by changing the blend ratio. Increasing the hydrophilicity and water uptake ability of the material while retaining its structural integrity and porosity provides moisture balance and removes excess exudates, thereby promoting wound healing. The effect of the blend ratio on the fiber morphology and wettability was investigated using scanning electron microscopy (SEM) and contact angle measurement, respectively. The structural determination of the prepared membranes was conducted using Fourier-transform infrared spectroscopy (FTIR). The release behavior of (E)-1-(3,4-dimethoxyphenyl) butadiene (DMPBD), a marker molecule with potent anti-inflammatory activity from the fiber blend, showed a controlled release characteristic. The essential oil-loaded electrospun membrane also showed antibacterial activity against S. aureus and E. coli. It also exhibited no toxicity to both human fibroblast and keratinocyte cells, suggesting that the prepared material is suitable for wound dressing application.

Binding interaction of potent HIV-1 NNRTIs, amino-oxy-diarylquinoline with the transport protein using spectroscopic and molecular docking.

In the present investigation, the intermolecular interaction of 4-(4'-cyanophenoxy)-2-(4''-cyanophenyl)-aminoquinoline (1), a potent non-nucleoside HIV-1 reverse transcriptase inhibitors, with the transport proteins, namely bovine serum albumin (BSA) and human serum albumin (HSA), has been investigated under physiological conditions employing UV-Vis, fluorescence spectrophotometry, competitive binding experiments and molecular docking methods. The results indicated that binding of (1) to the transport proteins caused fluorescence quenching though a static quenching mechanism. The number of binding site (n) and the apparent binding constant (Kb) between (1) and the transport proteins were determined to be about 1 and 104-105 L·mol-1 (at three different temperatures; 298, 308, 318 K), respectively. The interaction of (1) upon binding to the transport proteins was spontaneous. The enthalpic change (ΔH°) and the entropic change (ΔS°) were calculated to be -56.50 kJ·mol-1, -72.31 J·mol-1 K-1 for (1)/BSA, respectively and computed to be -49.35 kJ·mol-1, -58.64 J·mol-1 K-1, respectively for (1)/HSA, respectively. The results implied that the process of interaction force of (1) with the transport protein were Vander Waals force and/or hydrogen bonding interactions. The site maker competitive experiments revealed that the binding site of (1) with the transport proteins were mainly located within site I (sub-domain IIA) in both proteins. Additionally, the molecular docking experiment supported the above results which confirmed the binding interaction between (1) and the transport proteins. This study will come up with basic data for explicating the binding mechanisms of (1) with the transport protein and can be great significance in the opening to clarify the transport process of (1) in vivo.

Molecular Docking Studies and Synthesis of Amino-oxy-diarylquinoline Derivatives as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors.

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(A-D): interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8A: and 8D: were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8A: was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.

(-)-crebanine.

THE ASYMMETRIC UNIT OF THE TITLE COMPOUND [SYSTEMATIC NAME: 9,10-dimeth-oxy-7-methyl-6,7,7a,8-tetra-hydro-5H-benzo[g][1,3]benzodioxolo[6,5,4-de]quinoline], C(20)H(21)NO(4), contains two independent mol-ecules with very similar bond lengths and angles. The crystal packing exhibits voids of 131 Å(3).

Cytotoxic and antimicrobial activities of aporphine alkaloids isolated from Stephania venosa (Blume) Spreng.

The cytotoxic activity of five alkaloids, namely 4,5-dioxo-dehydrocrebanine (1), dehydrocrebanine (2), crebanine (3), oxostephanine (4), and thailandine (5) isolated from the tuber and leaves of Stephania venosa (Blume) Spreng was investigated. Thailandine showed the strongest activity against lung carcinoma cells (A549) (IC50 of 0.30 µg/mL) with very low cytotoxicity against normal embryonic lung cells (MRC-5). Thailandine also demonstrated strong activity against Plasmodium falciparum, K1 strain (IC50 of 20 ng/mL), and Mycobacterium tuberculosis H(37)Ra (MIC of 6.25 µg/mL) as well as gram-positive bacteria such as Streptococcus pneumoniae and Staphylococcus aureus. Oxostephanine exhibited strong activity against breast cancer (BC) and acute lymphoblastic leukemia cells (MOLT-3) with an IC50 of 0.24 and 0.71 µg/mL, respectively, and exhibited very low cytotoxicity against MRC-5 cells. Dehydrocrebanine demonstrated strong activity against promyelocytic leukemia cells (HL-60) with an IC50 of 2.14 µg/mL whereas crebanine showed weak activity against cancer cell lines. However, both of them showed cytotoxicity against MRC-5 cells.

Higher structure of cereulide, an emetic toxin from Bacillus cereus, and special comparison with valinomycin, an antibiotic from Streptomyces fulvissimus.

Cereulide and valinomycin are both 36-membered cyclic depsipeptides with 12 stereogenic centers that have a very similar sequence of cyclo [-D-O-Leu-D-Ala-L-O-Val-L-Val-]3 and cyclo [-D-O-Val-D-Val-L-O-Ala-L-Val-]3, respectively. Cereulide is an emetic toxin produced by Bacillus cereus through an unusual non-ribosomal peptide synthesis (NRPS), whereas valinomycin, produced by Streptomyces fulvissimus, is a known antibiotic drug. Both compounds are known as K+-ion-selective ionophores and cause a potassium-dependent drop in the transmembrane potential of mitochondria, arising from the uptake of a K+-ion-charged ionophore complex. Such compounds may affect mitochondrial function. In the three-dimensional structure of cereulide and valinomycin, cereulide has a vertical and horizontal mirror-image-like structure as is the case in valinomycin. The only difference is the side chains which are linked to a similar framework. Through the current 1H NMR spectroscopy and metal-complexation studies, we found that cereulide had a higher complexation ability to metal ions compared to valinomycin. Cereulide exhibited the K+-ion-selective ionophore property at a lower concentration than valinomycin. X-ray crystallographic analyses of the cereulide and valinomycin H+ form were compared, and revealed that the higher structures of both compounds also showed similarity in the crystal structures. The structure of cereulide-H+ form was found to be in agreement with the structure obtained by a combination of NMR spectroscopy and molecular-mechanics calculations, which afforded reasonable dihedral angles at the local-minimum-energy conformation of the cereulide-K+-ion complex.