T3P-Promoted Synthesis of a Series of 2-Aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones and Their Activity against the Kinetoplastid Parasite Trypanosoma brucei

A series of fourteen 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thionicotinic acid, two difficult substrates. The reactions were operationally simple, did not require specialized equipment or anhydrous solvents, could be performed as either two or three component reactions, and gave moderate–good yields as high as 63%. This provides ready access to N-phenyl compounds in this family, which have been generally difficult to prepare. As part of the study, the first crystal structure of neutral thionicotinic acid is also reported, and showed the molecule to be in the form of the thione tautomer. Additionally, the synthesized compounds were tested against T. brucei, the causative agent of Human African Sleeping Sickness. Screening at 50 µM concentration showed that five of the compounds strongly inhibited growth and killed parasites.     

The photocatalytic decomposition of chloroform by tetrachloroaurate(III)

Abstract  

Near-UV irradiation of solutions of (Bu₄N)AuCl₄ in aerated ethanol-stabilized chloroform causes the continuous decomposition of chloroform, as evidenced by the production of many equivalents of HCl and peroxides. At the outset of irradiation, most of the AuCl₄ ⁻ is reduced to AuCl₂ ⁻, but the reduction stops and is reversed. The same experiments done in ethanol-free chloroform cause chloroform decomposition only until the irreversible reduction of the gold is complete. In deoxygenated ethanol-free chloroform, irreversible reduction to AuCl₂ ⁻ is accompanied by the formation of HCl and CCl₄, while the main decomposition products in deoxygenated ethanol-stabilized chloroform are HCl and C₂Cl₆. It is proposed that, in ethanol-free chloroform, photoreduction of AuCl₄ ⁻ begins with the concerted elimination of HCl from an association complex of CHCl₃ with AuCl₄ ⁻, and that ethanol suppresses { \textCHCl₃ ·\textAuCl₄ ^- } \{ {\text{CHCl}}_{3} \cdot {\text{AuCl}}_{4}^{ - } \} complex formation, leaving a slower radical process to carry out the photoreduction of AuCl₄ ⁻ in ethanol-stabilized chloroform. In the presence of oxygen, the radical process causes a build-up of CCl₃OOH, which reoxidizes AuCl₂ ⁻ to AuCl₄ ⁻ and allows the photodecomposition of CHCl₃ to continue indefinitely.     

Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole‐Modified Cyclic Tetrapeptides

Fooling enzymes with mock amides : Analogues of apicidin, a cyclic‐tetrapeptide inhibitor of histone deacetylase (HDAC), were designed with a 1,4‐ or 1,5‐disubstituted 1,2,3‐triazole in place of a backbone amide bond to fix the bond in question in either a trans‐like or a cis‐like configuration. Thus, the binding affinity of distinct peptide conformations (see picture) could be probed. One analogue proved in some cases to be superior to apicidin as an HDAC inhibitor.

     

A lower bound for the symbolic multifractal spectrum of a self-similar multifractal with arbitrary overlaps

By now the multifractal structure of self-similar measures satisfying the so-called Open Set Condition is well understood. However, if the Open Set Condition is not satisfied, then almost nothing is known. In this paper we prove a nontrivial lower bound for the symbolic multifractal spectrum of an arbitrary self-similar measure. We emphasize that we are considering arbitrary self-similar measures (and sets) which are not assumed to satisfy the Open Set Condition or similar separation conditions. Our results also have applications to self-similar sets which do not satisfy the Open Set Condition (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Stereoelectronic effects on 1H nuclear magnetic resonance chemical shifts in methoxybenzenes

Investigation of all O-methyl ethers of 1,2,3-benzenetriol and 4-methyl-1,2,3-benzenetriol (3-16) by 1H NMR spectroscopy and density-functional calculations disclosed practically useful conformational effects on 1H NMR chemical shifts in the aromatic ring. While the conversion of phenol (2) to anisole (1) causes only small positive changes of 1H NMR chemical shifts (Delta delta < 0.08 ppm) that decrease in the order Hortho > Hmeta > Hpara, the experimental O-methylation induced shifts in ortho-disubstituted phenols are largest for Hpara, Delta delta equals; 0.19 +/- 0.02 ppm (n = 11). The differences are due to different conformational behavior of the OH and OCH3 groups; while the ortho-disubstituted OH group remains planar in polyphenols due to hydrogen bonding and conjugative stabilization, the steric congestion in ortho-disubstituted anisoles outweighs the conjugative effects and forces the Ar-OCH3 torsion out of the ring plane, resulting in large stereoelectronic effects on the chemical shift of Hpara. Conformational searches and geometry optimizations for 3-16 at the B3LYP/6-31G** level, followed by B3LYP/6-311++G(2d,2p) calculations for all low-energy conformers, gave excellent correlation between computed and observed 1H NMR chemical shifts, including agreement between computed and observed chemical shift changes caused by O-methylation. The observed regularities can aid structure elucidation of partly O-methylated polyphenols, including many natural products and drugs, and are useful in connection with chemical shift predictions by desktop computer programs.     

Generalising localisation schemes of orthogonal orbitals to the localisation of non-orthogonal orbitals

ABSTRACT

When a set of orthogonal orbitals is localised using orthogonal transformations, the orbital metric is conserved as the unit matrix during the localisation. In this paper we describe how non-orthogonal orbitals may be localised by requiring that the orbital metric is conserved. In particular, we demonstrate how exponential mappings may be used to parametrise orbital transformations such that the orbital metric is conserved. Using this parametrisation, the localisation of non-orthogonal orbitals becomes a generalisation of the localisation for orthogonal orbitals, where the conservation of a unit metric is replaced by the conservation of a non-unit metric. As a result, standard orbital localisation functions and optimisation algorithms that have been used for localising orthogonal orbitals may also be used to localise non-orthogonal orbitals. Numerical illustrations show that the thickness of the orbital tails may be reduced when a set of non-orthogonal orbitals is localised compared to the orthogonal counterpart, and further that the physical interpretation of occupied orbitals for representing chemical bonds is preserved.     

A robust force field based method for calculating conformational energies of charged drug-like molecules

The binding affinity of a drug-like molecule depends among other things on the availability of the bioactive conformation. If the bioactive conformation has a significantly higher energy than the global minimum energy conformation, then the molecule is unlikely to bind to its target. Determination of the global minimum energy conformation and calculation of conformational penalties of binding is a prerequisite for prediction of reliable binding affinities. Here, we present a simple and computationally efficient procedure to estimate the global energy minimum for a wide variety of structurally diverse molecules, including polar and charged compounds. Identifying global energy minimum conformations of such compounds with force field methods is problematic due to the exaggeration of intramolecular electrostatic interactions. We demonstrate that the global energy minimum conformations of zwitterionic compounds generated by conformational analysis with modified electrostatics are good approximations of the conformational distributions predicted by experimental data and with molecular dynamics performed in explicit solvent. Finally the method is used to calculate conformational penalties for zwitterionic GluA2 agonists and to filter false positives from a docking study.     

Expansion of the lysine acylation landscape

Leaving marks: the number of known posttranslational modifications for lysine has been expanded considerably. In addition to acetylation of side-chain amino functionalities of lysine residues in proteins, crotonylation, succinylation, and malonylation have now been identified as posttranslational modifications in histone and in non-histone proteins.     

Iridium‐Catalyzed Dehydrogenative Decarbonylation of Primary Alcohols with the Liberation of Syngas

A new iridium ‐ catalyzed reaction in which molecular hydrogen and carbon monoxide are cleaved from primary alcohols in the absence of any stoichiometric additives has been developed. The dehydrogenative decarbonylation was achieved with a catalyst generated in situ from [Ir(coe)₂Cl]₂ (coe=cyclooctene) and racemic 2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl (rac‐BINAP) in a mesitylene solution saturated with water. A catalytic amount of lithium chloride was also added to improve the catalyst turnover. The reaction has been applied to a variety of primary alcohols and gives rise to products in good to excellent yields. Ethers, esters, imides, and aryl halides are stable under the reaction conditions, whereas olefins are partially saturated. The reaction is believed to proceed by two consecutive organometallic transformations that are catalyzed by the same iridium(I)–BINAP species. First, dehydrogenation of the primary alcohol to the corresponding aldehyde takes place, which is then followed by decarbonylation to the product with one less carbon atom.