The GATA transcriptional program dictates cell fate equilibrium to establish the maternal-fetal exchange interface and fetal development.

The placenta establishes a maternal-fetal exchange interface to transport nutrients and gases between the mother and the fetus. Establishment of this exchange interface relies on the development of multinucleated syncytiotrophoblasts (SynT) from trophoblast progenitors, and defect in SynT development often leads to pregnancy failure and impaired embryonic development. Here, we show that mouse embryos with conditional deletion of transcription factors GATA2 and GATA3 in labyrinth trophoblast progenitors (LaTPs) have underdeveloped placenta and die by ~embryonic day 9.5. Single-cell RNA sequencing analysis revealed excessive accumulation of multipotent LaTPs upon conditional deletion of GATA factors. The GATA factor-deleted multipotent progenitors were unable to differentiate into matured SynTs. We also show that the GATA factor-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. Loss of either GATA2 or GATA3 in cytotrophoblast-derived human trophoblast stem cells (human TSCs) drastically inhibits SynT differentiation potential. Identification of GATA2 and GATA3 target genes along with comparative bioinformatics analyses revealed that GATA factors directly regulate hundreds of common genes in human TSCs, including genes that are essential for SynT development and implicated in preeclampsia and fetal growth retardation. Thus, our study uncovers a conserved molecular mechanism, in which coordinated function of GATA2 and GATA3 promotes trophoblast progenitor-to-SynT commitment, ensuring establishment of the maternal-fetal exchange interface.

Hippo signaling cofactor, WWTR1, at the crossroads of human trophoblast progenitor self-renewal and differentiation.

Healthy progression of human pregnancy relies on cytotrophoblast (CTB) progenitor self-renewal and its differentiation toward multinucleated syncytiotrophoblasts (STBs) and invasive extravillous trophoblasts (EVTs). However, the underlying molecular mechanisms that fine-tune CTB self-renewal or direct its differentiation toward STBs or EVTs during human placentation are poorly defined. Here, we show that Hippo signaling cofactor WW domain containing transcription regulator 1 (WWTR1) is a master regulator of trophoblast fate choice during human placentation. Using human trophoblast stem cells (human TSCs), primary CTBs, and human placental explants, we demonstrate that WWTR1 promotes self-renewal in human CTBs and is essential for their differentiation to EVTs. In contrast, WWTR1 prevents induction of the STB fate in undifferentiated CTBs. Our single-cell RNA sequencing analyses in first-trimester human placenta, along with mechanistic analyses in human TSCs revealed that WWTR1 fine-tunes trophoblast fate by directly regulating WNT signaling components. Importantly, our analyses of placentae from pathological pregnancies show that extreme preterm births (gestational time ≤28 wk) are often associated with loss of WWTR1 expression in CTBs. In summary, our findings establish the critical importance of WWTR1 at the crossroads of human trophoblast progenitor self-renewal versus differentiation. It plays positive instructive roles in promoting CTB self-renewal and EVT differentiation and safeguards undifferentiated CTBs from attaining the STB fate.

Formation and Transformation of Clathrate Hydrates under Interstellar Conditions.

ConspectusContinuing efforts by many research groups have led to the discovery of ∼240 species in the interstellar medium (ISM). Observatory- and laboratory-based astrochemical experiments have led to the discovery of these species, including several complex organic molecules (COMs). Interstellar molecular clouds, consisting of water-rich icy grains, have been recognized as the primordial sources of COMs even at extremely low temperatures (∼10 K). Therefore, it is paramount to understand the chemical processes of this region, which may contribute to the chemical evolution and formation of new planetary systems and the origin of life.This Account discusses our effort to discover clathrate hydrates (CHs) of several molecules and their structural varieties, transformations, and kinetics in a simulated interstellar environment. CHs are nonstochiometric crystalline host-guest complexes in which water molecules form cages of different sizes to entrap guest molecules. CHs are abundant on earth and require moderate temperatures and high pressures for their formation. Our focus has been to form CHs at extremely low pressure and temperature as in the ISM, although their existence under such conditions has been a long-standing question since water and guest molecules (CH4, CO2, CO, etc.) exist in space. In multiple studies conducted at ∼10-10 mbar, we showed that CH4, CO2, and C2H6 hydrates could be formed at 30, 10, and 60 K, respectively. Well-defined IR spectroscopic features supported by quantum chemical simulations and temperature-programmed desorption mass spectrometric analyses confirmed the existence of the 512 (for CH4 and CO2) and 51262 (for C2H6) CH cages. Mild thermal activation for long periods under ultrahigh vacuum (UHV) allowed efficient molecular diffusion, which is crucial for forming CHs. We also explored the formation of THF hydrate (a promoter/stabilizer for binary CHs), and a spontaneous method was found for its formation under UHV. In a subsequent study, we observed a binary THF-CO2 hydrate and its thermal processing at 130 K leading to the transportation of CO2 from the hydrate cages to the matrix of amorphous water. The findings imply that such systems possess a dynamic setting that facilitates the movement of molecules, potentially accounting for the chemical changes observed in the ISM. Furthermore, an intriguing fundamental phenomenon is the consequences of these CHs and their dynamics. We showed that preformed acetone and formaldehyde hydrates dissociate to form cubic (Ic) and hexagonal (Ih) ices at 130-135 K, respectively. These unique processes could be the mechanistic routes for the formation of various ices in astrophysical environments.Other than adding a new entry, namely, CHs, to the list of species found in ISM, its existence opens new directions to astrochemistry, observational astronomy, and astrobiology. Our work provides a molecular-level understanding of the formation pathways of CHs and their transformation to crystalline ices, which sheds light on the chemical evolution of simple molecules to COMs in ISM. Furthermore, CHs can be potential candidates for studies involving radiation, ionization, and electron impact to initiate chemical transformations between the host and guest species and may be critical in understanding the origin of life.

Partitioning photochemically formed CO2 into clathrate hydrate under interstellar conditions.

Clathrate hydrates (CHs), host-guest compounds of water forming hydrogen-bonded cages around guest molecules, are now known to exist under interstellar conditions. Experimental evidence demonstrated that prolonged thermal treatment of a solid mixture of water and CO2/CH4 produces CHs at 10-30 K under simulated interstellar conditions. However, in the current study, we show that CO2 produced photochemically by vacuum ultraviolet irradiation of H2O-CO mixtures at 10 K and ∼10-10 mbar, gets partitioned into its CH phase and a matrix phase embedded in amorphous ice. The process occurring under simulated interstellar conditions was studied at different temperatures and H2O-CO compositions. The formation of CO2 CH and other photoproducts was confirmed using reflection absorption infrared spectroscopy. The UV-induced photodesorption event of CO2 may provide the mobility required for the formation of CHs, while photoproducts like methanol can stabilize such CH structures. Our study suggests that new species originating during such energetic processing in ice matrices may form CH, potentially altering the chemical composition of astrophysical environments.

Catalyzing a Cure: Discovery and development of LRRK2 inhibitors for the treatment of Parkinson's disease.

Parkinson's disease (PD) is an age-related second most common progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no effective disease modifying therapeutics have reached clinics for treatment/management of PD. Leucine-rich repeat kinase 2 (LRRK2) which controls membrane trafficking and lysosomal function and its variant LRRK2-G2019S are involved in the development of both familial and sporadic PD. LRRK2, is therefore considered as a legitimate target for the development of therapeutics against PD. During the last decade, efforts have been made to develop effective, safe and selective LRRK2 inhibitors and also our understanding about LRRK2 has progressed. However, there is an urge to learn from the previously designed and reported LRRK2 inhibitors in order to effectively approach designing of new LRRK2 inhibitors. In this review, we have aimed to cover the pre-clinical studies undertaken to develop small molecule LRRK2 inhibitors by screening the patents and other available literature in the last decade. We have highlighted LRRK2 as targets in the progress of PD and subsequently covered detailed design, synthesis and development of diverse scaffolds as LRRK2 inhibitors. Moreover, LRRK2 inhibitors under clinical development has also been discussed. LRRK2 inhibitors seem to be potential targets for future therapeutic interventions in the treatment and management of PD and this review can act as a cynosure for guiding discovery, design, and development of selective and non-toxic LRRK2 inhibitors. Although, there might be challenges in developing effective LRRK2 inhibitors, the opportunity to successfully develop novel therapeutics targeting LRRK2 against PD has never been greater.

Synthesis and biological evaluation of Halogen-Substituted novel α-Ketoamides as potential protein aggregation modulators in Alzheimer's disease.

The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aß) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from ß,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aß aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aß aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10-6 cm/s. In addition to its Aß inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aß induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23's interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.

OlfactionBase: a repository to explore odors, odorants, olfactory receptors and odorant-receptor interactions.

Olfaction is a multi-stage process that initiates with the odorants entering the nose and terminates with the brain recognizing the odor associated with the odorant. In a very intricate way, the process incorporates various components functioning together and in synchronization. OlfactionBase is a free, open-access web server that aims to bring together knowledge about many aspects of the olfaction mechanism in one place. OlfactionBase contains detailed information of components like odors, odorants, and odorless compounds with physicochemical and ADMET properties, olfactory receptors (ORs), odorant- and pheromone binding proteins, OR-odorant interactions in Human and Mus musculus. The dynamic, user-friendly interface of the resource facilitates exploration of different entities: finding chemical compounds having desired odor, finding odorants associated with OR, associating chemical features with odor and OR, finding sequence information of ORs and related proteins. Finally, the data in OlfactionBase on odors, odorants, olfactory receptors, human and mouse OR-odorant pairs, and other associated proteins could aid in the inference and improved understanding of odor perception, which might provide new insights into the mechanism underlying olfaction. The OlfactionBase is available at https://bioserver.iiita.ac.in/olfactionbase/.

Synthesis, In vivo, and In silico Evaluation of New Pyrazoline- Benzothiazole Conjugates as Orally Administered Antiepileptic Agents.

New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. The antiepileptic potential of the synthesized compounds has been tested by following standard animal screening models which include maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The study concluded that compounds 9c, 9d, 9f, 9i, 9n, and 9o possessed good antiepileptic potential when compared with standard drugs like carbamazepine and phenytoin. The results of the rotarod performance test also established them without any neurotoxicity. The motor impairment test yielded that the synthesized compounds are also good antidepressants. In-silico studies have been performed to determine the eligibility of synthesized compounds as orally administered molecules and interactions with the target proteins. The result of in-silico studies reinforced results obtained by in vivo study of the synthesized compounds along with their possible mechanism of antiepileptic action i.e. via inhibiting voltage-gated sodium channels (VGSCs) and gamma-aminobutyric acid-A receptor.

Protein kinase inhibitors in the management of cancer: therapeutic opportunities from natural compounds.

Kinase is an enzyme that helps in the phosphorylation of the targeted molecules and can affect their ability to react with other molecules. So, kinase influences metabolic reactions like cell signaling, secretory processes, transport of molecules, etc. The increased activity of certain kinases may cause various types of cancer, i.e. leukemia, glioblastoma, and neuroblastomas. So, the growth of particular cancer cells can be prevented by the inhibition of the kinase responsible for those cancers. Natural products are the key resources for the development of new drugs where approximately 60% of anti-tumor drugs are being developed with the same including specific kinase dwellers. This study comprised molecular interactions of various molecules (obtained from natural sources) as kinase inhibitors for the treatment of cancer. It is expected that by analyzing the skeleton behavior, the process of action, and the body-related activity of these organic products, new cancer-avoiding molecules can be developed.

Application of sequence semantic and integrated cellular geography approach to study alternative biogenesis of exonic circular RNA.

BACKGROUND: Concurrent existence of lncRNA and circular RNA at both nucleus and cytosol within a cell at different proportions is well reported. Previous studies showed that circular RNAs are synthesized in nucleus followed by transportation across the nuclear membrane and the export is primarily defined by their length. lncRNAs primarily originated through inefficient splicing and seem to use NXF1 for cytoplasm export. However, it is not clear whether circularization of lncRNA happens only in nucleus or it also occurs in cytoplasm. Studies indicate that circular RNAs arise when the splicing apparatus undergoes a phenomenon of back splicing. Minor spliceosome (U12 type) mediated splicing occurs in cytoplasm and is responsible for the splicing of 0.5% of introns of human cells. Therefore, possibility of cRNA biogenesis mediated by minor spliceosome at cytoplasm cannot be ruled out. Secondly, information on genes transcribing both circular and lncRNAs along with total number of RBP binding sites for both of these RNA types is extractable from databases. This study showed how these apparently unconnected pieces of reports could be put together to build a model for exploring biogenesis of circular RNA. RESULTS: As a result of this study, a model was built under the premises that, sequences with special semantics were molecular precursors in biogenesis of circular RNA which occurred through catalytic role of some specific RBPs. The model outcome was further strengthened by fulfillment of three logical lemmas which were extracted and assimilated in this work using a novel data analytic approach, Integrated Cellular Geography. Result of the study was found to be in well agreement with proposed model. Furthermore this study also indicated that biogenesis of circular RNA was a post-transcriptional event. CONCLUSIONS: Overall, this study provides a novel systems biology based model under the paradigm of Integrated Cellular Geography which can assimilate independently performed experimental results and data published by global researchers on RNA biology to provide important information on biogenesis of circular RNAs considering lncRNAs as precursor molecule. This study also suggests the possible RBP-mediated circularization of RNA in the cytoplasm through back-splicing using minor spliceosome.

N-glycosylation induced changes in tau protein dynamics reveal its role in tau misfolding and aggregation: A microsecond long molecular dynamics study.

Various posttranslational modifications like hyperphosphorylation, O-GlcNAcylation, and acetylation have been attributed to induce the abnormal folding in tau protein. Recent in vitro studies revealed the possible involvement of N-glycosylation of tau protein in the abnormal folding and tau aggregation. Hence, in this study, we performed a microsecond long all atom molecular dynamics simulation to gain insights into the effects of N-glycosylation on Asn-359 residue which forms part of the microtubule binding region. Trajectory analysis of the stimulations coupled with essential dynamics and free energy landscape analysis suggested that tau, in its N-glycosylated form tends to exist in a largely folded conformation having high beta sheet propensity as compared to unmodified tau which exists in a large extended form with very less beta sheet propensity. Residue interaction network analysis of the lowest energy conformations further revealed that Phe378 and Lys353 are the functionally important residues in the peptide which helped in initiating the folding process and Phe378, Lys347, and Lys370 helped to maintain the stability of the protein in the folded state.

Differential gene expression and protein-protein interaction network profiling of sulfur mustard-exposed rabbit corneas employing RNA-seq data and bioinformatics tools.

Sulfur mustard (SM) ocular exposure severely damages the cornea and causes vision impairment. At present, no specific therapy exists to mitigate SM-induced corneal injury and vision loss. This study performed transcriptome profiling of naïve, SM-damaged, and SM-undamaged rabbit corneas using RNA-seq analysis and bioinformatic tools to gain a better mechanistic understanding and develop SM-specific medical countermeasures. The mRNA profiles of rabbit corneas 4 weeks post SM vapor exposure were generated using Illumina-NextSeq deep sequencing (Gene Expression Omnibus accession # GSE127708). The RNA sequences of naïve (n = 4), SM-damaged (n = 5), and SM-undamaged (n = 5) corneas were subjected to differential expression (DE) analysis after quality control profiling with FastQC. DE analysis was performed using HISAT2, StringTie, and DESeq2. The log2(FC)±2 and adjusted p˂0.05 were chosen to identify the most relevant genes. A total of 5930 differentially expressed genes (DEGs) (upregulated: 3196, downregulated: 2734) were found in SM-damaged corneas compared to naïve corneas, whereas SM-undamaged corneas showed 1884 DEGs (upregulated: 1029, downregulated: 855) compared to naïve corneas. DE profiling of SM-damaged corneas to SM-undamaged corneas revealed 985 genes (upregulated: 308, downregulated: 677). The DE profiles were subsequently subjected to signaling pathway enrichment, and protein‒protein interactions (PPIs) were analyzed. Pathway enrichment was performed for the genes associated with cellular apoptosis, death, adhesion, migration, differentiation, proliferation, extracellular matrix, and tumor necrosis factor production. To identify novel targets, we narrowed the pathway analysis to upregulated and downregulated genes associated with cell proliferation and differentiation, and PPI networks were developed. Furthermore, protein targets associated with cell differentiation and proliferation that may play vital roles in corneal fibrosis and wound healing post SM injury were identified.

Design of CO2 Thickeners and Role of Aromatic Rings in Enhanced Oil Recovery Using Molecular Dynamics.

Oligomers of PDMS (M1), polyFast (M2), modified PVEE (M3 and M4), and two new molecules with cyclic cores (M5 and M6) were studied to understand their ability to thicken the sc-CO2 at 377 K and 55 MPa, without any cosolvent. It was observed that PDMS and polyFast behaved in the known ways. PDMS does not improve the viscosity of the system without a cosolvent and PolyFast enhances the viscosity by a large margin. M3 and M4 also have not improved the viscosity significantly even with the introduction of a styrene component, but which has improved their solubilities in the fluid. M5 and M6, however, are observed to have enhanced the viscosity similar to that of polyFast due to their structural advantage and π-π interactions between the molecules. These molecules were also tested for their synthesizability, and their synthesis is found to be moderately easy.

Artificial intelligence assisted identification of potential tau aggregation inhibitors: ligand- and structure-based virtual screening, in silico ADME, and molecular dynamics study.

Alzheimer's disease (AD) is a severe, growing, multifactorial disorder affecting millions of people worldwide characterized by cognitive decline and neurodegeneration. The accumulation of tau protein into paired helical filaments is one of the major pathological hallmarks of AD and has gained the interest of researchers as a potential drug target to treat AD. Lately, Artificial Intelligence (AI) has revolutionized the drug discovery process by speeding it up and reducing the overall cost. As a part of our continuous effort to identify potential tau aggregation inhibitors, and leveraging the power of AI, in this study, we used a fully automated AI-assisted ligand-based virtual screening tool, PyRMD to screen a library of 12 million compounds from the ZINC database to identify potential tau aggregation inhibitors. The preliminary hits from virtual screening were filtered for similar compounds and pan-assay interference compounds (the compounds containing reactive functional groups which can interfere with the assays) using RDKit. Further, the selected compounds were prioritized based on their molecular docking score with the binding pocket of tau where the binding pockets were identified using replica exchange molecular dynamics simulation. Thirty-three compounds showing good docking scores for all the tau clusters were selected and were further subjected to in silico pharmacokinetic prediction. Finally, top 10 compounds were selected for molecular dynamics simulation and MMPBSA binding free energy calculations resulting in the identification of UNK_175, UNK_1027, UNK_1172, UNK_1173, UNK_1237, UNK_1518, and UNK_2181 as potential tau aggregation inhibitors.

Integrated use of ligand and structure-based virtual screening, molecular dynamics, free energy calculation and ADME prediction for the identification of potential PTP1B inhibitors.

Protein tyrosine phosphatases (PTPs) are the group of enzymes that control both cellular activity and the dephosphorylation of tyrosine (Tyr)-phosphorylated proteins. Dysregulation of PTP1B has contributed to numerous diseases including Diabetes Mellitus, Alzheimer's disease, and obesity rendering PTP1B as a legitimate target for therapeutic applications. It is highly challenging to target this enzyme because of its highly conserved and positively charged active-site pocket motivating researchers to find novel lead compounds against it. The present work makes use of an integrated approach combining ligand-based and structure-based virtual screening to find hit compounds targeting PTP1B. Initially, pharmacophore modeling was performed to find common features like two hydrogen bond acceptors, an aromatic ring and one hydrogen bond donor from the potent PTP1B inhibitors. The dataset of compounds matching with the common pharmacophoric features was filtered to remove Pan-Assay Interference substructure and to match the Lipinski criteria. Then, compounds were further prioritized using molecular docking and top fifty compounds with good binding affinity were selected for absorption, distribution, metabolism, and excretion (ADME) predictions. The top five compounds with high solubility, absorption and permeability holding score of - 10 to - 9.3 kcal/mol along with Ertiprotafib were submitted to all-atom molecular dynamic (MD) studies. The MD studies and binding free energy calculations showed that compound M4, M5 and M8 were having better binding affinity for PTP1B enzyme with ∆Gtotal score of - 24.25, - 31.47 and - 33.81 kcal/mol respectively than other compounds indicating that compound M8 could be a suitable lead compound as PTP1B inhibitor.

Synthesis, Biological Evaluation and in Silico Study of N-(2- and 3-Pyridinyl)benzamide Derivatives as Quorum Sensing Inhibitors against Pseudomonas aeruginosa.

The effectiveness of treating bacterial infections is seriously threatened by the emergence of bacterial resistance to chemical treatment. Growth of microbes in biofilm is one of the main causes of resistance to antimicrobial drugs. Quorum sensing (QS) inhibition, which targets the QS signalling system by obstructing cell-cell communication, was developed as an alternative treatment by creating innovative anti-biofilm drugs. Therefore, the goal of this study is to develop novel antimicrobial drugs that are effective against Pseudomonas aeruginosa by inhibiting QS and acting as anti-biofilm agents. In this study, N-(2- and 3-pyridinyl)benzamide derivatives were selected to design and syntheses. Antibiofilm activity was revealed by all the synthesized compounds and the biofilm was visibly impaired, and the OD595nm readings of solubilized biofilm cells presented a momentous difference between the treated and untreated biofilms. The best anti-QS zone was observed for compound 5d and found to be 4.96 mm. Through in silico research, the physicochemical characteristics and binding manner of these produced compounds were examined. For the purpose of understanding the stability of the protein and ligand complex, molecular dynamic simulation was also carried out. The overall findings showed that N-(2- and 3-pyridinyl)benzamide derivatives could be the key to creating effective newer anti-quorum sensing drugs that are effective against different bacteria.

Synthesis, in Silico Study and Biological Evaluation of N-(Benzothiazol/Thiazol-2-yl)benzamide Derivatives as Quorum Sensing Inhibitors against Pseudomonas aeruginosa.

The development of bacterial resistance to chemical therapy poses a severe danger to efficacy of treating bacterial infections. One of the key factors for resistance to antimicrobial medications is growth of bacteria in biofilm. Quorum sensing (QS) inhibition was created as an alternative treatment by developing novel anti-biofilm medicines. Cell-cell communication is impeded by QS inhibition, which targets QS signaling pathway. The goal of this work is to develop newer drugs that are effective against Pseudomonas aeruginosa by decreasing QS and acting as anti-biofilm agents. In this investigation, N-(benzo[d]thiazol-2-yl)benzamide/N-(thiazol-2-yl)benzamide derivatives 3a-h were designed and synthesized in good yields. Further, molecular docking analyses revealed that binding affinity values were founded -11.2 to -7.6 kcal/mol that were moderate to good. The physicochemical properties of these prepared compounds were investigated through in-silico method. Molecular dynamic simulation was also used to know better understanding of stability of the protein and ligand complex. Comparing N-(benzo[d]thiazol-2-yl)benzamide 3a to salicylic acid (4.40±0.10) that was utilised as standard for quorum sensing inhibitor, the anti-QS action was found greater for N-(benzo[d]thiazol-2-yl)benzamide 3a (4.67±0.45) than salicylic acid (4.40±0.10). Overall, research results suggested that N-(benzo[d]thiazol-2-yl)benzamide/N-(thiazol-2-yl)benzamide derivatives 3a-h may hold to develop new quorum sensing inhibitors.

Structural modification aimed for improving solubility of lead compounds in early phase drug discovery.

Many lead compounds fail to reach clinical trials despite being potent because of low bioavailability attributed to their insufficient solubility making solubility a primary and crucial factor in early phase drug discovery. Solubility improvement of poorly soluble lead compounds without losing potency is a challenging task for the medicinal chemist in a drug discovery setup. Solubility is an important factor not only to dissipate or liquefy a substance but also to attain an optimal concentration of drug in systemic circulation required for the desired therapeutic effect. It has been estimated that more than forty percent of newly developed molecules are practically insoluble in water. Molecules with poor solubility not only cause difficulty for in vitro and in vivo assays but also add significant burdens to drug development in the form of longer time taken and increased cost to optimize the solubility. To tackle this problem, different techniques are being used such as physical, chemical, and miscellaneous methods to enhance solubility. Among them, the medicinal chemistry approach focussed on structural modification is a versatile and unique approach in way that it can also improve other pharmacokinetic/physicochemical parameters simultaneously. In this review, we have begun with brief introduction of solubility and its role followed by recent successful examples of different structural modification tactics reported in the literature including synthesis of prodrugs, hydrophilic and ionizable group insertion, addition & removal of hydrogen bonding, bioisosterism, disruption of molecular symmetry and planarity. Moreover, we have included a section on the obstacles in the solubility optimization and also summarised different in silico tools with potential application in solubility prediction. Overall, this review encompasses various successfully used solubility optimization examples using structure modification.

Urea-thiazole/benzothiazole hybrids with a triazole linker: synthesis, antimicrobial potential, pharmacokinetic profile and in silico mechanistic studies.

Some urea-thiazole/benzothiazole hybrids with a triazole linker were synthesized via Cu(I)-catalysed click reaction. After successfully analysed by various spectral techniques including FTIR, NMR and HRMS, antimicrobial screening of the synthesized hybrids along with their precursors was carried out against two Gram (+) bacteria (Staphylococcus aureus and Bacillus endophyticus), two Gram (-) bacteria (Escherichia coli and Pseudomonas fluorescens) and two fungi (Candida albicans and Rhizopus oryzae). All the synthesized compounds (4a-4l) displayed better biological response than the standard fluconazole against both of the tested fungi. Compounds 4h and 4j were found to be the most active compounds against R. oryzae and C. albicans, respectively. Molecular docking of hybrid 4j and its alkyne precursor 1b in the active site of C. albicans target sterol 14-α demethylase was also performed and was also supported by molecular dynamics studies. In silico ADME prediction of synthesized urea-thiazole/benzothiazole hybrids with a triazole linker and their alkyne precursors was also predicted.

Comparison of the oropharyngeal leak pressure between three second generation supraglottic airway devices during laparoscopic surgery in pediatric patients.

BACKGROUND: Previous studies have shown Proseal LMA and I gel similar to endotracheal intubation in ventilatory ability in pediatric laparoscopic surgeries. AIMS: The primary aim of this study was to assess whether there is a significant difference in the oropharyngeal leak pressure between Ambu Auragrain, I-gel, and Proseal LMA during pediatric laparoscopic surgery. METHODS: In this randomized controlled trial, 90 male patients of American Society of Anesthesiologists physical status I aged between 6 months and 10 years who were scheduled for laparoscopic single-sided inguinal hernia repair were recruited and randomly allocated to three groups in which airway was secured with Ambu Auragain, I gel, or Proseal LMA. The primary outcome was oropharyngeal leak pressure. The secondary outcomes were peak pressures before and after pneumoperitoneum, fiberoptic view, insertion attempts, insertion time, manipulations, perioperative and postoperative anesthesia-related problems. Continuous variables were compared using the one-way analysis of variance or the Kruskal-Wallis test with post hoc Turkey analysis. Categorical and ordinal data were compared using the chi-square test or Fisher's exact test. RESULTS: Oropharyngeal leak pressure before pneumoperitoneum was higher with I gel as compared to Ambu Auragain (27.36 ± 5.72 cm of H2 O vs 23.56 ± 5.72 cm of H2 O) (p = .021) and PLMA (27.36 ± 5.72 cm of H2 O vs 23.24 ± 4.35 cm of H2 O) (p = .011). Oropharyngeal leak pressure after pneumoperitoneum was also higher with I gel as compared to Ambu Auragain (31.58 ± 4.35 cm of H2 O vs 26.83 ± 5.00 cm of H2 O) (p = .001) and Proseal LMA (31.58 ± 4.35 cm of H2 O vs 27.03 ± 3.80 cm of H2 O) (p = .002). Oropharyngeal leak pressures of Ambu Auragain and Proseal LMA were comparable. Postoperative complications were similar in all the supraglottic airway devices. No regurgitation or aspiration-related problem was observed in our study. CONCLUSION: I gel had a higher oropharyngeal leak pressure than the other two supraglottic airway devices and therefore may represent a better choice in situations where higher ventilatory pressures may be necessary, for example, in extremes of weight trendelenburg position, etc. CLINICAL TRIAL IDENTIFIER: Clinical trial registry of India (CTRI/2018/11/016445).