Cocrystals of the antibiotic trimethoprim with glutarimide and 3,3‐dimethylglutarimide held together by three hydrogen bonds

The antibiotic trimethoprim [5‐(3,4,5‐trimethoxybenzyl)pyrimidine‐2,4‐diamine] was cocrystallized with glutarimide (piperidine‐2,6‐dione) and its 3,3‐dimethyl derivative (4,4‐dimethylpiperidine‐2,6‐dione). The cocrystals, viz. trimethoprim–glutarimide (1/1), C₁₄H₁₈N₄O₃·C₅H₇NO₂, (I), and trimethoprim–3,3‐dimethylglutarimide (1/1), C₁₄H₁₈N₄O₃·C₇H₁₁NO₂, (II), are held together by three neighbouring hydrogen bonds (one central N—H...N and two N—H...O) between the pyrimidine ring of trimethoprim and the imide group of glutarimide, with an ADA/DAD pattern (A = acceptor and D = donor). These heterodimers resemble two known cocrystals of trimethoprim with barbituric acid and its 5,5‐diethyl derivative. Trimethoprim shows a conformation in which the planes of the pyrimidine and benzene rings are approximately perpendicular to one another. In its glutarimide coformer, five of the six ring atoms lie in a common plane; the C atom opposite the N atom deviates by about 0.6 Å. The crystal packing of each of the two cocrystals is characterized by an extended network of hydrogen bonds and contains centrosymmetrically related trimethoprim homodimers formed by a pair of N—H...N hydrogen bonds. This structural motif occurs in five of the nine published crystal structures in which neutral trimethoprim is present.     

Novel supramolecular polymer networks based on melamine‐ and imide‐containing oligomers

Reversible, supramolecular polymer networks based on commercially available bulk chemicals, and prepared using an industrially attractive route are described. The difunctional, low molecular weight polytetramethyleneoxide is functionalized with trimellitic imide, and reversibly crosslinked with the trifunctional melamine using the well known imide‐diaminopyridine triple hydrogen bonding pattern. Molecular modelling calculations as well as experimental studies on model compounds indicate that the aimed 1:3 melamine ‐ imide stoichiometry is obtained. The resulting reversible, supramolecular polymer structures show a rheological behaviour, that is typical for polymer networks. The results presented here describe an industrially accessible route to use supramolecular interactions in order to obtain materials with novel properties.     

Melt modification of poly(styrene‐co‐maleic anhydride) with alcohols in the presence of 1,3‐oxazolines

Various copolyesteramides were prepared by melt compounding at 220 °C involving reaction of poly(styrene‐co‐maleic anhydride), SMA, with 6, 17, and 28 wt % maleic anhydride content, and 1‐dodecanol, C12OH, in the presence of 2‐undecyl‐1,3‐oxazoline, C11OXA. Copolymer architectures were examined by means of ¹H NMR, FTIR, DSC, and TGA using model compounds prepared via solution reactions. While conversion of anhydride with alcohol was poor due to the thermodynamically favored anhydride ring formation, very high conversions were achieved when stoichiometric amounts of C11OXA were added. According to spectroscopic studies esteramide groups resulted from reaction of oxazoline with carboxylic acid intermediate. In the absence of alcohol, C11OXA reacted with anhydride to produce esterimides. Effective attachment of flexible n‐alkyl side chains via simultaneous reaction of C12OH and C11OXA resulted in lower glass‐transition temperatures of copolyesteramides. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1222–1231, 2000     

New polymer structures based on vinyl ether polymerization

Sequential living cationic polymerization of octadecyl vinyl ether (ODVE) and methyl vinyl ether (MVE) was used for the preparation of amphiphilic ABA‐type block copolymers. The polymerization of ODVE was initiated with the trimethyl silyl iodide/1,1,3,3‐tetramethoxy propane/ZnI₂ system at 0°C in toluene. The living bifunctional polyODVE thus obtained was used as initiator for the polymerization of MVE. Below the LCST of polyMVE (37°C), the copolymers are amphiphiles. Above the LCST of polyMVE, the polyMVE‐blocks become hydrophobic and the amphiphilic nature of the block copolymer is lost. This was demonstrated by using the block copolymers as emulsifiers for water/decane mixtures. The emulsions were stable for several hours at room temperature, while the emulsion stability decreased to about 30 seconds at 40°C. PolyMVE‐α,ω‐bis‐methacrylates were obtained by end‐capping of living bifunctional polyMVE with 2‐hydroxyethyl methacrylate (HEMA). Copolymerization of these bis‐macromers with HEMA leads to segmented networks. The networks showed a reversible swelling/deswelling behavior in water as a function of temperature. This is caused by a change of the hydrophilicity of the polyMVE segments in the networks. Hexa(chloromethyl)melamine, combined with zinc chloride was found to be an efficient hexafunctional initiator for the living cationic polymerization of vinyl ethers. This simple initiating system opens new ways for the synthesis of endgroup‐functionalized star‐shaped poly(vinyl ethers).     

Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules

Recent explosive growth of ‘make-on-demand’ chemical libraries brought unprecedented opportunities but also significant challenges to the field of computer-aided drug discovery. To address this expansion of the accessible chemical universe, molecular docking needs to accurately rank billions of chemical structures, calling for the development of automated hit-selecting protocols to minimize human intervention and error. Herein, we report the development of an artificial intelligence-driven virtual screening pipeline that utilizes Deep Docking with Autodock GPU, Glide SP, FRED, ICM and QuickVina2 programs to screen 40 billion molecules against SARS-CoV-2 main protease (Mpro). This campaign returned a significant number of experimentally confirmed inhibitors of Mpro enzyme, and also enabled to benchmark the performance of twenty-eight hit-selecting strategies of various degrees of stringency and automation. These findings provide new starting scaffolds for hit-to-lead optimization campaigns against Mpro and encourage the development of fully automated end-to-end drug discovery protocols integrating machine learning and human expertise.

Deep learning-accelerated docking coupled with computational hit selection strategies enable the identification of inhibitors for the SARS-CoV-2 main protease from a chemical library of 40 billion small molecules.     

Copper(II) Triflate Catalyzed Amination of 1,3-Dicarbonyl Compounds

A method to prepare α,α-acyl amino acid derivatives efficiently by Cu(OTf)(2) +1,10-phenanthroline (1,10-phen)-catalyzed amination of 1,3-dicarbonyl compounds with PhI?NSO(2) Ar is described. The mechanism is thought to initially involve aziridination of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, by the putative copper-nitrene/imido species generated from the reaction of the metal catalyst with the iminoiodane source. Subsequent ring opening of the resultant aziridinol adduct under the Lewis acidic conditions then provided the α-aminated product. The utility of this method was exemplified by the enantioselective synthesis of a precursor of 3-styryl-2-benzoyl-L-alanine.     

A Pricing Model for American Options with Gaussian Interest Rates

In this paper we introduce a new methodology to price American put options under stochastic interest rates. We derive an analytic approximation that can be evaluated very fast and is fairly accurate. The method uses the so-called forward risk adjusted measure to derive analytic prices. We show that for American puts the correlation between the stock price and the interest rate has different influences on European option values and early exercise premiums.     

The mixed and multi model line balancing problem: a comparison

The balancing problem deals with the assignment of tasks to work stations. We can distinguish two approaches in the literature on the mixed model line balancing problem, that both transform this problem into a single model line balancing problem. These approaches use combined precedence diagrams and adjusted task processing times, respectively.An experiment was carried out to compare several heuristics based on the combined precedence diagram. A new optimisation method has been developed. The results indicate that the position of common tasks in the precedence diagram of the different models has a significant effect on both the CPU time and the unequal distribution of the total work content of single models among work stations. Moreover, good solutions with respect to the number of required stations go together with long CPU times. For several instances, we decreased the CPU times considerably without deteriorating the performance of the methods, by using a reversed combined precedence diagram.     

A variational principle for fluid mechanics

Summary A variational principle for fluid mechanics is derived without calling for any additional postulates in any ad hoc way. In the principle derived here, the Lagrangian is essentially the sum of kinetic and heat energy transferred to the fluid, less the sum of its internal and potential energy, less the work done on its exterior (similar to the enthalpy concept), rather than the difference between only kinetic energy and internal energy, as obtained previously by Seliger and Whitham [1] for a more restricted mode of variation.     

The completions of a commutative lattice group with respect to the intrinsic topologies

In this paper we discuss the completions (, ) of a commutativel-groupG with respect to the intrinsic topologies . We give some conditions under which is the intrinsic topology of the same type on as and give the relations between these completions.