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Chagas disease has grown into a serious public health threat, with a high morbidity rate, major social impact, and global neglect. Therapeutic adhesion, unwanted side-effects, and resistance make its present therapy ineffective. Discovery of more effective drugs is hence needed. Using natural compounds conjointly with computational methods helps better to find promising compounds, speeding up drug discovery process and reducing its cost. In the present study, a docking protocol against cruzipain (PDB: 3l06), an important druggable target, was applied to a library of 50 sorted natural compounds. Compounds were further analysed for binding mode and interactions with cruzipain active site, conformational alignment studies and in-silico pharmacokinetic studies so as to predict their plausible anti-cruzipain mechanism. The results provided computational insights into the molecular interaction of naturals against T. cruzi cruzipain. Study also lead to identification of Hinokiflavone; BA = −10.2 kcal mol−1 as reasonably promising potential natural cruzipain inhibitor. [ABSTRACT FROM AUTHOR]

Quinazolinone and thiouracil derivatives are key scaffolds in anticancer development. This study used a molecular hybridization approach to synthesize new quinazolinone‐thiouracil derivatives and evaluated their anticancer activity against three human cancer cell lines, namely breast, lung, and glioblastoma, using SRB assay. Structural elucidation was performed using IR spectroscopy, 1H‐NMR, 13C‐NMR, mass spectrometry, and elemental analysis. Most compounds show moderate to significant cytotoxic effects, with compound 5d displaying the highest potency (IC50 values of 5.28, 4.02, and 2.88 µM, respectively). Compound 5d also demonstrated comparable potency to positive controls cisplatin and temozolomide in lung and glioblastoma cancer cell lines and was nearly as effective as mitochondrial division inhibitor‐1 (mdivi‐1). Furthermore, molecular docking analyses revealed strong binding interactions of the synthesized compounds with dynamin‐related protein‐1 (drp1). Protein–ligand stability studies and all‐atom simulation confirmed the stable binding of compound 5d with drp1. In conclusion, this study identified compound 5d as a potent drp1 inhibitor and promising anticancer drug candidate, deserving further investigation. [ABSTRACT FROM AUTHOR]

The current work comprises of development of a simple, rapid, and precise reverse phase‐high‐performance liquid chromatography method for simultaneous estimation of propyphenazone, flurbiprofen, and their mutual prodrug. Column C18 (Shimadzu Shim‐pack Gist, 250 × 4.6 mm, 5 μm) was employed as a stationary phase, and the ratio of acetonitrile:methanol:water (40:40:20 %v/v) was used as the mobile phase. The flow rate was held at 1 mL/min and detection was carried out at 245 nm using an ultraviolet detector. The retention time of propyphenazone, flurbiprofen, and their mutual prodrug was found to be 4.0, 2.5, and 10.0 min, respectively. The proposed method was validated according to the International Council on Harmonization Q2(R1) guideline in terms of accuracy, precision, linearity, limit of detection, limit of quantitation, and solution stability. Calibration plots were linear over the concentration ranges of 2–10 μg/mL (R2 = 0.9998, R2 = 0.9992 and R2 = 0.9994 for propyphenazone, flurbiprofen, and their mutual prodrug, respectively). Results of mean percentage recoveries were in the range of 99.6%–100.1% for flurbiprofen, 99.3%–100.2% for propyphenazone, and 99.9%–100.7% for prodrug, respectively. The developed method can be used for the assay of mutual prodrug and drug release study of the developed mutual prodrug also routine quality control evaluation of mutual prodrug in bulk form. [ABSTRACT FROM AUTHOR]

A series of 2-amino-5-nitrothiazole derived semicarbazones were designed, synthesised and investigated for MAO and ChE inhibition properties. Most of the compounds showed preferential inhibition towards MAO-B. Compound 4, (1-(1-(4-Bromophenyl)ethylidene)-4-(5-nitrothiazol-2-yl)semicarbazide) emerged as lead candidate (IC50 = 0.212 µM, SI = 331.04) against MAO-B; whereas compounds 21 1-(5-Bromo-2-oxoindolin-3-ylidene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0.264 µM) and 17 1-((4-Chlorophenyl) (phenyl)methylene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0.024 µM) emerged as lead AChE and BuChE inhibitors respectively; with activity of compound 21 almost equivalent to tacrine. Kinetic studies indicated that compound 4 exhibited competitive and reversible MAO-B inhibition while compounds 21 and 17 showed mixed-type of AChE and BuChE inhibition respectively. Docking studies revealed that these compounds were well-accommodated within MAO-B and ChE active sites through stable hydrogen bonding and/or hydrophobic interactions. This study revealed the requirement of small heteroaryl ring at amino terminal of semicarbazone template for preferential inhibition and selectivity towards MAO-B. Our results suggest that 5-nitrothiazole derived semicarbazones could be further exploited for its multi-targeted role in development of anti-neurodegenerative agents. A library of 2-amino-5-nitrothiazole derived semicarbazones (4-21) was designed, synthesised and evaluated for in vitro MAO and ChE inhibitory activity. Compounds 4, 21 and 17 (shown) have emerged as lead MAO-B (IC50:0.212 µM, competitive and reversible), AChE (IC50:0.264 µM, mixed and reversible) and BuChE (IC50:0.024 µM, mixed and reversible) inhibitor respectively. SAR studies disclosed several structural aspects significant for potency and selectivity and indicated the role of size of aryl binding site in potency and selectivity towards MAO-B. Antioxidant activity and neurotoxicity screening results further suggested their multifunctional potential for the therapy of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis. S tem C ells 2015;33:2628-2641 [ABSTRACT FROM AUTHOR]

The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP-ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2-Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype. [ABSTRACT FROM AUTHOR]