(<i>Z</i>)-1-Aryl-1-haloalkenes as Intermediates in the Vilsmeier Haloformylation of Aryl Ketones

Vilsmeier reagents give (Z)-1-aryl-1-haloalkenes from aryl ketones bearing an electron-donating substituent at the ortho- or para-position. These haloalkenes are intermediates in the Vilsmeier haloformylation of the aryl ketones. Another reaction mechanistic pathway is thus available in certain Vilsmeier haloformylations, in competition with the commonly accepted route by way of an enaminoketone

Fluorophore-Tagged Poly-Lysine RAFT Agents: Controlled Synthesis of Trackable Cell-Penetrating Peptide–Polymers

The conjugation of a fluorophore and a variety of cell-penetrating peptides onto a RAFT agent allowed for the synthesis of polymers of defined sizes with quantifiable cell-uptake. Each peptide–RAFT agent was used to polymerize acrylamide, acrylate, and styrene monomers to form high or low molecular weight polymers (here 50 or 7.5 kDa) with the peptide having no influence on the RAFT agent’s control. The incorporation of a single fluorophore per polymer chain allowed cellular analysis of the uptake of the size-specific peptide–polymers via flow cytometry and confocal microscopy. The cell-penetrating peptides had a direct effect on the efficiency of polymer uptake for both high and low molecular weight polymers, demonstrating the versatility of the strategy. These “all-in-one”, synthetically accessible RAFT agents allow highly controlled preparation of synthetic peptide–polymer conjugates and subsequent quantification of their delivery into cells

Solid-Phase Synthesis of <i>s</i>‑Tetrazines

An efficient synthesis of s-tetrazines by solid-phase methods is described. This synthesis route was compatible with different solid-phase resins and linkers and did not require metal catalysts or high temperatures. Monosubstituted tetrazines were routinely synthesized using thiol-promoted chemistry, using dichloromethane as a carbon source, while disubstituted unsymmetrical aryl or alkyl tetrazines were synthesized using readily available nitriles. This efficient approach enabled the synthesis of s-tetrazines in high yields (70–94%), eliminating the classical solution-phase problems of mixtures of symmetrical and unsymmetrical tetrazines, with only a single final purification step required, and paves the way to the rapid synthesis of s-tetrazines with various applications in bioorthogonal chemistry and beyond

Programmable and Flexible Fluorochromic Polymer Microarrays for Information Storage

Photoresponsive fluorochromic materials are regarded as an effective means for information storage. Their reversible changes of color and fluorescence facilitate the storage process and increase the possible storage capacity. Here, we propose an optically reconfigurable Förster resonance energy transfer (FRET) process to realize tunable emissions based on photochromic spiropyrans and common fluorophores. The kinetics of the photoisomerization of the spiropyran and the FRET process of the composite were systematically investigated. Through tuning the ratios of the acceptor spiropyran and donor fluorophore and external light stimuli, a programmable FRET process was developed to obtain tunable outputs. More importantly, flexible microarrays were fabricated from such fluorochromic mixtures by inkjet printing (230 ppi) and the dynamic FRET process could also be applied to generate tunable fluorescence in ready-made microstructures. The flexible patterns created using the microarrays could be used as novel optically readable media for information storage by altering the composition and optical performance of every feature within the microarray. A key aspect of information storage such is anti-counterfeiting, and these colorful displays can be fabricated and integrated in a simple and straightforward system. The reliable fabrication and programmable optical performances of these large-scale flexible polymer microarrays represent a substantial step toward high-density and high-security information storage platforms

Rational Design of 5-Phenyl-3-isoxazolecarboxylic Acid Ethyl Esters as Growth Inhibitors of <i>Mycobacterium tuberculosis</i>. A Potent and Selective Series for Further Drug Development

New antituberculosis (anti-TB) drugs are urgently needed to shorten the 6−12 month treatment regimen and especially to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains. In this study, we have continued our efforts to develop isoxazole-based anti-TB compounds by applying rational drug design approach. The biological activity and the structure−activity relationships (SAR) for a designed series of 5-phenyl-3-isoxazolecarboxylic acid ethyl ester derived anti-TB compounds were investigated. Several compounds were found to exhibit nanomolar activity against the replicating bacteria (R-TB) and low micromolar activity against the nonreplicating bacteria (NRP-TB). The series showed excellent selectivity toward Mtb, and in general, no cytotoxicity was observed in Vero cells (IC50 > 128 μM). Notably, selected compounds also retained their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. Hence, benzyloxy, benzylamino, and phenoxy derivatives of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters represent a highly potent, selective, and versatile series of anti-TB compounds and as such present attractive lead compounds for further TB drug development

Synthesis, Biological Evaluation, and Structure−Activity Relationships for 5-[(<i>E</i>)-2-Arylethenyl]-3-isoxazolecarboxylic Acid Alkyl Ester Derivatives as Valuable Antitubercular Chemotypes

Tuberculosis (TB), mostly caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death from infectious disease worldwide. Its coinfection with HIV and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains have further worsened the TB pandemic. Despite its global impact, TB is considered a neglected disease and no new anti-TB therapeutics have been introduced over the last four decades. The nonreplicating persistent form of TB (NRP-TB) is responsible for the length of the treatment and is the putative cause of treatment failure. Therefore, new anti-TB agents, which are active against both the replicating form of Mtb (R-TB) and NRP-TB, are urgently needed. Herein, we report the synthesis and structure−activity relationships (SAR) of a series of 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl esters as potent anti-TB agents. Several compounds had submicromolar minimum inhibitory concentrations (MIC) against R-TB and were active against NRP-TB in the low micromolar range, thus representing attractive lead compounds for the possible development of new anti-TB agents

Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating <i>Mycobacterium tuberculosis</i>

Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development

Flow and Microwave-Assisted Synthesis of <i>N</i>‑(Triethylene glycol)glycine Oligomers and Their Remarkable Cellular Transporter Activities

Peptidomimetics, such as oligo-<i>N</i>-alkylglycines (peptoids), are attractive alternatives to traditional cationic cell-penetrating peptides (such as R₉) due to their robust proteolytic stability and reduced cellular toxicity. Here, monomeric <i>N</i>-alkylglycines, incorporating amino-functionalized hexyl or triethylene glycol (TEG) side chains, were synthesized via a three-step continuous-flow reaction sequence, giving the monomers <i>N</i>-Fmoc-(6-Boc-aminohexyl)­glycine and <i>N</i>-Fmoc-((2-(2-Boc-aminoethoxy)­ethoxy)­ethyl)­glycine in 49% and 41% overall yields, respectively. These were converted into oligomers (5, 7, and 9-mers) using an Fmoc-based solid-phase protocol and evaluated as cellular transporters. Hybrid oligomers, constructed of alternating units of the aminohexyl and amino-TEG monomers, were non-cytotoxic and exhibited remarkable cellular uptake activity compared to the analogous fully TEG or lysine-like compounds

Kinetic analysis of the fluorogenic substrates.

<p>The kinetic parameters (n = 3) were determined for the fluorogenic substrates <b>1</b> and <b>5</b>–<b>14</b> (measured using substrate range of 0.1–8 μM) with caspase-3 and caspase-7. Substrate <b>4</b> or the d-amino acids containing <b>15</b>–<b>24</b> were not cleaved by either enzyme.</p

Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating <i>Mycobacterium tuberculosis</i>

Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development