Antimicrobial resistance (AMR) in common bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), is an increasingly dire public health threat, with MRSA accounting for up to 90% of S. aureus infections. To expand the treatment arsenal against MRSA infections, we developed a class of tunable three-dimensional tricyclic 2-pyridones, termed TriPcides, that can kill MRSA resistant to last-resort antibiotics and eliminate MRSA persister cells. No preexisting resistance was detected across hundreds of clinical isolates, and continuous exposure of MRSA to TriPcides did not elicit detectable resistance. Treatment with TriPcides causes a rapid decrease in membrane integrity and increased levels of reactive oxygen species. Last, TriPcides effectively reduce secretion of important virulence factors and result in reduced ulcer size and healing time in S. aureus murine skin and soft tissue infections but do not reduce bacterial burden.

We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes . Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes . Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.

We have developed an Ir(PPy)3 photoredox-catalyzed cross-coupling reaction that allows installation of quinoxalinones at the C7 position of thiazolino ring-fused 2-pyridones (TRPs) under mild conditions. The methodology tolerates various substituted quinoxalinones and biologically relevant substituents on the C8 position of the TRP. The TRP scaffold has large potential in the development of lead compounds, and while the coupled products are interesting from a drug-development perspective, the methodology will be useful for developing more potent and drug-like TRP-based candidates.

Bacteria resistant to one or several antibiotics are a very large problem, threatening not only treatment of infections but also surgery and cancer treatments. Thus, new types of antibacterial drugs are desperately needed.

A selective [4 + 2] cycloaddition reaction of thiazolo-2-pyridones with arynes has been demonstrated. The developed protocol allows rapid access to highly functionalized, structurally complex thiazolo-fused bridged isoquinolones in high yields, which are susceptible to further late-stage functionalization.

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

Increasing population and pollution has reached an alarming situation worldwide. Pollution of water bodies, soil, and agricultural land worldwide is deteriorating environmental and human health. Various physico-chemical techniques, pollution control rules, and safety standards all together are still unable to control the pollution at the desired level. The need of the hour is to move into the future with the adoption of sustainable technologies. This chapter summarises the progress of the sustainable aspects of phytoremediation in pollution control and abatement. Phytoremediation revolves around several approaches developed around the world during the few past decades. These include phytoextraction, phytovolatilisation, phytotransformation, etc. Though phytoremediation is still not commercialised at a large scale, it has obtained appreciation as a holistic approach with multiple benefits in removing environmental contaminates. The use of an economically important and local plant for phytoremediation technology would be a promising approach to generate income sources for the farmers and would help in the progress of technology. This chapter discusses various aspects of phytoremediation and future scenarios.

Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to life-long sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first generation compound KSK120, inhibits the developmental cycle of Chlamydia resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis and the effect was only observable upon re-infection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen C. muridarum and in C. caviae The molecular target of KSK213 may thus be different in C. trachomatis or non-essential in C. muridarum and C. caviae Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNAse III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

Due to its unique structure and the vast array of substituents that can be attached to its core, Meldrum's acid is a molecule with exceptional chemical properties. In water, it has a remarkably low pKa value of about 4.9. Its C5 position is readily involved in electrophilic substitution reactions whereas the C4 and C6 positions are easily attacked by nucleophiles. At elevated temperatures Meldrum's acid undergoes distinctive decomposition pathways, which can be used in cycloaddition and acylation reactions. In this Tutorial Review, the authors intend to introduce the principles of the synthetic chemistry of Meldrum's acid and provide the essential knowledge for the design and preparation of compounds with desired properties. As there are many reviews focusing on a specific detail of Meldrum's acid chemistry, we would like to give a broader picture of this diverse molecule for undergraduate and graduate students as well as experienced lab leaders. For achieving this goal, some recent advances in using Meldrum's acid derivatives in synthetic scenarios are presented with the hope to further stimulate and promote research leading to additional innovative applications of this synthetically highly relevant molecule.

Reaction of thiazolino fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generate N-alkenyl functionalized 2-pyridones. In the ...

A BF3·OEt2 catalyzed intramolecular Povarov reaction was used to synthesize 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with several O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogues substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

Thiazolino ring fused 2-pyridones are a valuable scaffold with varied and substitution dependent biological activity, accessed primarily by an acyl ketene-imine cycloaddition and rearrangement.Although powerful, some aspects of this chemistry such as the requirement for excess starting material and the production of gas can make larger scale synthesis challenging.Here we describe the development, application and scaling of a continuous flow process allowing larger scale synthesis, with better handling of hazards and more reliable scaling.Optimisation and control of conditions allows for a more efficient synthesis, with a lower equivalence of the acyl ketene precursor required.

Thiazolino fused 2-pyridones undergo thiazoline ring opening by reaction with 2-nitrobenzyl bromide through thi- oether attack, and base promoted fragmentation of the resulting sulfonium ions. Subs ...

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)- thiazolino-2-pyridones with al ...

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.