Beyond paraquats: Dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles as antibacterial agents

Dialkyl 4,4′-bipyridinium compounds, known as ‘paraquats’ (PQs), have a long history of use as herbicides, as redox indicators, and more recently as potent antibacterial agents. However, due to their ability to form reactive oxygen species (ROS) in vivo, PQs are also known to be toxic. We proposed that altering the electrochemical properties of PQ, specifically by preparing isomeric bipyridinium structures with 3,3′- and 3,4′-substitution of the nitrogen heteroatoms on the biaryl core, would maintain antibacterial activity, yet decrease toxicity. We have thus prepared a series of 17 amphiphiles, dubbed ‘metaquat’ (MQ) and ‘parametaquat’ (PMQ), respectively, and investigated their antibacterial and electrochemical properties. Optimal inhibition of bacterial growth was observed in symmetric, biscationic structures; minimum inhibitory concentration (MIC) values measured as low as 0.5 μM against both Gram-positive and Gram-negative bacteria for the compound PMQ-11,11. Electrochemical analysis demonstrated the redox properties of the dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles to be distinct from those of the 4,4′-bipyridinium isomer. Thus MQ and PMQ amphiphiles maintain the strong antibacterial activity of the PQ isomers, but show promise for reduced ROS toxicity.     

Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents

In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60 mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6 h at a dosage of 4.0 mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.     

Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome

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Gliotransmission and adenosine signaling promote axon regeneration

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RssB-mediated σS Activation is Regulated by a Two-Tier Mechanism via Phosphorylation and Adaptor Protein – IraD

Regulation of bacterial stress responding σ^S is a sophisticated process and mediated by multiple interacting partners. Controlled proteolysis of σ^S is regulated by RssB which maintains minimal level of σ^S during exponential growth but then elevates σ^S level while facing stresses. Bacteria developed different strategies to regulate activity of RssB, including phosphorylation of itself and production of anti-adaptors. However, the function of phosphorylation is controversial and the mechanism of anti-adaptors preventing RssB-σ^S interaction remains elusive. Here, we demonstrated the impact of phosphorylation on the activity of RssB and built the RssB-σ^S complex model. Importantly, we showed that the phosphorylation site - D58 is at the interface of RssB-σ^S complex. Hence, mutation or phosphorylation of D58 would weaken the interaction of RssB with σ^S. We found that the anti-adaptor protein IraD has higher affinity than σ^S to RssB and its binding interface on RssB overlaps with that for σ^S. And IraD-RssB complex is preferred over RssB-σ^S in solution, regardless of the phosphorylation state of RssB. Our study suggests that RssB possesses a two-tier mechanism for regulating σ^S. First, phosphorylation of RssB provides a moderate and reversible tempering of its activity, followed by a specific and robust inhibition via the anti-adaptor interaction.     

Rational design,synthesis and biological evaluation of ubiquinone derivatives as IDO1 inhibitors

Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive therapeutic target for the treatment of cancer, chronic viral infections and neurological disorders characterized by pathological immune stimulation. Herein, a series of known metal-chelating ubiquinone derivatives were designed, synthesized and evaluated for the IDO1 inhibiting activities. The docking studies showed that the compounds 11, 16, 18 and coenzyme-Q1 exhibited different binding modes to IDO1 protein. Among these compounds, the most active compound is 16d with an IC₅₀ of 0.13 μM in enzymatic assay. The results reveal that a possible halogen bonding interaction between the bromine atom (3-Br) and Cys129 significantly enhances the inhibition activity against IDO1. This study provides structural insights of the interactions between ubiquinone analogues and IDO1 protein for the further modification and optimization.     

Small RNA shuffling between murine sperm and their cytoplasmic droplets during epididymal maturation

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