Halogenated Phenazines that Potently Eradicate Biofilms,MRSA Persister Cells in Non‐Biofilm Cultures,and Mycobacterium tuberculosis

Conventional antibiotics are ineffective against non‐replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1 , that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC=0.2–12.5 μM), as well as the effective killing of MRSA persister cells in non‐biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non‐biofilm persisters alongside 14 . HP 13 displayed potent antibacterial activity against slow‐growing M. tuberculosis (MIC=3.13 μM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non‐toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.     

A Cyclopropene Electrophile that Targets Glutathione S‐Transferase Omega‐1 in Cells

Cyclopropenes are an important new addition to the portfolio of functional groups that can be used for bioorthogonal couplings. The inert nature of these highly strained compounds in complex biological systems is almost counterintuitive given their established electrophilic properties in organic synthesis. Here we provide the first demonstration of a cyclopropene that is capable of direct conjugation to protein targets in cells and show that this compound preferentially alkylates the active site cysteine of glutathione S‐transferase omega‐1 (GSTO1).     

A PDE6δ‐KRas Inhibitor Chemotype with up to Seven H‐Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2

Small‐molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (K _D<10 nm ), interference with Ras signaling and growth inhibition require 5–20 μm compound concentrations. We demonstrate that these findings can be explained by fast release of high‐affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and ‐dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas‐PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas.     

Exploring the Fundamental Structures of Life: Non‐Targeted,Chemical Analysis of Single Cells and Subcellular Structures

Cells are a basic functional and structural unit of living organisms. Both unicellular communities and multicellular species produce an astonishing chemical diversity, enabling a wide range of divergent functions, yet each cell shares numerous aspects that are common to all living organisms. While there are many approaches for studying this chemical diversity, only a few are non‐targeted and capable of analyzing hundreds of different chemicals at cellular resolution. Here, we review the non‐targeted approaches used to perform comprehensive chemical analyses, provide chemical imaging information, or obtain high‐throughput single‐cell profiling data. Single‐cell measurement capabilities are rapidly increasing in terms of throughput, limits of detection, and completeness of the chemical analyses; these improvements enable their application to understand ever more complex physiological phenomena, such as learning, memory, and behavior.     

Structure‐Based Design and Synthesis of the First Weak Non‐Phosphate Inhibitors for IspF,an Enzyme in the Non‐Mevalonate Pathway of Isoprenoid Biosynthesis

In this paper, we describe the structure‐based design, synthesis, and biological evaluation of cytosine derivatives and analogues that inhibit IspF, an enzyme in the non‐mevalonate pathway of isoprenoid biosynthesis. This pathway is responsible for the biosynthesis of the C₅ precursors to isoprenoids, isopentenyl diphosphate (IPP, 1 ) and dimethylallyl diphosphate (DMAPP, 2 ; Scheme 1). The non‐mevalonate pathway is the sole source for 1 and 2 in the protozoan Plasmodium parasites. Since mammals exclusively utilize the alternative mevalonate pathway, the enzymes of the non‐mevalonate pathway have been identified as attractive new drug targets in the fight against malaria. Based on computer modeling (cf. Figs. 2 and 3), new cytosine derivatives and analogues (Fig. 1) were selected as potential drug‐like inhibitors of IspF protein, and synthesized (Schemes 2–5). Determination of the enzyme activity by ¹³C‐NMR spectroscopy in the presence of the new ligands showed inhibitory activities for some of the prepared cytosine and pyridine‐2,5‐diamine derivatives in the upper micromolar range (IC₅₀ values; Table). The data suggest that it is possible to inhibit IspF protein without binding to the polar diphosphate binding site and the side chain of Asp56′, which interacts with the ribose moiety of the substrate and substrate analogues. Furthermore, a new spacious sub‐pocket was discovered which accommodates aromatic spacers between cytosine derivatives or analogues (binding to ‘Pocket III’) and rings that occupy the flexible hydrophobic region of ‘Pocket II’. The proposed binding mode remains to be further validated by X‐ray crystallography.     

Synthesis of Poly(Arylene Alkenylene)s by Pd‐Catalyzed Three‐Component Coupling Polycondensation of Diiodoarenes,Non‐Conjugated Dienes,and Nucleophiles that Involves Chain Walking Isomerization

The Pd‐catalyzed three‐component coupling polycondensation of diiodoarenes, nonconjugated dienes, and carbonucleophiles afforded poly(arylene alkenylene)s with moderate molecular weight in good yield. The reaction involves Mizoroki‐Heck coupling, olefin migration via chain walking, and addition of the carbonucleophile to the resulting π‐allylpalladium species. The polymerization with a slight excess of nucleophile with respect to diiodoarene also proceeded to give the polymer without significant decrease in molecular weight in spite of the nonstoichiometric mixture of the monomers. The Pd‐catalyzed three‐component coupling polycondensation of diiodoarenes, nonconjugated dienes, and diimide also proceeded. The base used in the reaction is critical for yield and molecular weight of the product. The reaction using NaHCO₃ afforded the product with low solubility, which can be explained by the high molecular weight of the polymer and/or the strong interaction of the electron donating dimethoxyphenylene groups and electron accepting diimide groups in the polymer. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2535–2542     

Delineating the Mechanism of Ionic Liquids in the Synthesis of Quinazoline‐2,4(1H,3H)‐dione from 2‐Aminobenzonitrile and CO2

Ionic liquids (ILs) are versatile solvents and catalysts for the synthesis of quinazoline‐2,4‐dione from 2‐aminobenzonitrile and CO₂. However, the role of the IL in this reaction is poorly understood. Consequently, we investigated this reaction and showed that the IL cation does not play a significant role in the activation of the substrates, and instead plays a secondary role in controlling the physical properties of the IL. A linear relationship between the pK _a of the IL anion (conjugate acid) and the reaction rate was identified with maximum catalyst efficiency observed at a pK _a of >14.7 in DMSO. The base‐catalyzed reaction is limited by the acidity of the quinazoline‐2,4‐dione product, which is deprotonated by more basic catalysts, leading to the formation of the quinazolide anion (conjugate acid pK _a 14.7). Neutralization of the original catalyst and formation of the quinazolide anion catalyst leads to the observed reaction limit.     

Optically Biaxial,Re‐entrant and Frustrated Mesophases in Chiral,Non‐symmetric Liquid Crystal Dimers and Binary Mixtures

Sixteen optically active, non‐symmetric dimers, in which cyanobiphenyl and salicylaldimine mesogens are interlinked by a flexible spacer, were synthesized and characterized. While the terminal chiral tail, in the form of either (R)‐2‐octyloxy or (S)‐2‐octyloxy chain attached to salicylaldimine core, was held constant, the number of methylene units in the spacer was varied from 3 to 10 affording eight pairs of (R & S) enantiomers. They were probed for their thermal properties with the aid of orthoscopy, conoscopy, differential scanning calorimetry and X‐ray powder diffraction. In addition, the binary mixture study was carried out using chiral and achiral dimers with the intensions of stabilizing optically biaxial phase/s, re‐entrant phases and important phase sequences. Notably, one of the chiral dimers as well as some mixtures exhibited a biaxial smectic A (SmA_b) phase appearing between a uniaxial SmA and a re‐entrant uniaxial SmA phases. The mesophases such as chiral nematic (N*) and frustrated phases viz., blue phases (BPs) and twist grain boundary (TGB) phases, were also found to occur in most of the dimers and mixtures. X‐ray diffraction studies revealed that the dimers possessing oxybutoxy and oxypentoxy spacers show interdigitated (SmA_d) phase where smectic periodicity is over 1.4 times the molecular length; whereas in the intercalated SmA (SmA_c) phase formed by a dimer having oxydecoxy spacer the periodicity was found to be approximately half the molecular length. The handedness of the helical structure of the N* phases formed by two enantiomers was examined with the aid of CD measurements; as expected, these enantiomers showed optical activities of equal magnitudes but with opposite signs. Overall, it appears that the chiral dimers and mixtures presented herein may serve as model systems in design and developing novel materials exhibiting the apolar SmA_b phase possessing D_2h symmetry and nematic‐type biaxiality.