Design of substituted tetrahydrofuran derivatives for HIV-1 protease inhibitors: synthesis, biological evaluation, and X-ray structural studies.

Substituted tetrahydrofuran derivatives were designed and synthesized to serve as the P2 ligand for a series of potent HIV-1 protease inhibitors. Both enantiomers of the tetrahydrofuran derivatives were synthesized stereoselectivity in optically active forms using lipase-PS catalyzed enzymatic resolution as the key step. These tetrahydrofuran derivatives are designed to promote hydrogen bonding and van der Waals interactions with the backbone atoms in the S2 subsite of the HIV-1 protease active site. Several inhibitors displayed very potent HIV-1 protease inhibitory activity. A high-resolution X-ray crystal structure of an inhibitor-bound HIV-1 protease provided important insight into the ligand binding site interactions in the active site.

Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation.

Structure-based design, synthesis, X-ray structural studies, and biological evaluation of a new series of potent HIV-1 protease inhibitors are described. These inhibitors contain various pyridyl-pyrimidine, aryl thiazole or alkylthiazole derivatives as the P2 ligands in combination with darunavir-like hydroxyethylamine sulfonamide isosteres. These heterocyclic ligands are inherent to kinase inhibitor drugs, such as nilotinib and imatinib. These ligands are designed to make hydrogen bonding interactions with the backbone atoms in the S2 subsite of HIV-1 protease. Various benzoic acid derivatives have been synthesized and incorporation of these ligands provided potent inhibitors that exhibited subnanomolar level protease inhibitory activity and low nanomolar level antiviral activity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important ligand-binding site interactions for further optimization of this class of protease inhibitors.

Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.

We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.

Design, Synthesis and X-Ray Structural Studies of Potent HIV-1 Protease Inhibitors Containing C-4 Substituted Tricyclic Hexahydro-Furofuran Derivatives as P2 Ligands.

The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2' ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso-diols as the key step. To obtain molecular insight, two high-resolution X-ray structures of inhibitor-bound HIV-1 protease were determined and structural analyses have been highlighted.

An innovative cell imaging by beet root extracted pigment.

Fluorescent dyes are of immense interest due to their nontrivial applications in cell imaging to observe different micro organelles and their functions. We have discovered organic Beet-root extracted water soluble fluorescent (BREWSF) dye as an efficient pigment for effective cell imaging. The extraction of this pigment from beet root and its preservation is very easy and cost effective. The BREWSF dye is characterized by IR, UV-Vis, NMR, mass, fluorescence spectroscopy and flowcytometry. By applying this dye on different types of human cells we obtained very good results in fluorescence microscopy, flowcytometry and confocal cell imaging. We also have noticed that this dye takes very less internalization time to produce very good fluorescence image and flowcytometry results of cells and also remains stable at different pH levels.

Improvement of Anticancer Drug Release by Cobalt Ferrite Magnetic Nanoparticles through Combined pH and Temperature Responsive Technique.

This work reports the application possibilities of cobalt ferrite (CoFe2 O4 ) magnetic nanoparticles (CFMNPs) for stimuli responsive drug delivery by magnetic field induced hyperthermia technique. The CFMNPs were characterized by X-ray diffraction (XRD) with Rietveld analysis, field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED), fourier transform infrared spectroscopy (FTIR), thermogravimetry and differential thermal analysis (TG-DTA), vibrating sample magnetometer (VSM) and superconducting quantum interference device (SQUID) magnetometry. Particles were functionalized with folic acid (FA) by EDC-NHS coupling method and loaded with anticancer drug (DOX) by activated folate ions. The drug release was studied as a function of time at two different temperatures (37 and 44 °C) under pH∼5.5 and 7. It was observed that the drug release rate is higher at elevated temperature (44 °C) and acidic pH∼5.5 as compared to our normal body temperature and pH∼7 using the CFMNPs. This way, we have developed a pH and temperature sensitive drug delivery system, which can release the anticancer drug selectively by applying ac magnetic field as under ac field particles are heated up. We have calculated the amount of heat generation by the particles around 1.67 °C per second at ∼600 Hz frequency. By MTT assay on cancer cell and normal cell, it was confirmed that CFMNPs are nontoxic and biocompatible in nature, which assures that our synthesized particles can be successfully used in localized cancer treatment by stimuli responsive drug delivery technique.

Application of strongly overcoupled resonant modes of long-period fiber gratings to measure the adulteration of olive oil.

We have shown that strongly overcoupled resonant modes of long-period fiber gratings (LPFGs) can be used to assess the adulteration of olive oil. In this background, we investigate the response characteristics of strongly overcoupled resonant modes of different orders to a surrounding medium, the refractive index (RI) of which is greater than that of the fiber cladding, and in the range where a precise refractive index measurement is immensely useful for inspecting the quality of olive oils and other edible oils. A theoretical simulation that would help in designing a sensor with suitable sensitivity and range of measurement has been presented in detail and also validated with experimental results. It was interesting to observe that in a high RI surrounding, a lower order overcoupled resonant mode is much more sensitive as compared to a higher-order one having a similar coupling coefficient. A quantitative analysis demonstrates that for a particular LPFG, the sensitivity of a strongly overcoupled LP06 mode was found to be ∼2000 dB/RIU, while that of the LP07 mode having similar coupling strength was ∼550 dB/RIU in the surrounding refractive index range from 1.458 to 1.520. The results have been validated experimentally.

Generation of an elliptic hollow beam using Mathieu and Bessel functions.

A new (to our knowledge) technique for the generation of a propagation-invariant elliptic hollow beam is reported. It avoids the use of the radial Mathieu function and hence is mathematically simpler. Bessel functions with their arguments having elliptic locus are used to generate the mask, which is then recorded using holographic technique. To generate such an elliptic beam, both the angular Mathieu function, i.e., elliptic vortex term, and the expression for the circular vortex are used separately. The resultant mask is illuminated with a plane beam, and the proper filtering of its Fourier transform generates the expected elliptic beam. Results with both vortex terms are satisfactory. It has been observed that even for higher ellipticity the vortices do not separate.

Generation of an elliptic Bessel beam.

In an elliptic coordinate system the solution for a diffraction-free beam is given by a Mathieu beam, which is mathematically complicated and therefore takes considerable computational time and a large memory space. A technique is reported for the generation of elliptic hollow beams, which are actually scaled versions of higher-order Bessel beams. The analysis is based on the fact that stretching coordinates in the space domain results in a contraction of the coordinates in the frequency domain, along with a change in the overall amplitude of the spectrum. The beam, produced holographically, is structurally stable and retains its shape up to approximately 1 m.

Vortex line ordering in the driven three-dimensional vortex glass.

Resistively shunted junction dynamics is applied to the three-dimensional uniformly frustrated XY model with randomly perturbed couplings, as a model for driven steady states in a type-II superconductor with quenched point pinning. For a disorder strength p strong enough to produce a vortex glass in equilibrium, we map the phase diagram as a function of temperature T and uniform driving current I. Using finite size analysis and averaging over many realizations of quenched randomness we find a first-order melting T(m)(I) from a vortex line smectic to an anisotropic liquid.

Frequency response characteristics of a birefringent lens with off-axis aberrations.

We report the frequency response characteristics of an optical system consisting of a lens made of a uniaxial birefringent crystal sandwiched between two linear polarizers; the lens has prespecified off-axis aberrations such as primary astigmatism and primary coma. An analytical expression is obtained for the optical transfer function of the proposed system by use of the autocorrelation of the pupil function over the lens aperture. Some specific cases are computed and illustrated graphically. It has been shown that the proposed system has imaging characteristics distinctly different from those of an ordinary glass lens, and these may be advantageous for better balancing of aberrations in conventional imaging systems.

High tolerance to spherical aberrations and defects of focus with a birefringent lens.

We report a systematic investigation of the imaging behavior of an optical system consisting of a lens from a uniaxial birefringent crystal sandwiched between two linear polarizers into which primary spherical aberration has been introduced. The proposed system has higher tolerance to primary spherical aberration and has a larger depth of focus than an imaging system found with an isotropic lens. Some specific cases are computed and illustrated graphically.