N-(1H-Pyrazol-3-yl)quinazolin-4-amines as a novel class of casein kinase 1δ/ε inhibitors: Synthesis,biological evaluation and molecular modeling studies

Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/ε inhibitor development targeting neurodegenerative disorders and cancer.     

Burden of depression and anxiety among leprosy affected and associated factors—A cross sectional study from India

BackgroundLeprosy is a Neglected Tropical Diseases (NTDs) known to cause stigma and discrimination in low-and middle-income countries. It often results in visible impairments, thus pre-disposing to poor mental health. Aim of the study was to estimate the prevalence of depression and anxiety among people affected by Leprosy and to determine the associated factors.Methodology/Principal findingsA multi-centric, cross-sectional study was carried out in four leprosy endemic states of India—Chhattisgarh, Maharashtra, West Bengal and Tamil Nadu in randomly selected blocks (a sub-unit of district), from one district in each state. From selected blocks those registered for leprosy treatment at public health or referral centres, people above the age of 18 years were interviewed with PHQ-9 and GAD-7 questionnaires for Depression and Anxiety, respectively. Disease profile like leprosy classification, deformity grade, number and site of the patches and socio-economic status were collected along with individual data.Of the total 220 respondents, prevalence of depression and anxiety symptoms was, 33% (73) and 19% (42), respectively. Presence of disability (47%) and Female gender (46%) were significantly associated with depression. Presence of disability (32%), Lower income group (27%) and low education (22%) were significantly associated with symptoms of anxiety. As the severity of disability increased, risk of developing depression and anxiety increased.ConclusionThe study indicates that more than 30% of people affected by leprosy have mental health problems, which emphasizes the importance of mental health care services in leprosy. Women, those who had lower level of education, those belonging to lower socio-economic status and those with any level of disability due to leprosy are at risk of developing depression and/or anxiety. The study concludes more attention to be paid to the categories identified to be at risk.     

Unravelling the Selectivity of 6,7-Dimethyl Quinoxaline Analogs for Kinase Inhibition: An Insight towards the Development of Alzheimer's Therapeutics

Untangling the most selective kinase inhibitors via pharmacological intervention remains one of the challenging affairs to date. In accordance to this drift, herein we describe the design and synthesis of a set of new heterocyclic analogs consisting of 6,7-dimethyl Quinoxaline, appended to a connector, employing Schiff base strategy (Compounds I – IX ). The compounds were characterized by various spectroscopic techniques and the kinase inhibition assay were performed on few prime members of the CMGC family namely the GSK3β, DYRK1A and CLK1 receptors, respectively, that have been known to be directly involved in hyperphosphorylation of Tau. Interestingly the biological evaluation results revealed that Compounds IV and V , with bromo/chloro functionalities in the aromatic core were advantaged of being highly selective towards the target GSK3β over others. To strengthen our analysis, we adopted molecular modelling studies, where compounds IV/V were redocked in the same grid 4AFJ, as that of the reference ligand, 5-aryl-4-carboxamide-1,3-oxazole. Surprisingly, our investigation underpinned that for both the compounds IV/V , a primary H-bonding existed between the designed molecules ( IV/V ) and Val 135 residue in the receptor GSK3β, in line with the reference ligand. We attribute this interaction to instigate potency in the compounds. Indeed the other non-covalent interaction, between the derivative's aromatic nucleus and Arg 141/Thr 138 in the receptor GSK3β, might have been responsible for enhancing the selectivity in the targets. Overall, we feel that the present work depicts a logical demonstration towards fine tuning the efficacy of the inhibitors through systematic adjustment of electron density at appropriate positions in the aromatic ring be it the main quinoxaline or the other aromatic nucleus. Thus this pathway offers a convenient strategy for the development of efficient therapeutics for diversified neurodegenerative diseases like that of Alzheimer's.     

Docking Studies of Adenosine Analogues with NS5 Methyltransferase of Yellow Fever Virus

Yellow fever virus (YFV) is caused by single stranded positive RNA virus called Flavivirus. Till now no specific antiviral agents are available for the treatment of YFV, and despite a commercial YFV vaccine, there are still approximately 30,000 deaths worldwide each year and cases have been increasing in the last 20 years. Here, the effects of adenosine analogues and commercially available adenosine derivative drugs on NS5 methyltransferase of YFV have been performed by the comparative docking study. Based on the docking score, the glide energy and the number of interactions of the adenosine analogues with the Pubchem ID 13792 and 1077 showed the better scoring function than the best ranked commercially available adenosine analogue derived antiviral drug Cc3ado. From the docking result it reveals that these adenosine analogues can bind to the active site of NS5 methyltransferase protein and inhibit the viral replication.     

A newly synthesized 6-methyl-7H,8H,9H-[1,2,4]triazolo[4,3-b][1,2,4]triazepin-8-one for potential inhibitor of adenosine A1 receptor: a combined experimental and computational studies

Abstract

6-Methyl-7H,8H,9H-[1,2,4]triazolo[4,3-b][1,2,4]triazepin-8-onehas been synthesized, characterized by spectroscopic techniques (FT-IR, ¹H and ¹³C NMR) and finally the structure was confirmed by single crystal X-ray diffraction studies. In the title molecule, C₆H₇N₅O, the 7-membered ring adopts a bowl-like conformation. In the crystal, the molecules form stacks along the c-axis direction through offset π-stacking interactions between the 5-membered rings and C–H···N hydrogen bonds. The stacks are associated via a combination of N–H···N, C–H···O and C–H···N hydrogen bonds. Further, the Hirshfeld surface analysis reveals the nature of molecular interactions and the fingerprint plot provides information about the percentage contribution from each individual molecular contact to the surface. In addition, due to its biological interest the target molecule adenosine A1 receptor was found based on Structural Activity Relationship (SAR) analysis and, further, subjected into molecular docking and molecular dynamics analysis to understand the binding interaction and stability of the molecule in adenosine A1 receptor system. Furthermore, the Density Functional Theory (DFT) calculations were carried for free compound and the compound in active site (single point DFT), to know the internal stability.

Communicated by Ramaswamy H. Sarma     

TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion

Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell–cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor β (TGF-β)–induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF-β/ALK5–enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-β–induced EMT.     

Halocin SH10 production by an extreme haloarchaeon Natrinema sp. BTSH10 isolated from salt pans of South India

Halobacteria, members of the domain Archaea that live under extremely halophilic conditions, are often considered as dependable source for deriving novel enzymes, novel genes, bioactive compounds and other industrially important molecules. Protein antibiotics have potential for application as preserving agents in food industry, leather industry and in control of infectious bacteria. Halocins are proteinaceous antibiotics synthesized and released into the environment by extreme halophiles, a universal characteristic of halophilic bacteria. Herein, we report the production of halocin (SH10) by an extremely halophilic archeon Natrinema sp. BTSH10 isolated from salt pan of Kanyakumari, Tamilnadu, India and optimization of medium for enhanced production of halocin. It was found that the optimal conditions for maximal halocin production were 42 °C, pH 8.0, and 104 h of incubation at 200 rpm with 2% (V/V) inoculum concentration in Zobell’s medium containing 3 M NaCl, Galactose, beef extract, and calcium chloride as additional supplements. Results indicated scope for fermentation production of halocin for probable applications using halophilic archeon Natrinema sp. BTSH10.     

Insufficient (Sub-native) Helix Content in Soluble/Solid Aggregates of Recombinant and Engineered Forms of IL-2 Throws Light on How Aggregated IL-2 is Biologically Active

Interleukin 2 (IL-2) is an extremely aggregation-prone, all-alpha helical cytokine. In its receptor-bound state,?~72?% of the polypeptide chain adopts helical structure and there is no beta sheet content whatsoever. In the past, recombinant IL-2 has been formulated and used therapeutically in humans, following production in E. coli. Therapeutic IL-2 consists entirely of functionally-active soluble aggregates with?~30 subunits per aggregate particle. Side-effects attributed to aggregation resulted in discontinuation of usage over a decade ago. Structurally, and biochemically, activity in IL-2 aggregates can potentially be explained in one of two ways : (a) individual IL-2 chains exist in sterically-accessible, receptor binding-competent (native) structures, allowing aggregates to bind directly to IL-2 receptors (IL-2R); alternatively, (b) IL-2 chains dissociate from aggregates, become free to adopt native structure, and then bind to IL-2R. We produced native IL-2 and numerous engineered forms in E. coli with the objective of obtaining insights into these possibilities. Each IL-2 variant was subjected to size exclusion chromatography, circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR). All forms produced and studied (including those with native IL-2 sequences) turned out to aggregate and also display less than?~50?% helix content as well as significant beta sheet content. No conditions were found that obviate aggregation. Aggregated IL-2 is thus insufficiently native-like to bind to IL-2R. Activity in aggregates thus probably owes to adoption of receptor binding-competent structures by chains that have already dissociated from aggregates.