Substitution Pattern Research Articles

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions.

Redox active phenotellurazine catalysts have been recently utilized in two different cross-dehydrogenative coupling reactions. In this study, we revisit the design of the phenotellurazine redox catalysts. In particular, we investigate the level of cooperativity between the Te- and N-centers, the effect of secondary versus tertiary N-centers, the effect of heterocyclic versus non-heterocyclic structures, and the effect of substitution patterns on the redox catalytic activity.

Design, Synthesis, in vitro biological evaluation and in silico molecular docking study of chloro substituted Benzimidazole-Thiazole hybrid derivatives as potential Anti-Alzheimer’s agents

In order to explore new acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors, a series of benzimidazole-fused-thiazole bearing Schiff base derivatives (1–16) were designed and synthesized and further their precise structures were elucidated using various spectroscopic tools including 1H NMR, 13C NMR and HREI-MS. All the synthesized derivatives demonstrated better acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory potential with IC50 values ranging from 0.10 ± 0.10 µM to 11.60 ± 0.40 µM (against AChE) and 0.90 ± 0.10 µM to 22.10 ± 0.60 µM (BuChE) when the results were compared with Donepezil (IC50 = 2.16 ± 0.12 µM (against AChE) & 4.5 ± 0.11 µM (against BuChE) as standard inhibitor. Specifically, the analogues 4, 5, 11, 14 and 15 were identified to be significant potent, even more active than standard drug having IC50 values of 0.80 ± 0.10, 0.50 ± 0.10, 0.60 ± 0.10, 0.10 ± 0.10, 0.10 ± 0.10 µM (against AChE) and 2.40 ± 0.10, 1.10 ± 0.10, 1.30 ± 0.10, 0.90 ± 0.10 & 0.80 ± 0.10 µM (against BuChE) respectively. The structure–activity relationship (SAR) studies were carried out for all synthesized derivatives based on substitution pattern around aryl ring. Furthermore, the molecular docking approach was developed to explore the binding mode of interactions between most active scaffolds and active sites of targeted acetylcholinesterase and butyrylcholinesterase enzymes.

Increased Positive Selection in Highly Recombining Genes Does not Necessarily Reflect an Evolutionary Advantage of Recombination.

It is commonly thought that the long-term advantage of meiotic recombination is to dissipate genetic linkage, allowing natural selection to act independently on different loci. It is thus theoretically expected that genes with higher recombination rates evolve under more effective selection. On the other hand, recombination is often associated with GC-biased gene conversion (gBGC), which theoretically interferes with selection by promoting the fixation of deleterious GC alleles. To test these predictions, several studies assessed whether selection was more effective in highly recombining genes (due to dissipation of genetic linkage) or less effective (due to gBGC), assuming a fixed distribution of fitness effects (DFE) for all genes. In this study, I directly derive the DFE from a gene's evolutionary history (shaped by mutation, selection, drift, and gBGC) under empirical fitness landscapes. I show that genes that have experienced high levels of gBGC are less fit and thus have more opportunities for beneficial mutations. Only a small decrease in the genome-wide intensity of gBGC leads to the fixation of these beneficial mutations, particularly in highly recombining genes. This results in increased positive selection in highly recombining genes that is not caused by more effective selection. Additionally, I show that the death of a recombination hotspot can lead to a higher dN/dS than its birth, but with substitution patterns biased towards AT, and only at selected positions. This shows that controlling for a substitution bias towards GC is therefore not sufficient to rule out the contribution of gBGC to signatures of accelerated evolution. Finally, although gBGC does not affect the fixation probability of GC-conservative mutations, I show that by altering the DFE, gBGC can also significantly affect nonsynonymous GC-conservative substitution patterns.

Decoding the molecular Symphony: Unravelling neurologically crucial GSK-3 inhibition through 2D QSAR modelling with MLR, PLS, and ANN approaches

This study aimed to decipher the encoded information within the molecular structure of a dataset of GSK-3β inhibitors through a comprehensive quantity structural-activity relationship (QSAR) investigation employing traditional physicochemical descriptors. Various statistical techniques were applied, encompassing linear methods such as Multiple Linear Regression (MLR) and Partial Least Squares (PLS), along with non-linear approaches such as Artificial Neural Networks (ANN). Rigorous validation using diverse statistical tools confirmed the models’ precision and predictability. The model exhibited exceptional statistical relevance, as evidenced by standard parameters: S-value (0.37), F-value (37.17), r (0.93), r2 (0.855), and r2CV (0.78). They assessed predictive power and robustness by involving specific statistical parameters. Key descriptors analyzed, including Verloop L (subs 2), Lipole Z component (whole molecule), and VAMP Dipole Z component, offered crucial insights into their respective contributions. This analysis implies that targeted modifications in the substitution pattern potentially enhance GSK-3β inhibitory activity significantly. The established model clarified how bioactivity depends on structure and offered valuable recommendations for creating new compounds with better inhibitory activity profiles against the GSK-3β enzyme.

Antibacterial resistance and the cost of affecting demand: The case of UK antibiotics

Consumption of broad-spectrum antibiotics is associated with rising antimicrobial resistance (AMR) levels. The use of broad-spectrum drugs, particularly of cephalosporins, quinolones, and co-amoxiclav contributes the most to the rise in AMR. We use aggregate sales data on antibiotics from the UK to estimate structural demand models and reveal drug substitution patterns. We then simulate alternative tax schemes to evaluate the effectiveness of shifting demand from broad- to narrow-spectrum drugs. Our estimates suggest that these policies can be highly effective in demand management and come at a relatively low cost regarding changes in consumer and producer surplus.

Synthetic techniques for thermodynamically disfavoured substituted six-membered rings.

Six-membered rings are ubiquitous structural motifs in bioactive compounds and multifunctional materials. Notably, their thermodynamically disfavoured isomers, like disubstituted cyclohexanes featuring one substituent in an equatorial position and the other in an axial position, often exhibit enhanced physical and biological activities in comparison with their opposite isomers. However, the synthesis of thermodynamically disfavoured isomers is, by its nature, challenging, with only a limited number of possible approaches. In this Review, we summarize and compare synthetic methodologies that produce substituted six-membered rings with thermodynamically disfavoured substitution patterns. We place particular emphasis on elucidating the crucial stereoinduction factors within each transformation. Our aim is to stimulate interest in the synthesis of these unique structures, while simultaneously providing synthetic chemists with a guide to approaching this synthetic challenge.

Caught in the Act of Substitution: Interadsorbate Effects on an Atomically Precise Fe/Co/Se Nanocluster.

Directing groups guide substitution patterns in organic synthetic schemes, but little is known about pathways to control reactivity patterns, such as regioselectivity, in complex inorganic systems such as bioinorganic cofactors or extended surfaces. Interadsorbate effects are known to encode surface reactivity patterns in inorganic materials, modulating the location and binding strength of ligands. However, owing to limited experimental resolution into complex inorganic structures, there is little opportunity to resolve these effects on the atomic scale. Here, we utilize an atomically precise Fe/Co/Se nanocluster platform, [Fe3(L)2Co6Se8L'6]+ ([1(L)2]+; L = CN t Bu, THF; L' = Ph2PN(-)Tol), in which allosteric interadsorbate effects give rise to pronounced site-differentiation. Using a combination of spectroscopic techniques and single-crystal X-ray diffractometry, we discover that coordination of THF at the ligand-free Fe site in [1(CN t Bu)2]+ sets off a domino effect wherein allosteric through-cluster interactions promote the regioselective dissociation of CN t Bu at a neighboring Fe site. Computational analysis reveals that this active site correlation is a result of delocalized Fe···Se···Co···Se covalent interactions that intertwine edge sites on the same cluster face. This study provides an unprecedented atom-scale glimpse into how interfacial metal-support interactions mediate a collective and regiospecific path for substrate exchange across multiple active sites.

Phonological substitution patterns in Yemeni Ibbi Arabic child speech: a markedness and natural phonology perspective

Phonological substitution patterns in Yemeni Ibbi Arabic child speech: a markedness and natural phonology perspective

Global Firms in Large Devaluations

Abstract I investigate the consequences of firms’ joint import and export decisions in the context of large devaluations. I provide empirical evidence that large devaluations are characterized by an increase in the aggregate share of imported inputs in total input spending and by reallocation of resources toward import-intensive firms, contrary to what standard quantitative trade models predict. These facts are explained by the expansion of exporters, which are intense importers. I develop a model where firms globally decide their import and export strategies and discipline it to match salient features of the Mexican micro data. After a devaluation, the model reproduces the pattern of low aggregate substitution and firm reallocation observed in the data. Compared with a benchmark without global firms, the model predicts higher growth of total exports and imports and a smaller reduction in the trade deficit.

High prevalence of PRDM9-independent recombination hotspots in placental mammals

In many mammals, recombination events are concentrated in hotspots directed by a sequence-specific DNA-binding protein named PRDM9. Intriguingly, PRDM9 has been lost several times in vertebrates, and notably among mammals, it has been pseudogenized in the ancestor of canids. In the absence of PRDM9, recombination hotspots tend to occur in promoter-like features such as CpG islands. It has thus been proposed that one role of PRDM9 could be to direct recombination away from PRDM9-independent hotspots. However, the ability of PRDM9 to direct recombination hotspots has been assessed in only a handful of species, and a clear picture of how much recombination occurs outside of PRDM9-directed hotspots in mammals is still lacking. In this study, we derived an estimator of past recombination activity based on signatures of GC-biased gene conversion in substitution patterns. We quantified recombination activity in PRDM9-independent hotspots in 52 species of boreoeutherian mammals. We observe a wide range of recombination rates at these loci: several species (such as mice, humans, some felids, or cetaceans) show a deficit of recombination, while a majority of mammals display a clear peak of recombination. Our results demonstrate that PRDM9-directed and PRDM9-independent hotspots can coexist in mammals and that their coexistence appears to be the rule rather than the exception. Additionally, we show that the location of PRDM9-independent hotspots is relatively more stable than that of PRDM9-directed hotspots, but that PRDM9-independent hotspots nevertheless evolve slowly in concert with DNA hypomethylation.

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines.

Three bis- or tris-brominated 2-trifluoromethylquinolines have been successfully applied in palladium-catalysed Sonogashira reactions, leading to several examples of alkynylated quinolines in good to excellent yields. Optical properties of selected products have been studied by steady state absorption and fluorescence spectroscopy which give insights of the influence of the substitution pattern and of the type of substituents on the optical properties.

Antiaromaticity of Cycloheptatrienyl Anions: Structure, Acidity, and Magnetic Properties.

Investigations of the nature and degree of antiaromaticity of cycloheptatrienyl anion derivatives using both experimental and computational tools are presented. The ground state of cycloheptatrienyl anion in the gas phase is triplet, planar and Baird-aromatic. In DMSO, it assumes a singlet distorted allylic form with a paratropic ring current. The other derivatives in both phases assume either allylic or diallylic conformations depending on the substituent pattern. A combination of experimental and computational methods was used to determine the pKa values of 16 derivatives in DMSO, which ranged from 36 to -10.7. We revealed that the stronger stabilization of the anionic system, which correlates with acidity, does not necessarily imply a lower degree of antiaromaticity in terms of magnetic properties. Conversely, the substitution pattern first affects the geometry of the ring through the bulkiness of the substituents and their better conjugation with a more distorted system. Consequently, the distortion reduces the cyclic conjugation in the π-system and thereby decreases the paratropic current in a magnetic field, which manifests itself as a decrease in the NICS. The triplet-state geometries and magnetic properties are nearly independent on the substitution pattern, which is typical for simple aromatic systems.

Synthesis of modified 1,3,4-thiadiazole incorporating substituted thiosemicarbazide derivatives: Elucidating the in vitro and in silico studies to develop promising anti-diabetic agent

Hybrid molecules based on the 1,3,4-thiadiazole were always the choice of different researchers due to their significant application in medicinal as well as pharmaceutical application. In the present study, twenty analogs of 1,3,4-thiadiazole-bearingthiosemicarbazide moiety (1–20) were synthesized and screened for their anti-diabetic profile. The synthesized compounds were spectroscopically characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, and HREI-MS. Comparing the whole set of afforded compounds to the standard glimepiride drugs (16.01 ± 0.02 μM), the inhibition profiles against α-amylase ranged from 21.02 ± 0.08 to 54.08 ± 0.04 μM. Comparing synthetic analogs to normal glimepiride (IC50 = 14.06 ± 0.05 μM), the range of α-glucosidase activity was likewise variable, ranging from 18.04 ± 0.07 μM to IC50 = 51.05 ± 0.03 μM (against α-glucosidase). Compound 19 demonstrated high potency among the produced analogs since it had both ortho-nitrosubstitution at the aryl ring. The pattern of substitutions around the aryl ring was used for all analogs to determine the structure–activity relationship. In addition, a molecular docking study was conducted on the potent analogs to examine the interactions between the active residues of the targeted enzymes with the synthesized compound. The synthesized molecule showed different types of interactions with amino acid. The outcome demonstrates that these compounds provide several essential interactions with the active sites of enzymes, hence strengthening their enzymatic activity for the future prediction as drug competitors.

Electrochemical Synthesis of C(sp3)‐Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds

AbstractAlkylamines form the backbone of countless nitrogen‐containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three‐dimensional α‐substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report the design of a catalyst‐free electroreductive manifold that merges amines, carbonyl compounds and carbon‐based radical acceptors under ambient conditions without rigorous exclusion of air and moisture. Key to this aminative carbofunctionalization process is the chemoselective generation of nucleophilic α‐amino radical intermediates that readily couple with electrophilic partners, providing straightforward access to architecturally intricate alkylamines and drug‐like scaffolds which are inaccessible by conventional means.

Insights into genetic diversity and functional significance of the bHLH genes in cotton fiber development

This study investigated the identification and distribution of single nucleotide polymorphisms (SNPs) within basic Helix-Loop-Helix (bHLH) transcription factors (TFs) across diverse cotton (Gossypium hirsutum) accessions, including wild, landrace, and improved varieties. Comprehensive genomic analyses revealed substantial SNP diversity in wild cotton, distinct from that observed in landraces and improved accessions. Comparative analysis showed notable variations in SNP abundance and impact levels across different accessions, with missense SNPs being prevalent. Nucleotide substitution patterns highlighted the dominance of G>A and A>G substitutions. Population genetic analyses unveiled significant genetic diversity within wild accessions and distinct clustering between wild and improved accessions. Temporal expression profiling of bHLH genes during cotton fiber development demonstrated dynamic expression patterns, emphasizing their roles in fiber initiation, elongation, and cellulose biosynthesis. Moreover, association analysis identified SNPs significantly associated within bHLH genes, particularly GhbHLH149, with fiber quality traits, indicating their potential functional significance. Population genetic analyses further revealed evidence of positive selection on GhbHLH149 during cotton improvement. This study provides a comprehensive understanding of SNP diversity, gene expression dynamics, and genetic selection in bHLH genes, offering valuable insights for future cotton breeding efforts aimed at improving fiber quality traits in cotton.

Electrochemical Synthesis of C(sp3)-Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds.

Alkylamines form the backbone of countless nitrogen-containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three-dimensional α-substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report the design of a catalyst-free electroreductive manifold that merges amines, carbonyl compounds and carbon-based radical acceptors under ambient conditions without rigorous exclusion of air and moisture. Key to this aminative carbofunctionalization process is the chemoselective generation of nucleophilic α-amino radical intermediates that readily couple with electrophilic partners, providing straightforward access to architecturally intricate alkylamines and drug-like scaffolds which are inaccessible by conventional means.

Exploring the Antiproliferative Potential of Morpholine‐Functionalized Aurones: Design, Synthesis, SAR, DFT, Hirshfeld Surface, 3D Energy Frameworks and Molecular Docking Analysis

AbstractIn quest of generating a diverse array of potential cytotoxic candidates through molecular hybridization approach, herein we have designed a library of forty‐one morpholine‐functionalized aurones 7(a–ao), each with a distinct substitution pattern. These aurones were obtained by reacting 6‐hydroxyaurones, with 4‐(2‐chloroethyl)morpholine hydrochloride, characterized by various spectroscopic techniques including single crystal XRD (7b) and in‐vitro screened for their antiproliferative potential against human gastric adenocarcinoma (AGS) cells. Most of the synthesized compounds have exhibited excellent cytotoxic results. Twenty analogs were found to have cytotoxic potential better than the reference drug Leucovorin and analog 7j emerged as the most potent with IC50=5.98 μM nearly one fifth to the standard drug Leucovorin (IC50=30.8 μM). This library, consisting of twenty three novel and eighteen reported morpholine‐functionalized aurones, bearing diverse substitution pattern, further helped in making a concrete structure‐activity relationship for antiproliferative potential. Additionally, in‐silico molecular docking, Hirshfeld surface analysis and two dimensional fingerprint plots were also studied to understand the molecular interactions and various structural aspects. Further computational investigations of these compounds were conducted using the DFT/B3LYP method, for the determination of HOMO and LUMO energy values as well as the calculation of chemical softness, hardness, electronegativity and electrophilic index etc.

Strategies for Accessing cis-1-Amino-2-Indanol.

cis-1-amino-2-indanol is an important building block in many areas of chemistry. Indeed, this molecule is currently used as skeleton in many ligands (BOX, PyBOX…), catalysts and chiral auxiliaries. Moreover, it has been incorporated in numerous bioactive structures. The major issues during its synthesis are the control of cis-selectivity, for which various strategies have been devised, and the enantioselectivity of the reaction. This review highlights the various methodologies implemented over the last few decades to access cis-1-amino-2-indanol in racemic and enantioselective manners. In addition, the various substitution patterns on the aromatic ring and their preparations are listed.

Double Helix of Icosahedra Structure and Spin Glass Magnetism of the δ-Co2.5Zn17.5-xMnx (x = 0.4-3.5) Pseudo-Binary Alloys.

We have synthesized δ-Co2.5Zn17.5-xMnx (x = 0.4-3.5) pseudo-binary alloys of 10 different compositions by a high-temperature solid-state synthetic route, determined their crystal structures and the Mn substitution pattern, and estimated the existence range of the δ-phase. The alloys crystallize in two chiral enantiomorphic space groups P62 and P64, where the basic atomic polyhedron of the chiral structure is an icosahedron and the neighboring icosahedra share vertices to form an infinitely long double helix along the hexagonal axis (like in the δ-Co2.5Zn17.5 parent binary phase). The alloys are pure δ-phase up to the Mn content x ≈ 3.5. The Mn atoms partially substitute Zn atoms at particular crystallographic sites located on the icosahedra. The study of magnetism was performed on the Co2.5Zn17.1Mn0.4 alloy with the lowest Mn content. Contrary to the expectation that structural chirality may induce the formation of a nontrivial magnetic state, a spin glass state with no relation to the structural chirality was found. The magnetic sublattice contains all of the necessary ingredients (randomness and frustration) for the formation of a spin glass state. Typical out-of-equilibrium dynamic phenomena of a spin system with broken ergodicity were detected below the spin freezing temperature Tf ≈ 8 K.

Synthesis of Styrylbenzazole Photoswitches and Evaluation of their Photochemical Properties.

Styrylbenzazoles form a promising yet under-represented class of photoswitches that can perform a light-driven E-Z isomerization of the central alkene double bond without undergoing irreversible photocyclization, typical of the parent stilbene. In this work, we report the synthesis and photochemical study of 23 styrylbenzazole photoswitches. Their thermal stabilities, quantum yields, maximum absorption wavelengths and photostationary state (PSS) distributions can be tuned by changing the benzazole heterocycle and the substitution pattern on the aryl ring. In particular, we found that push-pull systems show large redshifts of the maximum absorption wavelengths and the highest quantum yields, whereas ortho-substituted styrylbenzazole photoswitches exhibit the most favorable PSS ratios. Taking advantage of both design principles, we produced 2,6-dimethyl-4-(dimethylamino)-styrylbenzothiazole, a thermally stable and efficient P-type photoswitch which displays negative photochromism upon irradiation with visible light up to 470 nm to obtain a near-quantitative isomerization with a very high quantum yield of 59 %. Furthermore, 4-hydroxystyrylbenzoxazole was demonstrated to be a pH-sensitive switch which exhibits a 100 nm redshift upon deprotonation. Ortho-methylation of its benzothiazole analogue improved the obtained PSS ratio in its deprotonated state from E : Z=53 : 47 to E : Z=18 : 82. We anticipate that this relatively unexplored class of photoswitches will form a valuable expansion of the current family of photoswitches.