Update on novel synthetic approaches towards the construction of carbazole nuclei: a review.

The carbazole scaffold is a significant entity in organic compounds due to its variety of biological and synthetic applications. Traditionally, carbazole skeletons have been synthesized either via the Grabe-Ullman method, Clemo-Perkin method or Tauber method. With the passage of time, these methods have been modified and explored to accomplish the synthesis of target compounds. These methods include hydroarylations, C-H activations, annulations and cyclization reactions mediated by a variety of catalysts to construct carbazole-based compounds. This brief review article intends to provide recent updates on important methodological developments reported for the synthesis of carbazole nuclei covering 2019-2023.

Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues/derivatives.

The exploitation of natural products and their analogues in the field of pharmacology has been regarded as of great importance. It can be attributed to the fact that these scaffolds exhibit diverse chemical properties, distinct biological activities and zenith specificity in their biochemical processes, enabling them to act as favorable structures for lead compounds. The synthesis of natural products has been a crafty and hard-to-achieve task. Steglich esterification reaction has played a significant role in that area. It is a mild and efficient technique for constructing ester linkages. This technique involves the establishment of ester moiety via a carbodiimide-based condensation of a carboxylic acid with an alcohol, thiol or an amine catalyzed by dimethyl aminopyridine (DMAP). Specifically, labile reagents with multiple reactive sites are esterified efficiently with the classical and modified Steglich esterification conditions, which accounts for their synthetic utility. This review encloses the performance of the Steglich esterification reaction in forging the ester linkage for executing the total synthesis of natural products and their derivatives since 2018.

Recent Trends in the Petasis Reaction: A Review of Novel Catalytic Synthetic Approaches with Applications of the Petasis Reaction.

The Petasis reaction, also called the Petasis Borono-Mannich reaction, is a multicomponent reaction that couples a carbonyl derivative, an amine and boronic acids to yield substituted amines. The reaction proceeds efficiently in the presence or absence of a specific catalyst and solvent. By employing this reaction, a diverse range of chiral derivatives can easily be obtained, including α-amino acids. A broad substrate scope, high yields, distinct functional group tolerance and the availability of diverse catalytic systems constitute key features of this reaction. In this review article, attention has been drawn toward the recently reported methodologies for executing the Petasis reaction to produce structurally simple to complex aryl/allyl amino scaffolds.

Driving drowsiness detection using spectral signatures of EEG-based neurophysiology.

Introduction: Drowsy driving is a significant factor causing dire road crashes and casualties around the world. Detecting it earlier and more effectively can significantly reduce the lethal aftereffects and increase road safety. As physiological conditions originate from the human brain, so neurophysiological signatures in drowsy and alert states may be investigated for this purpose. In this preface, A passive brain-computer interface (pBCI) scheme using multichannel electroencephalography (EEG) brain signals is developed for spatially localized and accurate detection of human drowsiness during driving tasks. Methods: This pBCI modality acquired electrophysiological patterns of 12 healthy subjects from the prefrontal (PFC), frontal (FC), and occipital cortices (OC) of the brain. Neurological states are recorded using six EEG channels spread over the right and left hemispheres in the PFC, FC, and OC of the sleep-deprived subjects during simulated driving tasks. In post-hoc analysis, spectral signatures of the δ, θ, α, and ß rhythms are extracted in terms of spectral band powers and their ratios with a temporal correlation over the complete span of the experiment. Minimum redundancy maximum relevance, Chi-square, and ReliefF feature selection methods are used and aggregated with a Z-score based approach for global feature ranking. The extracted drowsiness attributes are classified using decision trees, discriminant analysis, logistic regression, naïve Bayes, support vector machines, k-nearest neighbors, and ensemble classifiers. The binary classification results are reported with confusion matrix-based performance assessment metrics. Results: In inter-classifier comparison, the optimized ensemble model achieved the best results of drowsiness classification with 85.6% accuracy and precision, 89.7% recall, 87.6% F1-score, 80% specificity, 70.3% Matthews correlation coefficient, 70.2% Cohen's kappa score, and 91% area under the receiver operating characteristic curve with 76-ms execution time. In inter-channel comparison, the best results were obtained at the F8 electrode position in the right FC of the brain. The significance of all the results was validated with a p-value of less than 0.05 using statistical hypothesis testing methods. Conclusions: The proposed scheme has achieved better results for driving drowsiness detection with the accomplishment of multiple objectives. The predictor importance approach has reduced the feature extraction cost and computational complexity is minimized with the use of conventional machine learning classifiers resulting in low-cost hardware and software requirements. The channel selection approach has spatially localized the most promising brain region for drowsiness detection with only a single EEG channel (F8) which reduces the physical intrusiveness in normal driving operation. This pBCI scheme has a good potential for practical applications requiring earlier, more accurate, and less disruptive drowsiness detection using the spectral information of EEG biosignals.

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review.

The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing agents (phosphines). It is a renowned stereoselective reaction which inverts the stereochemical configuration of end products. One of the most important applications of the Mitsunobu reaction is its role in the synthesis of natural products. This review article will focus on the contribution of the Mitsunobu reaction towards the total synthesis of natural products, highlighting their biological potential during recent years.

Challenges and innovation: Disease modeling using human-induced pluripotent stem cell-derived cardiomyocytes.

Disease modeling using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has both challenges and promise. While patient-derived iPSC-CMs provide a unique opportunity for disease modeling with isogenic cells, the challenge is that these cells still demonstrate distinct properties which make it functionally less akin to adult cardiomyocytes. In response to this challenge, numerous innovations in differentiation and modification of hiPSC-CMs and culture techniques have been developed. Here, we provide a focused commentary on hiPSC-CMs for use in disease modeling, the progress made in generating electrically and metabolically mature hiPSC-CMs and enabling investigative platforms. The solutions are bringing us closer to the promise of modeling heart disease using human cells in vitro.

How Functional Genomics Can Keep Pace With VUS Identification.

Over the last two decades, an exponentially expanding number of genetic variants have been identified associated with inherited cardiac conditions. These tremendous gains also present challenges in deciphering the clinical relevance of unclassified variants or variants of uncertain significance (VUS). This review provides an overview of the advancements (and challenges) in functional and computational approaches to characterize variants and help keep pace with VUS identification related to inherited heart diseases.

Effect of biochar modified with magnetite nanoparticles and HNO3 for efficient removal of Cr(VI) from contaminated water: A batch and column scale study.

Chromium (Cr) poses serious consequences on human and animal health due to its potential carcinogenicity. The present study aims at preparing a novel biochar derived from Chenopodium quinoa crop residues (QBC), its activation with magnetite nanoparticles (QBC/MNPs) and strong acid HNO3 (QBC/Acid) to evaluate their batch and column scale potential to remove Cr (VI) from polluted water. The QBC, QBC/MNPs and QBC/Acid were characterized with SEM, FTIR, EDX, XRD as well as point of zero charge (PZC) to get an insight into their adsorption mechanism. The impact of different process parameters including dose of the adsorbent (1-4 g/L), contact time (0-180 min), initial concentration of Cr (25-200 mg/L) as well as solution pH (2-8) was evaluated on the Cr (VI) removal from contaminated water. The results revealed that QBC/MNPs proved more effective (73.35-93.62-%) for the Cr (VI) removal with 77.35 mg/g adsorption capacity as compared with QBC/Acid (55.85-79.8%) and QBC (48.85-75.28-%) when Cr concentration was changed from 200 to 25 mg/L. The isothermal experimental results follow the Freundlich adsorption model rather than Langmuir, Temkin and Dubinin-Radushkevich adsorption isotherm models. While kinetic adsorption results were well demonstrated by pseudo second order kinetic model. Column scale experiments conducted at steady state exhibited excellent retention of Cr (VI) by QBC, QBC/MNPs and QBC/Acid at 50 and 100 mg Cr/L. The results showed that this novel biochar (QBC) and its modified forms (QBC/Acid and QBC/MNPs) are applicable with excellent reusability and stability under acidic conditions for the practical treatment of Cr (VI) contaminated water.

Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon.

Human ether a-go-go related gene (hERG) or KV11.1 potassium channels mediate the rapid delayed rectifier current (IKr) in cardiac myocytes. Drug-induced inhibition of hERG channels has been implicated in the development of acquired long QT syndrome type (aLQTS) and fatal arrhythmias. Several marketed drugs have been withdrawn for this reason. Therefore, there is considerable interest in developing better tests for predicting drugs which can block the hERG channel. The drug-binding pocket in hERG channels, which lies below the selectivity filter, normally contains K+ ions and water molecules. In this study, we test the hypothesis that these water molecules impact drug binding to hERG. We developed 3D QSAR models based on alignment independent descriptors (GRIND) using docked ligands in open and closed conformations of hERG in the presence (solvated) and absence (non-solvated) of water molecules. The ligand-protein interaction fingerprints (PLIF) scheme was used to summarize and compare the interactions. All models delineated similar 3D hERG binding features, however, small deviations of about ~0.4 Å were observed between important hotspots of molecular interaction fields (MIFs) between solvated and non-solvated hERG models. These small changes in conformations do not affect the performance and predictive power of the model to any significant extent. The model that exhibits the best statistical values was attained with a cryo_EM structure of the hERG channel in open state without water. This model also showed the best R2 of 0.58 and 0.51 for the internal and external validation test sets respectively. Our results suggest that the inclusion of water molecules during the docking process has little effect on conformations and this conformational change does not impact the predictive ability of the 3D QSAR models.

Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities.

The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinformatics strategy using combined ligand and structure based models for the prediction of hERG inhibition potential (IC50) of new chemical entities (NCEs) during early stages of drug design and development. Integrated GRid-INdependent Descriptor (GRIND) models, and lipophilic efficiency (LipE), ligand efficiency (LE) guided template selection for the structure based pharmacophore models have been used for virtual screening and subsequent hERG activity (pIC50) prediction of identified hits. Finally selected two hits were experimentally evaluated for hERG inhibition potential (pIC50) using whole cell patch clamp assay. Overall, our results demonstrate a difference of less than ±1.6 log unit between experimentally determined and predicted hERG inhibition potential (IC50) of the selected hits. This revealed predictive ability and robustness of our models and could help in correctly rank the potency order (lower µM to higher nM range) against hERG.

Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches.

Polio viral proteinase 2A performs several essential functions in genome replication. Its inhibition prevents viral replication, thus making it an excellent substrate for drug development. In this study, the three-dimensional structure of 2A protease was determined and optimized by homology modelling. To predict the molecular basis of the interaction of small molecular agonists, docking simulations were performed on a structurally diverse dataset of poliovirus 2A protease (PV2Apr°) inhibitors. Docking results were employed to identify high risk missense mutations that are highly damaging to the structure, as well as the function, of the protease. Intrinsic disorder regions (IDRs), drug binding sites (DBS), and protein stability changes upon mutations were also identified among them. Our results demonstrated dominant roles for Lys 15, His 20, Cys 55, Cys 57, Cys 64, Asp 108, Cys 109 and Gly 110, indicating the presence of various important drug binding sites of the protein. Upon subjecting these sites to single-nucleotide polymorphism (SNP) analysis, we observed that out of 155 high risk SNPs, 139 residues decrease the protein stability. We conclude that these missense mutations can affect the functionality of the 2A protease, and that identified protein binding sites can be directed for the attachment and inhibition of the target proteins.

A canonical splice site mutation in GIPC3 causes sensorineural hearing loss in a large Pakistani family.

With homozygosity mapping we have identified two large homozygous regions on chromosome 3q13.11-q13.31 and chromosome 19p13.3-q31.32 in a large Pakistani family suffering from autosomal recessive nonsyndromic hearing impairment (arNSHI). The region on chromosome 19 overlaps with the previously described deafness loci DFNB15, DFNB72 and DFNB95. Mutations in GIPC3 have been shown to underlie the nonsyndromic hearing impairment linked to these loci. Sequence analysis of all exons and exon-intron boundaries of GIPC3 revealed a homozygous canonical splice site mutation, c.226-1G>T, in GIPC3. This is the first mutation described in GIPC3 that affects splicing. The c.226-1G>T mutation is located in the acceptor splice site of intron 1 and is predicted to affect the normal splicing of exon 2. With a minigene assay it was shown to result in the use of an alternative acceptor site in exon 2, resulting in a frameshift and a premature stop codon. This study expands the mutational spectrum of GIPC3 in arNSHI.