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A simple, straightforward strategy is described for preparing polyheterocyclic compounds (PHCs), which has involved iterative cycles of palladium-catalyzed Sonogashira coupling, followed by iodocyclization by using [I.sub.2] or ICl. Heterocyclic units, including benzofurans, benzothiophenes, indoles, and isocoumarins, is incorporated under mild conditions.

A variety of iodo-substituted isochromenes, dihydroisobenzofurans and pyranopyridines are prepared by the iodocyclization of 2-(1-alkynyl)benzylic alcohols or 2-(1-alkynyl)-3-(hydroxymethyl)pyridines. The 5-exo-dig cyclization mode, leading to dihydroisobenzofurans, is seen in the case of substrates bearing a tertiary alcoholic group, while the 6-endo-dig cyclization mode, leading to isochromene or pyranopyridines, is a preferred pathway in the case of substrates bearing a primary or secondary alcoholic group.

The studies of the relative reactivity of various functional groups toward alkyne electrophilic cyclization reactions are reported. The reaction outcome is found to depend on the nucleophilicity of the competing functional groups, polarization of the alkyne triple bond, and the cationic nature of the intermediate.

The synthesis of highly substituted isoxazoles, 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles by the electrophilic cyclization of 2-alkyn-1-one O-methyl oximes is reported. The reaction provides selective route to ICI-induced dehydration of a heterocyclic derivative that provides iodinated pyrazoles.

Acute undifferentiated febrile illnesses (AFIs) represent a significant health burden worldwide. AFIs can be caused by infection with a number of different pathogens including dengue (DENV) and Chikungunya viruses (CHIKV), and their differential diagnosis is critical to the proper patient management. While rapid diagnostic tests (RDTs) for the detection of IgG/IgM against a single pathogen have played a significant role in enabling the rapid diagnosis in the point-of-care settings, the state-of-the-art assay scheme is incompatible with the multiplex detection of IgG/IgM to more than one pathogen. In this paper, we present a novel assay scheme that uses twocolor latex labels for rapid multiplex detection of IgG/IgM. Adapting this assay scheme, we show that 4-plex detection of the IgG/IgM antibodies to DENV and CHIKV is possible in 10 min by using it to correctly identify 12 different diagnostic scenarios. We also show that blue, mixed, and red colorimetric signals corresponding to IgG, IgG/IgM, and IgM positive cases, respectively, can be associated with distinct ranges of hue intensities, which could be exploited by analyzer systems in the future for making accurate, automated diagnosis. This represents the first steps toward the development of asingle RDT-based system for the differentia] diagnosis of numerous AFIs of interest. [ABSTRACT FROM AUTHOR]

The solution-phase parallel synthesis of a diverse 71-member library of multisubstituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I2. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki--Miyaura, Sonogashira, carbonylative amidation, and Heck chemistry using sublibraries of commercially available building blocks. [ABSTRACT FROM AUTHOR]

The electrophilic cyclization of 2-(l-alkynyl)-benzamides affords high yields of cyclic imidates, instead of the previously reported isoindolin-l-ones, where cyclization proceeds on the oxygen of the carbonyl group rather than the nitrogen of the amide functionality. X-ray crystallography and spectroscopic techniques have been used to characterize the products. A correction is hereby provided in order to rectify the previous misassignment of structure. [ABSTRACT FROM AUTHOR]

A variety of iodo-substituted isochromenes, dihydroisobenzofurans, and pyranopyridines are readily prepared in good to excellent yields under mild conditions by the iodocyclization of readily available 2-(1-alkynyl)benzylic alcohols or 2-(1-alkynyl)-3-(hydroxymethyl)pyridines. Reactions are carried out in MeCN at 25°C with 3 equiv of I2 as the iodine source and NaHCO3 (3 equiv) as the base. The regiochemical outcome of the reaction strongly depends on the substitution pattern of the starting material. In particular, the 5-exo-dig cyclization mode, leading to dihydroisobenzofurans, is observed in the case of substrates bearing a tertiary alcoholic group, owing to the gem-dialkyl effect, while the 6-endo-dig cyclization mode, leading to isochromene or pyranopyridines, is the usually preferred pathway in the case of substrates bearing a primary or secondary alcoholic group. [ABSTRACT FROM AUTHOR]

Malaria and typhoid fever are two febrile illnesses prevalent in the tropics that often present overlapping symptoms. In this work, we demonstrate an optical reader-based diagnostics platform for rapid codetection and quantification of two antigen targets: lipopolysaccharide (LPS) for typhoid fever and plasmodium lactate dehydrogenase (pLDH) for malaria infections. We report a limit of detection (LoD) of 5 ng/mL for LPS and 10 ng/mL for pLDH in a spiked serum test. We also validated the duplex test's performance of differentiating malaria infection, typhoid fever infection, and coinfection by testing clinical samples in human serum. Our platform provides the potential for further multiplexing by encoding different color codes to various detection targets. The rapid result (∼15 min), low cost (∼$2), and minimal volume requirement for human serum clinical samples (4 μL) of our diagnostic platform offer great potential for deployment in resource-limited settings to help distinguish common causes for acute febrile illnesses at the point-of-need.

Antimicrobial resistance is recognized as one of the greatest emerging threats to public health. Antimicrobial resistant (AMR) microorganisms affect nearly 2 million people a year in the United States alone and place an estimated $20 billion burden on the healthcare system. The rise of AMR microorganisms can be attributed to a combination of overprescription of antimicrobials and a lack of accessible diagnostic methods. Delayed diagnosis is one of the primary reasons for empiric therapy, and diagnostic methods that enable rapid and accurate results are highly desirable to facilitate evidence-based treatment. This is particularly true for clinical situations at the point-of-care where access to state-of-the-art diagnostic equipment is scarce. Here, we present a capillary-based antimicrobial susceptibility testing platform (cAST), a unique approach that offers accelerated assessment of antimicrobial susceptibility in a low-cost and simple testing format. cAST delivers an expedited time-to-readout by means of optical assessment of bacteria incubated in a small capillary form factor along with a resazurin dye. cAST was designed using a combination of off-the-shelf and custom 3D-printed parts, making it extremely suitable for use in resource-limited settings. We demonstrate that growth of bacteria in cAST is approximately 25% faster than in a conventional microplate, further validate the diagnostic performance with clinical isolates, and show that cAST can deliver accurate antimicrobial susceptibility test results within 4-8 h.

In this work, we demonstrate a rapid diagnostic platform with potential to transform clinical diagnosis of acute febrile illnesses in resource-limited settings. Acute febrile illnesses such as dengue and chikungunya, which pose high burdens of disease in tropical regions, share many nonspecific symptoms and are difficult to diagnose based on clinical history alone in the absence of accessible laboratory diagnostics. Through a unique color-mixing encoding and readout strategy, our platform enabled consistent and accurate multiplexed detection of dengue and chikungunya IgM/IgG antibodies in human clinical samples within 30 min. Our multiplex assay offers several advantages over conventional rapid diagnostic tests deployed in resource-limited settings, including a low sample volume requirement and the ability to concurrently detect four analytes. Our platform is a step toward multiplexed diagnostics that will be transformative for disease management in resource-limited settings by enabling informed treatment decisions through accessible evidence-based diagnosis.

Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N -[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein-ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein-ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors.

The quantification of analyte concentrations using lateral flow assays is a low-cost and user-friendly alternative to traditional lab-based assays. However, sandwich-type immunoassays are often limited by the high-dose hook effect, which causes falsely low results when analytes are present at very high concentrations. In this paper, we present a reaction kinetics-based technique that solves this problem, significantly increasing the dynamic range of these devices. With the use of a traditional sandwich lateral flow immunoassay, a portable imaging device, and a mobile interface, we demonstrate the technique by quantifying C-reactive protein concentrations in human serum over a large portion of the physiological range. The technique could be applied to any hook effect-limited sandwich lateral flow assay and has a high level of accuracy even in the hook effect range.

The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).

The iodocyclization of O-methyloximes of 2-alkyn-1-ones affords 4-iodoisoxazoles, which undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles. The palladium-catalyzed processes have been adapted to parallel synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries. Accordingly, a diverse 51-member library of 3,4,5-trisubstituted isoxazoles has been generated.