2-(1,3-Dioxoisoindolin-2-yl)acetic acid–N′-[(E)-2-methoxybenzylidene]pyridine-4-carbohydrazide (1/1)

In the title 1:1 cocrystal, C10H7NO4·C14H13N3O2, molecules are linked by intermolecular C—H...O, N—H...O and O—H...N hydrogen bonds, forming a three-dimensional network. In addition, π–π stacking interactions [with centroid–centroid distances of 3.5723 (19) and 3.6158 (18) Å] are observed

2-(1,3-Dioxoisoindolin-2-yl)acetic acid–N′-[(E)-4-methoxybenzylidene]pyridine-4-carbohydrazide (2/1)

In the crystal structure of the title compound, 2C10H7NO4·C14H13N3O2, the two independent acid molecules are connected through strong O—H...N and O—H...O hydrogen bonds to the central molecule of the antitubercular drug N′-[(E)-4-methoxybenzylidene]pyridine-4-carbohydrazide. Two such trimolecular units related by an inversion centre interact through a pair of N—H...O hydrogen bonds, forming a 3 + 3 molecular aggregate. The dihedral angle between the aromatic rings of the hydrazone molecule is 1.99 (12)°. The crystal packing features weak C—H...O and π–π stacking interactions, with centroid–centroid distances of 3.8460 (19) and 3.8703 (13) Å

Rapid onset of cardiomyopathy in STZ-induced female diabetic mice involves the downregulation of pro-survival Pim-1

BACKGROUND: Diabetic women are five times more likely to develop congestive heart failure compared with two fold for men. The underlying mechanism for this gender difference is not known. Here we investigate the molecular mechanisms responsible for this female disadvantage and attempt safeguarding cardiomyocytes viability and function through restoration of pro-survival Pim-1. METHODS AND RESULTS: Diabetes was induced by injection of streptozotocin in CD1 mice of both genders. Functional and dimensional parameters measurement using echocardiography revealed diastolic dysfunction in female diabetic mice within 8 weeks after STZ-induced diabetes. This was associated with significant downregulation of pro-survival Pim-1 and upregulation of pro-apoptotic Caspase-3, microRNA-1 and microRNA-208a. Male diabetic mice did not show any significant changes at this time point (P < 0.05 vs. female diabetic). Further, the onset of ventricular remodelling was quicker in female diabetic mice showing marked left ventricular dilation, reduced ejection fraction and poor contractility (P < 0.05 vs. male diabetic at 12 and 16 weeks of STZ-induced diabetes). Molecular analysis of samples from human diabetic hearts confirmed the results of pre-clinical studies, showing marked downregulation of Pim-1 in the female diabetic heart (P < 0.05 vs. male diabetic). Finally, in vitro restoration of Pim-1 reversed the female disadvantage in diabetic cardiomyocytes. CONCLUSIONS: We provide novel insights into the molecular mechanisms behind the rapid onset of cardiomyopathy in female diabetics. These results suggest the requirement for the development of gender-specific treatments for diabetic cardiomyopathy

Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei

Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei , Trypanosoma brucei gambiense , and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC(50) = 47 nM) and T. b. rhodesiense (IC(50) = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug targe