Synthesis of 6‐Fluoro‐7‐cyclic Amino‐substituted Dicarboxylic Acid Quinolones and their Antibacterial Activity

Novel 1‐carboxymethyl‐6‐fluoro‐7‐cyclic amino‐substituted‐4‐oxo‐1,4‐dihydroquinolone‐3‐carboxylic acids 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i , 7j , 7k , 7l , 7m , 7n were synthesized as a new class of quinolones. Ethyl‐6‐fluoro‐7‐chloro‐1,4‐dihydro‐4‐quinoline‐3‐carboxylic acid was prepared from conventional method and reacted with ethyl bromoacetate to furnish N‐carboxymethyl derivatives. The compounds were screed against various Gram‐positive and Gram‐negative bacterial strains. Antibacterial activity data is validated by molecular docking studies.     

Selective targeting of antibody conjugated multifunctional nanoclusters (nanoroses) to epidermal growth factor receptors in cancer cells

The ability of smaller than 100 nm antibody (Ab) nanoparticle conjugates to target and modulate the biology of specific cell types may enable major advancements in cellular imaging and therapy in cancer. A key challenge is to load a high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. A versatile method called thin autocatalytic growth on substrate (TAGs) has been developed in our previous study to form ultrathin and asymmetric gold coatings on iron oxide nanocluster cores producing exceptional near-infrared (NIR) absorbance. AlexaFluor 488 labeled Abs were used to correlate the number of Abs conjugated to iron oxide/gold nanoclusters (nanoroses) with the hydrodynamic size. A transition from submonolayer to multilayer aggregates of Abs on the nanorose surface was observed for 54 Abs and an overall particle diameter of ～60-65 nm. The hydrodynamic diameter indicated coverage of a monolayer of 54 Abs, in agreement with the prediction of a geometric model, by assuming a circular footprint of 16.9 nm diameter per Ab molecule. The targeting efficacy of nanoclusters conjugated with monoclonal Abs specific for epidermal growth factor receptor (EGFR) was evaluated in A431 cancer cells using dark field microscopy and atomic absorbance spectrometry (AAS) analysis. Intense NIR scattering was achieved from both high uptake of nanoclusters in cells and high intrinsic NIR absorbance of individual nanoclusters. Dual mode imaging with dark field reflectance microscopy and fluorescence microscopy indicates the Abs remained attached to the Au surfaces upon the uptake by the cancer cells. The ability to load intense multifunctionality, specifically strong NIR absorbance, conjugation of an Ab monolayer in addition to a strong r2 MRI contrast that was previously demonstrated in a total particle size of only 63 nm, is an important step forward in development of theranostic agents for combined molecular specific imaging and therapy.     

Gold-catalyzed 1,2-difunctionalizations of aminoalkynes using only N- and O-containing oxidants

We report two viable routes for the 1,2-difunctionalization of aminoalkynes using only oxidants. In the presence of a gold catalyst, nitrones enable the oxoamination of aminoalkynes 1 to form 2-aminoamides 2. With a suitable gold catalyst, nitrosobenzenes implement an alkyne/nitroso metathesis of the same substrates to give 2-oxoiminylamides 3. These two novel oxidations also provide 1,2-aminoalcohols with opposite regioselectivity via NaBH(4) reduction in situ.     

Design and synthesis of a new class of membrane-permeable triazaborolopyridinium fluorescent probes

A new class of fluorescent triazaborolopyridinium compounds was synthesized from hydrazones of 2-hydrazinylpyridine (HPY) and evaluated as potential dyes for live-cell imaging applications. The HPY dyes are small, their absorption/emission properties are tunable through variation of pyridyl or hydrazone substituents, and they offer favorable photophysical characteristics featuring large Stokes shifts and general insensitivity to solvent or pH. The stability, neutral charge, cell membrane permeability, and favorable relative influences on the water solubility of HPY conjugates are complementary to existing fluorescent dyes and offer advantages for the development of receptor-targeted small-molecule probes. This potential was assessed through the development of a new class of cysteine-derived HPY-conjugate imaging agents for the kinesin spindle protein (KSP) that is expressed in the cytoplasm during mitosis and is a promising chemotherapeutic target. Conjugates possessing the neutral HPY or charged Alexa Fluor dyes that function as potent, selective allosteric inhibitors of the KSP motor were compared using biochemical and cell-based phenotypic assays and live-cell imaging. These results demonstrate the effectiveness of the HPY dye moiety as a component of probes for an intracellular protein target and highlight the importance of dye structure in determining the pathway of cell entry and the overall performance of small-molecule conjugates as imaging agents.     

Simple UV and visible spectrophotometric methods for the determination of doxycycline hyclate in pharmaceuticals

Doxycycline hyclate (DOX), a broad spectrum antibiotic with activity against a wide range of gram-positive and gram-negative bacteria, is widely used as a pharmacological agent and as an effector molecule in inducible gene expression system. Three simple, selective, rapid, accurate, precise and cost-effective spectrophotometric methods for the determination of DOX in bulk drug and in tablets have been developed and validated. First method (method A) is based on the measurement of absorbance of DOX in 0.1 M HCl at 240 nm. The second method (method B) is based on the measurement of yellow chromogen at 375 nm which is formed in 0.1 M NaOH. The third method is based on the measurement of 2: 1 complex formed between DOX and iron(III) in H₂SO₄ medium, the complex peaking at 420 nm (method C). The optimum conditions for all the three methods are optimized. Beer’s law was obeyed over the ranges 2.5–50.0, 1.50–30.0 and 10–100 g/mL for method A, method B and method C, respectively. The apparent molar absorptivity values are calculated to be 1.03 × 10⁴, 1.73 × 10⁴, and 5.21 × 10³ L mol⁻¹ cm⁻¹ for method A, method B, and method C, respectively. The Sandell sensitivity, limit of detection (LOD) and limit quantification (LOQ) values are also reported. All the methods were validated in accordance with current ICH guidelines. The developed methods were employed with high degree of precision and accuracy for the estimation of total drug content in commercial tablet formulations of DOX.     

Conformationally rigid aromatic amino acids as potential building blocks for abiotic foldamers

This communication describes the development of conformationally constrained unnatural aromatic amino acids, constructed on rigid backbone wherein the carboxyl and amino groups project in two dimensions (planes) on the aromatic framework. Such a feature offers the possibility of design and development of conformationally ordered synthetic oligomers with intriguing structural architectures distinct from those classically observed. Furthermore, such amino acids will have the potential to extend the conformational space available for foldamer design with diverse backbone conformation and structural architectures.     

Approximate analytical solutions of a class of boundary layer equations over nonlinear stretching surface

Third order nonlinear ordinary differential equations, subject to appropriate boundary conditions arising in fluid dynamics, are solved using three different methods viz., the Dirichlet series, method of stretching of variables, and asymptotic function method. Similarity transformations are used to convert the governing partial differential equations into nonlinear ordinary differential equations. The numerical results obtained from the above methods for various problems are given in terms of skin friction. Our study revealed that the results obtained from these methods agree well with those of direct numerical simulation of ordinary differential equations. Also, these methods have advantages over pure numerical methods in obtaining derived quantities such as velocity profile accurately for various values of the parameters at a stretch.     

Selective synthesis of strained [7]cycloparaphenylene: an orange-emitting fluorophore

[n]Cycloparaphenylenes, which are short fragments of carbon nanotubes, have unique size-dependent optical properties. In this communication, we describe the first synthesis of [7]cycloparaphenylene ([7]CPP), the smallest cycloparaphenylene prepared to date. In order to access this structure, we have developed a synthetic route that capitalizes on successive orthogonal Suzuki-Miyaura coupling reactions. [7]CPP has 83 kcal/mol of strain energy and an orange emission at 592 nm.     

Chitosan nanoparticles of 5-fluorouracil for ophthalmic delivery: characterization, in-vitro and in-vivo study

The aim of this investigation was to develop 5-fluorouracil (5-FU) loaded chitosan nanoparticles (CH-DNPs) for ophthalmic delivery. CH-DNPs were fabricated by ionotropic gelation mechanism using chitosan (CH) and a polyanion (TPP). The nanoparticles were smooth and spherical, confirmed by scanning electron microscopy (SEM) and atomic force microscope (AFM). CH/TPP mass ratio and TPP significantly changed the particles size morphology and encapsulation efficiency. The nanoparticles size ranged from approximately 114 to 192 nm and had a positive zeta potential (30±4 mV). The encapsulation efficiency, loading capacity and recovery of DNPs were 8.12-34.32%, 3.14-15.24% and 24.22 to 67% respectively. Physical characterization was done by Fourier transform infrared (FT-IR) and X-ray diffraction (XRD). No interaction was observed in between drug and polymer and crystallinity of drug was not changed in drug loaded nanoparticles. In-vitro release study of DNPs showed diffusion controlled release. Bioavailability study of batch CS9 was studied in rabbit eye and compare to 5-FU solution. 5-FU level was significantly higher in aqueous humor of rabbit eye. Ocular tolerance was studied in the eye of New Zealand rabbits and tested formulation was non-irritant with no sign of inflammation.