Hydrogen- and halogen-bonding-directed trimeric supramolecular motifs in dihalogenated 1,2,4-triazoles.

Hydrogen-bonding and halogen-bonding interactions are important noncovalent interactions that play a significant role in the crystal structure of organic molecules. An in-depth analysis is given of the crystal packing of two previously reported crystal structures of dihalogenated 1,2,4-triazole derivatives, namely 3,5-dichloro-1H-1,2,4-triazole and 3,5-dibromo-1H-1,2,4-triazole. This work provides insights into the complex interplay of hydrogen-bonding and halogen-bonding interactions resulting in the formation of multiple trimeric motifs in the crystal structure of 1,2,4-triazole derivatives. Analysis of the crystal packing of these isostructural crystal structures revealed that the molecular arrangement in these molecules is primarily stabilized by the formation of different trimeric motifs stabilized by N-H...N hydrogen bonds, N-H...X (X = Cl/Br) halogen bonds and C-X...X halogen-bonding interactions. Computational studies further revealed that all these trimers are energetically stable. A crystallographic database search further reveals that while the cyclic trimers reported in this study are present in other molecules, structures analyzed in this study are the sole instances where all are present simultaneously.

Preventing Cancer by Inhibiting Ornithine Decarboxylase: A Comparative Perspective on Synthetic vs. Natural Drugs.

This perspective delves into the investigation of synthetic and naturally occurring inhibitors, their patterns of inhibition, and the effectiveness of newly utilized natural compounds as inhibitors targeting the Ornithine decarboxylase enzyme. This enzyme is known to target the MYC oncogene, thereby establishing a connection between polyamine metabolism and oncogenesis in both normal and cancerous cells. ODC activation and heightened polyamine activity are associated with tumor development in numerous cancers and fluctuations in ODC protein levels exert a profound influence on cellular activity for inhibition or suppressing tumor cells. This perspective outlines efforts to develop novel drugs, evaluate natural compounds, and identify promising inhibitors to address gaps in cancer prevention, highlighting the potential of newly designed synthetic moieties and natural flavonoids as alternatives. It also discusses natural compounds with potential as enhanced inhibitors.

Rational design for novel heterocyclic based Donepezil analogs for Alzheimer's disease: an in silico approach.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and has devastating impacts on the elderly population. During the last two decades, there has been a significant focus on developing effective and safe treatments for AD. Acetylcholinesterase (AChE) has been identified as one of the primary therapeutic targets for developing drug candidates for AD. However, there is still a need for more efficient therapies. In this study, our aim is to design a new series of heterocyclic-based AChE inhibitors inspired by a standard drug. Here, we carried out molecular docking, drug-likeliness characteristics, and molecular dynamics (MD) to predict important pharmacophore features and understand the inhibitory mechanism of the designed inhibitors towards the AChE. We have designed 112 new derivatives by replacing the piperidine moiety of Donepezil with the different five and six-membered heterocyclic rings and selected 15 compounds that show higher or comparable docking scores as compared to standard Donepezil and pose no risk for carcinogenicity. Furthermore, MD results imply the structural stability of the selected docked complexes and seven exhibit a stronger binding affinity towards the AChE than Donepezil. Thus, heterocyclic-based derivatives based on oxazole, pyrazole, and tetrahydropyran may be potential therapeutic candidates for AD. Our structure-based drug design approach allows us to identify and gain insight into the structural stability of the inhibitor-protein complex and the inhibition mechanism of the newly designed inhibitors. The present finding might be an initial selection for developing a new inhibitor for AD and provide a direction for further experiments on its biological activities.Communicated by Ramaswamy H. Sarma.

H2O2(s) and H2O2·2H2O(s) crystals compared with ices: DFT functional assessment and D3 analysis.

The H2O and H2O2 molecules resemble each other in a multitude of ways as has been noted in the literature. Here, we present density functional theory (DFT) calculations for the H2O2(s) and H2O2·2H2O(s) crystals and make selected comparisons with ice polymorphs. The performance of a number of dispersion-corrected density functionals-both self-consistent and a posteriori ones-are assessed, and we give special attention to the D3 correction and its effects. The D3 correction to the lattice energies is large: for H2O2(s) the D3 correction constitutes about 25% of the lattice energy using PBE, much more for RPBE, much less for SCAN, and it primarily arises from non-H-bonded interactions out to about 5 Å.The large D3 corrections to the lattice energies are likely a consequence of several effects: correction for missing dispersion interaction, the ability of D3 to capture and correct various other kinds of limitations built into the underlying DFT functionals, and finally some degree of cell-contraction-induced polarization enhancement. We find that the overall best-performing functionals of the twelve examined are optPBEvdW and RPBE-D3. Comparisons with DFT assessments for ices in the literature show that where the same methods have been used, the assessments largely agree.

Exploring the electron donor-acceptor duality of B3N3 in noncovalent interactions.

Boron nitrides are very important and are used as lubricants, insulating agents, etc. Interactions of such systems with small molecules are important. This study examined the potential of B3N3 (triboron trinitride) to act as both an electron acceptor and an electron donor in the formation of noncovalent interactions. The anisotropic electronic distribution observed in the electrostatic potential map supported the B3N3's ability to exhibit the predicted electron donor-acceptor duality. Further computational investigations on optimized gas-phase complexes of B3N3:(NH3)n=1-3, B3N3:(NCH)n=1-6, B3N3:(N2H2)n=1-3 and (B3N3)2 confirmed that the B3N3 molecule can participate in B⋯N triel bonding interactions and H···N hydrogen bonding interactions. These energetically stable complexes are primarily governed by electrostatic and polarization interactions.

A quantum chemical study: thoughtful exploration for optimal donors in Y-type dual donor-based dye sensitizers.

This research explores the influence of different dual donors on the effectiveness of dye sensitizers. We selected 35 diverse donors to construct Y-type dual donor-based dyes, connecting them with thiophene as the π-spacer and cyanoacrylic acid as the acceptor. Density functional theory calculations indicate that these dual donor-based dyes exhibit superior optoelectronic properties compared to their single donor counterparts. Notably, significant variations in charge distribution among the different dual donors affect their donor capabilities. Our calculations specifically highlight the enhanced thermodynamic parameters, including light harvesting efficiency (LHE), the free energy of dye injection (ΔGinject), and regeneration (ΔGreg), for donor moieties containing nitrogen atoms, such as NS-3 (N,N-dimethylaniline), NS-5 (diphenylamine), NS-6 (triphenylamine), and NS-8 (4-methoxy-N-(4-methoxyphenyl)-N-phenylaniline). These results suggest that nitrogen-containing donor moieties act as promising candidates for donors for efficient dye sensitizers. However, further experimental validation in the near future will be necessary to confirm our findings.

Catalytic and Mechanistic Approach to the Metal-Free N-Alkylation of 2-Aminopyridines with Diketones.

N-alkylation of amines is an important catalytic reaction in synthetic chemistry. Herein, we report a simple strategy for the N-alkylation of 2-aminopyridines with 1,2-diketones using BF3·OEt2 as a catalyst. The reaction proceeds under aerobic conditions, leading to the formation of a diverse range of substituted secondary amines in good to excellent yields. A close inspection of the mechanistic pathway using various spectroscopic techniques and the computational study revealed that the reaction proceeds through the formation of an iminium-keto intermediate with the liberation of CO2.

Mechanistic Understanding of KOt Bu-Mediated Direct Amidation of Esters with Anilines: An Experimental Study and Computational Approach.

A sustainable and cost-effective protocol has been reported for the synthesis of amide bonds from unactivated esters and non-nucleophilic amines promoted by potassium tert-butoxide under aerobic conditions. The reaction proceeds under relatively mild conditions, encompassing wide substrate scope. A combined experimental and quantum chemical study has been performed to shed light on the mechanism, which implied that a radical pathway is operating for the present protocol.

Identification of Alkaloids from Terminalia chebula as Potent SARS- CoV-2 Main Protease Inhibitors: An In Silico Perspective.

Natural compounds in medicinal plants are best remedies for different diseases and are important to develop new drugs. This work was dedicated to understand the role of different natural compounds of Terminalia Chebula, a well-known herbal plant, in the treating of Covid 19. In this article, we have investigated interactions of such natural compounds from Terminalia Chebula with the main protease (Mpro) of the SARS-CoV-2, which is a key component for cleavage of viral polyprotein, and an important target for the development of drugs towards COVID-19. We have performed molecular docking study on 22 different molecules of Terminalia Chebula and proposed that 7 of the natural compounds (triterpenoids and sterols) interacts with a comparable or stronger interactions than the inhibitor N3. Molecular dynamics simulations (100 ns) revealed that 7 Mpro-Terminalia Chebula complexes are stable, conformationally less fluctuated, slightly less compact, and marginally expanded than ligand-free conformation of Mpro. The intermolecular H-bonding and detailed MM/PBSA and MM-GBSA analysis showed Daucosterol interaction to be the most strong, whereas comparable interactions were observed for Arjunetin, Maslinic acid, and Bellericoside. Our study suggested that these natural compounds can act as potent Mpro inhibitors for SARS-CoV-2, and may evolve as promising anti-COVID-19 drugs in the near future.

Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (mpro): a molecular docking, molecular dynamics and structure-activity relationship studies.

SARS-COV-2, the novel coronavirus and root of global pandemic COVID-19 caused a severe health threat throughout the world. Lack of specific treatments raised an effort to find potential inhibitors for the viral proteins. The recently invented crystal structure of SARS-CoV-2 main protease (Mpro) and its key role in viral replication; non-resemblance to any human protease makes it a perfect target for inhibitor research. This article reports a computer-aided drug design (CADD) approach for the screening of 118 compounds with 16 distinct heterocyclic moieties in comparison with 5 natural products and 7 repurposed drugs. Molecular docking analysis against Mpro protein were performed finding isatin linked with a oxidiazoles (A2 and A4) derivatives to have the best docking scores of -11.22 kcal/mol and -11.15 kcal/mol respectively. Structure-activity relationship studies showed a good comparison with a known active Mpro inhibitor and repurposed drug ebselen with an IC50 value of -0.67 µM. Molecular Dynamics (MD) simulations for 50 ns were performed for A2 and A4 supporting the stability of the two compounds within the binding pocket, largely at the S1, S2 and S4 domains with high binding energy suggesting their suitability as potential inhibitors of Mpro for SARS-CoV-2.

Triazole based isatin derivatives as potential inhibitor of key cancer promoting kinases- insight from electronic structure, docking and molecular dynamics simulations.

Computer Aided Drug Design approaches have been applied to predict potential inhibitors for two different kinases, namely, cyclin-dependent kinase 2 (CDK2) and Epidermal Growth Factor Receptor (EGFR) which are known to play crucial role in cancer growth. We have designed alkyl and aryl substituted isatin-triazole ligands and performed molecular docking to rank and predict possible binding pockets in CDK2 and EGFR kinases. Best-scoring ligands in the kinase-binding pocket were selected from the docking study and subjected to molecular dynamics simulation. Absolute binding affinities were estimated from the MD trajectories using the MM/PBSA approach. The results suggest that aryl substituted isatin-triazole ligands are better binder to the kinases relative to its alkyl analogue. Furthermore, aryl substituted isatin-triazole ligands prefer binding to EGFR kinases relative to CDK2. The ligand binding pockets of the kinases are primarily hydrophobic in nature. Ligand-kinase binding is favoured by electrostatic and Van der Waals interactions, later being the major contributor. Large estimated negative binding affinities (~ -10 to -25 kcal/mol) indicate that the ligands might inhibit the kinases. Physicochemical property analysis suggests that the proposed ligands could be orally bio-available.

CricShotClassify: An Approach to Classifying Batting Shots from Cricket Videos Using a Convolutional Neural Network and Gated Recurrent Unit.

Recognizing the sport of cricket on the basis of different batting shots can be a significant part of context-based advertisement to users watching cricket, generating sensor-based commentary systems and coaching assistants. Due to the similarity between different batting shots, manual feature extraction from video frames is tedious. This paper proposes a hybrid deep-neural-network architecture for classifying 10 different cricket batting shots from offline videos. We composed a novel dataset, CricShot10, comprising uneven lengths of batting shots and unpredictable illumination conditions. Impelled by the enormous success of deep-learning models, we utilized a convolutional neural network (CNN) for automatic feature extraction, and a gated recurrent unit (GRU) to deal with long temporal dependency. Initially, conventional CNN and dilated CNN-based architectures were developed. Following that, different transfer-learning models were investigated-namely, VGG16, InceptionV3, Xception, and DenseNet169-which freeze all the layers. Experiment results demonstrated that the VGG16-GRU model outperformed the other models by attaining 86% accuracy. We further explored VGG16 and two models were developed, one by freezing all but the final 4 VGG16 layers, and another by freezing all but the final 8 VGG16 layers. On our CricShot10 dataset, these two models were 93% accurate. These results verify the effectiveness of our proposed architecture compared with other methods in terms of accuracy.

Exploiting hydrogen bonding interactions to probe smaller linear and cyclic diamines binding to G-quadruplexes: a DFT and molecular dynamics study.

G-quadruplexes are formed by the association of four guanine bases through Hoogsteen hydrogen bonding in guanine-rich sequences of DNA and exist in the telomere as well as in promoter regions of certain oncogenes. The sequences of G-quadruplex-DNA are targets for the design of molecules that can bind and can be developed as anti-cancer drugs. The linear and cyclic protonated diamines have been explored to bind to G-quadruplex-DNA through hydrogen bonding interactions. The quadruplex-DNA binders exploit π-stacking and hydrogen bonding interactions with the phosphate backbone of loops and grooves. In this study, linear and cyclic protonated diamines showed remarkable binding affinity for G-tetrads using hydrogen bonding interactions. The DFT M06-2X/6-31G(d)//B3LYP/6-31+G(d) level of theory showed that the cyclic ee-1,2-CHDA (equatorial-equatorial form of 1,2-disubstituted cyclohexadiamine di-cation) binds to the G-tetrads very strongly (∼70.0 kcal mol-1), with a much higher binding energy than the linear protonated diamines. The binding affinity of ligands for G-tetrads with counterions has also been examined. The binding preference of these small ligands for G-tetrads is higher than for DNA-duplex. The binding affinity of an intercalated acridine-based ligand (BRACO-19) for G-quadruplexes has been examined and the binding energy is relatively lower than that for the 1,2 disubstituted cyclohexadiamine di-cation with G-tetrads. The atoms-in-molecules (AIM) analysis reveals that the hydrogen bonding interactions between the organic systems with G-tetrads are primarily electrostatic in nature. The molecular dynamics simulations performed using a classical force field (GROMACS) also supported the phosphate backbone sites of G-quadruplex-DNA to bind to these diamines. To mimic the structural pattern of BRACO-19, the designed inhibitor N,2-bis-2(3,4-aminocyclohexyl) acetamide (9) examined possesses two 1,2-CHDA moieties linked through an acetamide group. The molecular dynamics results showed that the designed molecule 9 can efficiently bind to the base-pairs and the phosphate backbone of G quadruplex-DNA using H-bonding interactions. The binding affinity calculated for the intercalated acridine-based drug (BRACO-19) with G-quadruplexes is weaker compared to ee-1,2-CHDA. These ligands deliver a different binding motif (hydrogen bonding) compared to the reported G-quadruplex binders of π-delocalized systems and will kindle interest in examining such scaffolds to stabilize DNA.

In silico studies toward understanding the interactions of DNA base pairs with protonated linear/cyclic diamines.

Protonated amino groups are ubiquitous in nature and important in the fields of chemistry and biology. In search of efficient polyamine analogues, we have performed DFT calculations on the interactions of some simple cyclic and constrained protonated diamines with the DNA base pairs and compared the results with those obtained for the corresponding interactions involving linear diamines, which mimic biogenic polyamines such as spermine. The interactions are mainly governed by the strong hydrogen bonding between the ligand and the DNA base pairs. The DFT calculations suggest that the major-groove N7 interaction (GC base pair) with linear diamine is energetically more favored than other possible interactions, as reported with spermine. The cyclic diamines exhibited better interactions with the N7 site of the AT and GC base pairs of DNA than the linear diamines. The net atomic charges calculated for the protonated amine hydrogens were higher for the cyclic systems than for the linear diamines, inducing better binding affinity with the DNA base pairs. The stable conformers of cyclic diamines were predicted using the MP2/aug-cc-pVDZ level of theory. The positions of the protonated diamine groups in these cyclic systems are crucial for effective binding with the DNA base pairs. The DFT-calculated results show that diequatorial (ee) 1,2-cyclohexadiamine (CHDA) is a promising candidate as a polyamine analogue for biogenic polyamines. Molecular dynamics simulations were performed using explicit water molecules for the interaction of representative ligands with the DNA base pairs to examine the influence of solvent molecules on such interactions.

Is dual morphology of rock-salt crystals possible with a single additive? The answer is yes, with barbituric acid.

Crystal face lift: barbituric acid is shown to be a new crystal-habit modifier for sodium chloride crystals. Two morphologies of salt crystals can be prepared separately with this new additive. It is of the few additives able to induce rhombic dodecahedron crystals for NaCl, and is required only a trace of amount, unlike other additives, such as glycine.

Photosensitization of nanoparticulate TiO2 using a Re(I)-polypyridyl complex: studies on interfacial electron transfer in the ultrafast time domain.

We have synthesized a new photoactive rhenium(i)-complex having a pendant catechol functionality [Re(CO)(3)Cl(L)] (1) (L is 4-[2-(4'-methyl-2,2'-bipyridinyl-4-yl)vinyl]benzene-1,2-diol) for studying the dynamics of the interfacial electron transfer between nanoparticulate TiO(2) and the photoexcited states of this Re(i)-complex using femtosecond transient absorption spectroscopy. Our steady state absorption studies revealed that complex 1 can bind strongly to TiO(2) surfaces through the catechol functionality with the formation of a charge transfer (CT) complex, which has been confirmed by the appearance of a new red-shifted CT band. The longer wavelength absorption band for 1, bound to TiO(2) through the proposed catecholate functionality, could also be explained based on the DFT calculations. Dynamics of the interfacial electron transfer between 1 and TiO(2) nanoparticles was investigated by studying kinetics at various wavelengths in the visible and near infrared regions. Electron injection into the conduction band of the nanoparticulate TiO(2) was confirmed by detection of the conduction band electron in TiO(2) ([e(-)](TiO(2)(CB))) and the cation radical of the adsorbed dye (1˙(+)) in real time as monitored by transient absorption spectroscopy. A single exponential and pulse-width limited (<100 fs) electron injection was observed. Back electron transfer dynamics was determined by monitoring the decay kinetics of 1˙(+) and .

What is the minimum number of water molecules required to dissolve a potassium chloride molecule?

This work answers an unsolved question that consists of determining the least number of water molecules necessary to separate a potassium chloride molecule. The answer based on accurate quantum chemical calculations suggests that tetramers are the smallest clusters necessary to dissociate KCl molecules. The study was made with Møller-Plesset second-order perturbation theory modified with the cluster theory having single, double, and perturbative triple excitations. With this extensive study, the dissociation of KCl molecule in different water clusters was evaluated. The calculated results show that four water molecules stabilize a solvent separated K(+)/Cl(-) ion-pair in prismatic structure and with six water molecules further dissociation was observed. Attenuated total reflection infrared spectroscopy of KCl dissolved in water establishes that clusters are made of closely bound ions with a mean of five water molecules per ion-pair [K(+)(H(2)O)(5)Cl(-)]. (Max and Chapados, Appl Spectrosc 1999, 53, 1601; Max and Chapados, J Chem Phys 2001, 115, 2664.) The calculated results tend to support that five water molecules leads toward the formation of contact ion-pair. The structures, energies, and infrared spectra of KCl molecules in different water clusters are also discussed.

Sensitization of nanocrystalline TiO2 anchored with pendant catechol functionality using a new tetracyanato ruthenium(II) polypyridyl complex.

We have synthesized a new photoactive ruthenium(II) complex having a pendant catechol functionality (K(2)[Ru(CN)(4)(L)] (1) (L is 4-[2-(4'-methyl-2,2'-bipyridinyl-4-yl)vinyl]benzene-1,2-diol) for studying the dynamics of the interfacial electron transfer between nanoparticulate TiO(2) and the photoexcited states of this Ru(II) complex using femtosecond transient absorption spectroscopy. Steady-state absorption and emission studies revealed that the complex 1 showed a strong solvatochromic behavior in solvents or solvent mixtures of varying polarity. Our steady-state absorption studies further revealed that 1 is bound to TiO(2) surfaces through the catechol functionality, though 1 has two different types of functionalities (catecholate and cyanato) for binding to TiO(2) surfaces. The longer wavelength absorption band tail for 1, bound to TiO(2) through the proposed catecholate functionality, could also be explained on the basis of the DFT calculations. Dynamics of the interfacial electron transfer between 1 and TiO(2) nanoparticles was investigated by studying kinetics at various wavelengths in the visible and near-infrared region. Electron injection to the conduction band of the nanoparticulate TiO(2) was confirmed by detection of the conduction band electron in TiO(2) ([e(-)](TiO(2))(CB)) and cation radical of the adsorbed dye (1(*+)) in real time as monitored by transient absorption spectroscopy. A single exponential and pulse-width limited (<100 fs) electron injection was observed. Back electron transfer dynamics was determined by monitoring the decay kinetics of 1(*+) and [e(-)](TiO(2))(CB). This is the first report on ultrafast ET dynamics on TiO(2) nanoparticle surface using a solvatochromic sensitizer molecule.

First principle study towards the influence of Cd2+ on the morphology of sodium chloride.

The influence of Cd(2+) on the morphology of sodium chloride has been investigated with Density functional methods. The preferential interactions of Cd(2+) ion with the {111} surface of NaCl support the observed octahedron morphology of NaCl. The calculations were performed both in the gas phase and aqueous phase using continuum model (COSMO). We have examined the interaction of Cd(2+) with various surface sites of sodium chloride such as, flat face, steps and kinks. The stabilization of {111} NaCl surface by mixed Cd(2+) ion and explicit water molecules in the ratio of (1:3) is in agreement with the SXRD results (Surf. Sci. 599 (2005) 196 [17]). The Cd(2+) ion prefers to interact with {100} surface of NaCl by surrounding with water molecules, whereas, the mixed layer formation on {111} is not specific in nature. The interaction of CdCl(2) with the surface of sodium chloride is ineffective to induce this phenomenon.