Synthetic access to diverse thiazetidines via a one-pot microwave assisted telescopic approach and their interaction with biomolecules.

A one-pot microwave assisted telescopic approach is reported for the chemo-selective synthesis of substituted 1,3-thiazetidines using readily available 2-aminopyridines/pyrazines/pyrimidine, substituted isothiocyanates and 1,2-dihalomethanes. The procedure involves thiourea formation from 2-aminopyridines/pyrazines/pyrimidine with the substituted isothiocyanates followed by a base catalysed nucleophilic attack of the CS bond on the 1,2-dihalomethane. Subsequently, a cyclization reaction occurs to yield substituted 1,3-thiazetidines. These four membered strained ring systems are reported to possess broad substrate scope with high functional group tolerance. The above synthetic sequence for the formation of four membered heterocycles is proven to be a modular and straightforward approach. Further the mechanistic pathway for the formation of 1,3-thiazetidines was supported by computational evaluations and X-ray crystallography analyses. The relevance of these thiazetidines in biological applications is evaluated by studying their ability to bind bio-macromolecules like proteins and nucleic acids.

An in silico approach to investigate the theranostic potential of coumarin-derived self-immolative luminescent probes.

Till date the challenge exists in the treatments of cancer for various reasons. Most importantly, the available diagnostics are expensive with research gap for enhancing the cancer detection sensitivity. Herein, a series of coumarin-derived fluorescent theranostic probes are reported that can serve as potent anticancer agents as well as in the detection of cancer cells. The potential of these probes to efficiently block one of the well-known cancer drug targets NADPH quinone oxidoreductase-1 (NQO1) is evaluated through various pharmacokinetic methods including absorption, distribution, metabolism and excretion (ADME) properties evaluation, PASS (prediction of activity spectra for substance) algorithm along with molecular docking and dynamic simulations. Further the luminescent properties of these molecules were evaluated by investigating their electronic properties in the ground and excited states with the help of density functional theory methods. Results indicate that the proposed molecules can potentially block the NADPH (reduced form of nicotinamide adenine dinucleotide) binding site of NQO1, thereby inhibiting the activity of the enzyme to ultimately disrupt the metabolism of cancer cells.

Click-derived multifunctional metal complexes for diverse applications.

The Click reaction that involves Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) serves as the most potent and highly dependable tool for the development of many complex architectures. It has paved the way for the synthesis of numerous drug molecules with enhanced synthetic flexibility, reliability, specificity and modularity. It is all about bringing two different molecular entities together to achieve the required molecular properties. The utilization of Click chemistry has been well demonstrated in organic synthesis, particularly in reactions that involve biocompatible precursors. In pharmaceutical research, Click chemistry is extensively utilized for drug delivery applications. The exhibited bio-compatibility and dormancy towards other biological components under cellular environments makes Click chemistry an identified boon in bio-medical research. In this review, various click-derived transition metal complexes are discussed in terms of their applications and uniqueness. The scope of this chemistry towards other streams of applied sciences is also discussed.

In Silico Design and Investigation of Novel Thiazetidine Derivatives as Potent Inhibitors of PrpR in Mycobacterium tuberculosis.

Tuberculosis is one of the most life-threatening acute infectious diseases diagnosed in humans. In the present investigation, a series of 16 new disubstituted 1,3-thiazetidines derivatives is designed, and investigated via various in silico methods for their potential as anti-tubercular agent by evaluating their ability to block the active site of PrpR transcription factor protein of Mycobacterium tuberculosis. The efficacy of the molecules was initially assessed with the help of AutoDock Vina algorithm. Further Glide module is used to redock the previously docked complexes. The binding energies and other physiochemical properties of the designed molecules were evaluated using the Prime-MM/GBSA and the QikProp module, respectively. The results of docking revealed the nature, site of interaction and the binding affinity between the proposed candidates and the active site of PrpR. Further the inhibitory effect of the scaffolds was predicted and evaluated employing a machine learning-based algorithm and was used accordingly. Further, the molecular dynamics simulation studies ascertained the binding characteristics of the unique 13, when analysed across a time frame of 100 ns with GROMACS software. The results show that the proposed 1,3-thiazetidine derivatives such as 10, 11, 13 and 14 could be potent and selective anti-tubercular agents as compared to the standard drug Pyrazinamide. Finally, this study concludes that designed thiazetidines can be employed as anti-tubercular agents. Undeniably, the results may guide the experimental biologists to develop safe and non-toxic drugs against tuberculosis by demanding further in vivo and in vitro analyses.

Identification of novel inhibitors for Prp protein of Mycobacterium tuberculosis by structure based drug design, and molecular dynamics simulations.

In this study, we assess the effective inhibition of a series of thiazolidine derivatives (1a-1q) were adopting structure-based drug design. Thiazolidine is a five-membered ring structure with thioether and amino groups at positions 1 and 3. Although, thiazolidine may bind to a wide range of protein targets, it is a major heterocyclic core in medicinal chemistry. Different scoring utilities including AutoDock Vina, Glide, and MM/GBSA analysis were performed to commensurate the improvement of screening progress. The evaluated binding affinities were validated by molecular dynamics simulations over a period of 20 ns for the interactions between the Mycobacterium tuberculosis protein PrpR with three novel scaffolds (1b, 1j, and 1k). All the scaffolds exhibited distinct stable interactions with the significant residues like Arg169, Arg197, Tyr248, Arg308, and Gly311 respectively. Further, the inhibitory activities of scaffolds were predicted and evaluated by machine learning based algorithm to rank the above proposed compounds. This study reveals the potential of 1k and 1j as effective inhibitor candidates for the treatment of tuberculosis.

A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's Disease and Type 2 Diabetes.

Alzheimer's Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resistance. Reportedly, two non-canonical Receptor Tyrosine Kinases (RTKs), ALK and RYK, both targets of the same micro RNA miR-1271, exhibit significant and consistent functional down-regulation in post-mortem AD and T2D tissues. Incidentally, both have Grb2 as a common downstream adapter and NOX4 as a common ROS producing factor. Here we show that Grb2 and NOX4 play critical roles in reducing the severity of both the diseases. The study demonstrates that the abundance of Grb2 in degenerative conditions, in conjunction with NOX4, reverse cytoskeletal degradation by counterbalancing the network of small GTPases. PAX4, a transcription factor for both Grb2 and NOX4, emerges as the key link between the common pathways of AD and T2D. Down-regulation of both ALK and RYK through miR-1271, elevates the PAX4 level by reducing its suppressor ARX via Wnt/ß-Catenin signaling. For the first time, this study brings together RTKs beyond Insulin Receptor (IR) family, transcription factor PAX4 and both AD and T2D pathologies on a common regulatory platform.

Light emitting probes - approaches for interdisciplinary applications.

Though the field of fluorescent sensors has been known for more than 150 years, tremendous developments were made in the past two decades with the emergence of fluorescence-based optical sensors that are now inevitable tools for sensing a variety of biological, chemical and environmental analytes. These probes are simple, highly sensitive, selective and specific towards detection. There are several unique mechanisms adopted by these probes towards sensing analytes. This tutorial review introduces various fluorescent probes that are being employed in the development of chemo- and bio-sensors for the detection of various charged and neutral species, including biomacromolecules like proteins and nucleic acids. This review mainly focuses on basic principles involved in the design of probes with different sensing methods like self-immolation, peptide beacon, FRET, photo-induced electron/charge transfer, etc. The complexity observed in biological systems with interference from numerous other analytes and the necessity to use multiple probes was overcome by using multiple responsive probes. Herein we have discussed the design and sensing mechanism of various probes that find applications in physical, chemical and biological sciences, diagnostics and therapeutics.

Insights on Chemical Crosslinking Strategies for Proteins.

Crosslinking of proteins has gained immense significance in the fabrication of biomaterials for various health care applications. Various novel chemical-based strategies are being continuously developed for intra-/inter-molecular crosslinking of proteins to create a network/matrix with desired mechanical/functional properties without imparting toxicity to the host system. Many materials that are used in biomedical and food packaging industries are prepared by chemical means of crosslinking the proteins, besides the physical or enzymatic means of crosslinking. Such chemical methods utilize the chemical compounds or crosslinkers available from natural sources or synthetically generated with the ability to form covalent/non-covalent bonds with proteins. Such linkages are possible with chemicals like carbodiimides/epoxides, while photo-induced novel chemical crosslinkers are also available. In this review, we have discussed different protein crosslinking strategies under chemical methods, along with the corresponding crosslinking reactions/conditions, material properties and significant applications.

Exploration of potential inhibitors for tuberculosis via structure-based drug design, molecular docking, and molecular dynamics simulation studies.

Drug resistance in tuberculosis is major threat to human population. In the present investigation, we aimed to identify novel and potent benzimidazole molecules to overcome the resistance management. A series of 20 benzimidazole derivatives were examined for its activity as selective antitubercular agents. Initially, AutodockVina algorithm was performed to assess the efficacy of the molecules. The results are further enriched by redocking by means of Glide algorithm. The binding free energies of the compounds were then calculated by MM-generalized-born surface area method. Molecular docking studies elucidated that benzimidazole derivatives has revealed formation of hydrogen bond and strong binding affinity in the active site of Mycobacterium tuberculosis protein. Note that ARG308, GLY189, VAL312, LEU403, and LEU190 amino acid residues of Mycobacterium tuberculosis protein PrpR are involved in binding with ligands of benzimidazoles. Interestingly, the ligands exhibited same binding potential to the active site of protein complex PrpR in both the docking programs. In essence, the result portrays that benzimidazole derivatives such as 1p, 1q, and 1 t could be potent and selective antitubercular agents than the standard drug isoniazid. These compounds were then subjected to molecular dynamics simulation to validate the dynamics activity of the compounds against PrpR. Finally, the inhibitory behavior of compounds was predicted using a machine learning algorithm trained on a data collection of 15,000 compounds utilizing graph-based signatures. Overall, the study concludes that designed benzimidazoles can be employed as antitubercular agents. Indeed, the results are helpful for the experimental biologists to develop safe and non-toxic drugs against tuberculosis.

Antitumor Effects of Ir(III)-2H-Indazole Complexes for Triple Negative Breast Cancer.

In this work, we have synthesized a series of novel C,N-cyclometalated 2H-indazole-ruthenium(II) and -iridium(III) complexes with varying substituents (H, CH3, isopropyl, and CF3) in the R4 position of the phenyl ring of the 2H-indazole chelating ligand. All of the complexes were characterized by 1H, 13C, high-resolution mass spectrometry, and elemental analysis. The methyl-substituted 2H-indazole-Ir(III) complex was further characterized by single-crystal X-ray analysis. The cytotoxic activity of new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and MDA-MB-468) and colon cancer cell line HCT-116 to investigate their structure-activity relationships. Most of these new complexes have shown appreciable activity, comparable to or significantly better than that of cisplatin in TNBC cell lines. R4 substitution of the phenyl ring of the 2H-indazole ligand with methyl and isopropyl substituents showed increased potency in ruthenium(II) and iridium(III) complexes compared to that of their parent compounds in all cell lines. These novel transition metal-based complexes exhibited high specificity toward cancer cells by inducing alterations in the metabolism and proliferation of cancer cells. In general, iridium complexes are more active than the corresponding ruthenium complexes. The new Ir(III)-2H-indazole complex with an isopropyl substituent induced mitochondrial damage by generating large amounts of reactive oxygen species (ROS), which triggered mitochondrion-mediated apoptosis in TNBC cell line MDA-MB-468. Moreover, this complex also induced G2/M phase cell cycle arrest and inhibited cellular migration of TNBC cells. Our findings reveal the key roles of the novel C-N-cyclometalated 2H-indazole-Ir(III) complex to specifically induce toxicity in cancer cell lines through contributing effects of ROS-induced mitochondrial disruption along with chromosomal and mitochondrial DNA target inhibition.

An assessment study of known pyrazolopyrimidines: Chemical methodology and cellular activity.

Heterocyclic compounds with nitrogen atom play a key role in the normal life cycle of a cell. Pyrazolopyrimidine is a privileged class of nitrogen containing fused heterocyclic compound contributing to a major portion of all lead molecules in medicinal chemistry. The thumbprint of pyrazolopyrimidine as a pharmacophore is always noticeable due to its analogy with the adenine base in DNA. Pyrazolopyrimidines are divided into five types [I, II, III, IV, V] based on the mechanism of action on the specific target conferring a wide scope of research which has accelerated the interest of researchers to investigate its biological profile. In 1956, the anti-cancer activity of pyrazolopyrimidine was evaluated for the first time with appreciable results. Since then, medicinal chemists centered their work on various methods of synthesis and evaluating the biological profile of pyrazolopyrimidine isomers. This report consists of novel methodologies followed to synthesize pyrazolopyrimidine isomers along with a note on their biological significance. To the best of our knowledge, this review article will be first of its kind to encompass different synthetic procedures along with anti-cancer, kinase inhibition, phosphodiesterase inhibition and receptor blocking activity of pyrazolopyrimidine moieties. IC50 values of potent compounds are added wherever necessary to understand the suitability of pyrazolopyrimidine skeletons for a specific biological activity.

One-Pot, Telescopic Approach for the Chemoselective Synthesis of Substituted Benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides and Their Significance in Biological Systems †.

The one-pot telescopic approach has been developed for the chemoselective synthesis of substituted benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides using readily available 2-aminopyridines/pyrazines/pyridazine and 2-chloro benzene sulfonyl chloride. This one-pot procedure involves the chemoselective sulfonylation of 2-aminopyridines/pyrazines/pyridazine with 2-chloro benzene sulfonyl chloride followed by a Cu(I)-catalyzed Ullmann-type C-N coupling reaction to obtain benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides with broad substrate scope and high functional group tolerance. The synthetic sequence merges well with the nucleophilic attack on the 2-amino group of pyridines/pyrazines/pyridazines on the 2-chloro benzene sulfonyl chloride, followed by Cu(I)-catalyzed ipso chloro displacement to C-N bond formation resulting in a more modular and straightforward approach. Moreover, the biological significance of the synthesized benzothiadiazine dioxides was evaluated by following their ability to bind to protein macromolecules and their anti-inflammatory activity.

Environment dependent photophysical and fluorescence turn-off sensing properties of Fe(iii) by substituted phenyl isochromenopyrrol-5-ones.

Analogues of isochromenopyrrolone were synthesized using Montomorillonite K10 as a catalyst and characterized. The electronic structure and geometry of all the synthesized compounds were investigated experimentally by UV-visible absorption and fluorescence spectroscopy. A negligible shift was observed in the absorption spectrum while a large red shift was observed in the fluorescence spectrum upon changing from non-polar to polar solvents. The experimental results were compared with those from density functional theory calculations. The observed photophysical properties were induced from the solvent environment. Except for chlorosubstituition, other functional groups like methyl, dimethyl, diethyl or methoxy, did not influence the electronic properties of the molecules significantly. The experimental results were in good agreement with the theoretical interpretations. Moreover, these isochromenopyrrolones possess excellent sensing ability for Fe(iii) ions via the fluorescence turn-off mechanism with a detection limit of ∼10-6 M and an association constant of ∼103 M-1. It is proposed that these molecules can find their use in environment sensing applications.

Altered Levels of Long NcRNAs Meg3 and Neat1 in Cell And Animal Models Of Huntington's Disease.

Altered expression levels of protein-coding genes and microRNAs have been implicated in the pathogenesis of Huntington's disease (HD). The involvement of other ncRNAs, especially long ncRNAs (lncRNA), is being realized recently and the related knowledge is still rudimentary. Using small RNA sequencing and PCR arrays we observed perturbations in the levels of 12 ncRNAs in HD mouse brain, eight of which had human homologs. Of these, Meg3, Neat1, and Xist showed a consistent and significant increase in HD cell and animal models. Transient knock-down of Meg3 and Neat1 in cell models of HD led to a significant decrease of aggregates formed by mutant huntingtin and downregulation of the endogenous Tp53 expression. Understanding Meg3 and Neat1 functions in the context of HD pathogenesis is likely to open up new strategies to control the disease.

Control of regioselectivity over gold nanocrystals of different surfaces for the synthesis of 1,4-disubstituted triazole through the click reaction.

Gold nanocubes, octahedra, and rhombic dodecahedra were examined for facet-dependent catalytic activity in the formation of triazoles. Rhombic dodecahedra gave 100% regioselective 1,4-triazoles. The product yield was increased by decreasing the particle size. However, a mixture of 1,4- and 1,5-triazoles was obtained in lower yields when cubes and octahedra of similar sizes were used. The lowest Au-atom density on the {110} surface and largest unsaturated coordination number of surface Au atoms may explain their best catalytic efficiency and product regioselectivity. Various spectroscopic techniques were employed to verify the formation of the Au-acetylide intermediate and establish the reaction mechanism, in which phenylacetylene binds to the Au {110} surface through the terminal-binding mode to result in the exclusive formation of 1,4-triazoles. The smallest rhombic dodecahedra can give diverse 1,4-disubstituted triazoles in good yields by coupling a wide variety of alkynes and organic halides.

Quantitative Investigation of Neuroprotective Role of ROR1 in a Cell Culture Model of Alzheimer's Disease.

Cytoskeletal and microtubule atrophy are major hallmarks of Alzheimer's disease (AD). A method to investigate endogenous proteins that can interact/stabilize the cytoskeleton (under pathological cues) is rare. Here, we describe how receptor tyrosine kinase-like orphan receptor 1 (ROR1), a receptor tyrosine kinase (RTK), can act as a neuroprotective molecule by promoting neurite outgrowth, stabilizing cytoskeletal components, and altering the dynamics of actin assembly in a cell culture model of AD.

Imaging and Assay of the Dynamics of Cytotoxic Huntingtin (HTT) Protein Aggregates Regulated by lncRNAs.

Huntington's disease (HD) pathogenesis involves deregulation of coding and noncoding RNA transcripts of which the involvement of long noncoding RNAs (lncRNA) has been realized recently. Of these, Meg3, Neat1, and Xist showed a consistent and significant increase in HD cell and animal models. In the present study, we formulate a methodology to visualize and quantify intracellular aggregates formed by mutant HTT protein. This method employs the use of both confocal laser scanning and super resolution (N-SIM) microscopy to accurately estimate aggregate numbers. Further, to determine the role of two lncRNAs Meg3 and Neat1 in the formation of aggregates of mutant HTT, we used commercially available siRNAs against Meg3 and Neat1 for transiently knocking them down in mouse Neuro2a and human SHSY5Y cells. Co-transfection of 83Q-DsRed and siRNA specific for Neat1 or Meg3 resulted in decreased intracellular aggregates of 83Q-DsRed in both the cell lines. We have established a quantitative method to estimate and directly or indirectly modulate the formation of mutant HTT aggregates.

Anti-cancer property and DNA binding interaction of first row transition metal complexes: A decade update.

Metal ions carry out a wide variety of functions, including acid-base/redox catalysis, structural functions, signaling, and electron transport. Understanding the interactions of transition metal complexes with biomacromolecules is essential for biology, medicinal chemistry, and the production of synthetic metalloenzymes. After the coincidental discovery of cisplatin, importance of the metal complexes in biochemistry became a top priority for inquiry. In this review, a decade update on various synthetic strategies to first row transition metal complex and their interaction with DNA through non-covalent binding are explored. Moreover, this effort provides an excellent analysis on the efficacy of theoretical and practical approaches to the systematic generation of new non-platinum based metallodrugs for anti-cancer therapeutics.

Novel neuroprotective 5,6-dihydropyrido[2',1':2,3]imidazo[4,5-c]quinoline derivatives acting through cholinesterase inhibition and CB2 signaling modulation.

A novel group of 5,6-dihydropyrido [2',1':2,3]imidazo [4,5-c]quinolines was prepared via a microwave assisted one-pot telescopic approach. The synthetic sequence involves the formation of an amine precursor of imidazo [1,2-a]pyridine via condensation and reduction under microwave irradiation. Subsequently, the Pictet-Spengler cyclisation reaction occurs with ketones (cyclic or acyclic) to obtain substituted 5,6-dihydropyrido [2',1':2,3]imidazo [4,5-c]quinolines in excellent yields. The compounds were tested as neuroprotective agents. Observed protection of neuron-like cells, SH-SY5Y differentiated with ATRA, in Parkinson's and Huntington's disease models inspired further mechanistic studies of protective activity against damage induced by 1-methyl-4-phenylpyridinium (MPP+), a compound causing Parkinson's disease. The novel compounds exhibit similar or higher potency than ebselen, an established drug with antioxidant activity, in the cells against MPP + -induced total cellular superoxide production and cell death. However, they exhibit a significantly higher capacity to reduce mitochondrial superoxide and preserve mitochondrial membrane potential. We also observed marked differences between a selected derivative and ebselen in terms of normalizing MPP + -induced phosphorylation of Akt and ERK1/2. The cytoprotective activity was abrogated when signaling through cannabinoid receptor CB2 was blocked. The compounds also inhibit both acetylcholine and butyrylcholine esterases. Overall the data show that novel 5,6-dihydropyrido [2',1':2,3]imidazo [4,5-c]quinoline have a broad cytoprotective activity which is mediated by several mechanisms including mitoprotection.

Synaptically-targeted long non-coding RNA SLAMR promotes structural plasticity by increasing translation and CaMKII activity.

Long noncoding RNAs (lncRNAs) play crucial roles in maintaining cell homeostasis and function. However, it remains largely unknown whether and how neuronal activity impacts the transcriptional regulation of lncRNAs, or if this leads to synapse-related changes and contributes to the formation of long-term memories. Here, we report the identification of a lncRNA, SLAMR, which becomes enriched in CA1-hippocampal neurons upon contextual fear conditioning but not in CA3 neurons. SLAMR is transported along dendrites via the molecular motor KIF5C and is recruited to the synapse upon stimulation. Loss of function of SLAMR reduces dendritic complexity and impairs activity-dependent changes in spine structural plasticity and translation. Gain of function of SLAMR, in contrast, enhances dendritic complexity, spine density, and translation. Analyses of the SLAMR interactome reveal its association with CaMKIIα protein through a 220-nucleotide element also involved in SLAMR transport. A CaMKII reporter reveals a basal reduction in CaMKII activity with SLAMR loss-of-function. Furthermore, the selective loss of SLAMR function in CA1 disrupts the consolidation of fear memory in male mice, without affecting their acquisition, recall, or extinction, or spatial memory. Together, these results provide new molecular and functional insight into activity-dependent changes at the synapse and consolidation of contextual fear.