Reaction-based machine learning representations for predicting the enantioselectivity of organocatalysts

Hundreds of catalytic methods are developed each year to meet the demand for high-purity chiral compounds. The computational design of enantioselective organocatalysts remains a significant challenge, as catalysts are typically discovered through experimental screening. Recent advances in combining quantum chemical computations and machine learning (ML) hold great potential to propel the next leap forward in asymmetric catalysis. Within the context of quantum chemical machine learning (QML, or atomistic ML), the ML representations used to encode the three-dimensional structure of molecules and evaluate their similarity cannot easily capture the subtle energy differences that govern enantioselectivity. Here, we present a general strategy for improving molecular representations within an atomistic machine learning model to predict the DFT-computed enantiomeric excess of asymmetric propargylation organocatalysts solely from the structure of catalytic cycle intermediates. Mean absolute errors as low as 0.25 kcal mol⁻¹ were achieved in predictions of the activation energy with respect to DFT computations. By virtue of its design, this strategy is generalisable to other ML models, to experimental data and to any catalytic asymmetric reaction, enabling the rapid screening of structurally diverse organocatalysts from available structural information.

A machine learning model for enantioselectivity prediction using reaction-based molecular representations.     

Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation,Intracellular Oxidative Stress,and Neuroinflammation

Many (poly-)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid-β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril-like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate-induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV-2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μm (83 % cell survival), whereas curcumin only showed very low protection at 10 μm (21 % cell survival).     

Determination of the dimerization constant of pinacyanol: role of the thermochromic effect

Pinacyanol (PIN), as other cyanine dyes, has demonstrated a unique ability to form associates such as dimers, and H- and J-aggregates. This association is strongly favoured in water, and even at low dye concentrations, dimers and superior order aggregates are present. As a consequence, the determination of the dimerization constant involves sometimes a significant error when these aggregates are neglected. As an increase in temperature shifts the equilibrium among the different species towards the lowest order aggregates, we have obtained the spectra of PIN at several temperatures. By extrapolating some spectral characteristics at high temperatures, a spectrum of the dimer without any contribution of other aggregates was obtained. From this spectrum and that of the monomer, the dimerization constant was calculated, as well as the Gibbs energy change associated to the reaction. The enthalpy and entropy changes of the dimerization were determined from the dependence of the dimerization constants on the temperature. From these results it can be inferred that the driving force of the dimerization is of enthalpic origin.     

On the Binding of Congo Red to Amyloid Fibrils

Amyloids are characterized by their capacity to bind Congo red (CR), one of the most used amyloid‐specific dyes. The structural features of CR binding were unknown for years, mainly because of the lack of amyloid structures solved at high resolution. In the last few years, solid‐state NMR spectroscopy enabled the determination of the structural features of amyloids, such as the HET‐s prion forming domain (HET‐s PFD), which also has recently been used to determine the amyloid–CR interface at atomic resolution. Herein, we combine spectroscopic data with molecular docking, molecular dynamics, and excitonic quantum/molecular mechanics calculations to examine and rationalize CR binding to amyloids. In contrast to a previous assumption on the binding mode, our results suggest that CR binding to the HET‐s PFD involves a cooperative process entailing the formation of a complex with 1:1 stoichiometry. This provides a molecular basis to explain the bathochromic shift in the maximal absorbance wavelength when CR is bound to amyloids.     

Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3-d]pyrimidine-7(8H)-ones from arylguanidines

A practical protocol was developed for the synthesis of 2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones from ??,??-unsaturated esters, malononitrile, and an aryl substituted guanidine via the corresponding 3-aryl-3,4,5,6- tetrahydropyrido[2,3-d]pyrimidin-7(8H)-ones. Such compounds are formed upon treatment of 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles with an aryl substituted guanidine in 1,4-dioxane and are converted to the desired 4-aminopyridopyrimidines with NaOMe/MeOH through a Dimroth rearrangement. The overall yields of this three-step protocol are, generally speaking, higher than the multicomponent reaction, previously developed by our group, between an ??,??-unsaturated ester, malononitrile, and an aryl substituted guanidine.     

Algebraic Characterizations for Universal Fragments of Logic

In this paper we address our efforts to extend the well-known connection in equational logic between equational theories and fully invariant congruences to other–possibly infinitary–logics. In the special case of algebras, this problem has been formerly treated by H. J. Hoehnke [10] and R. W. Quackenbush [14]. Here we show that the connection extends at least up to the universal fragment of logic. Namely, we establish that the concept of (infinitary) universal theory matches the abstract notion of fully invariant system. We also prove that, inside this wide group of theories, the ones which are strict universal Horn correspond to fully invariant closure systems, whereas those which are universal atomic can be characterized as principal fully invariant systems.