5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structureactivity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC 99 under irondeficient conditions of 0.049 µM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require arylcapped siderphores for virulence.

Lycorine potently inhibits flaviviruses in cell culture. At 1.2-μM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 102- to 104-fold. However, the compound did not inhibit an alphavirus (Western equine encephalitis virus) or a rhabdovirus (vesicular stomatitis virus), indicating a selective antiviral spectrum. The compound exerts its antiviral activity mainly through suppression of viral RNA replication. A Val→Met substitution at the 9th amino acid position of the viral 2K peptide (spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins) confers WNV resistance to lycorine, through enhancement of viral RNA replication. Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound’s potency, while reducing its cytotoxicity. Taken together, the results have established lycorine as a flavivirus inhibitor for antiviral development. The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis.

Freshwater fishes worldwide face an array of threats from dam construction, river fragmentation, pollution, over‐exploitation and interactions with introduced species. Such impacts are especially prevalent in densely populated countries undergoing rapid development, and their effects are felt most strongly where regional fish diversity is high. We reviewed studies of the distribution of freshwater fish species throughout China to map a biogeographical pattern and ascertain the environmental factors contributing to this distribution. We then linked this information to identify geographic areas to be recommended as the focus of conservation efforts. A total of 920 species in 302 genera, 54 families and 21 orders were recorded. Among the recorded species, 73% were Cypriniformes and 12% were Siluriformes. Cyprinidae was the most dominant family with 473 species, followed by Balitoridae with 157 species. The administrative division of the biogeography of China's freshwater fishes consisted of nine regions, including the Qinghai‐Tibetan Plateau Region, Oriental Region, Northwest Region, South Region, Loess Plateau Region, Heilongjiang Region, Upper Yangtze Region, 3H Plain Region and Middle‐Lower Yangtze Plain Region. The river system was the primary factor in determining China's freshwater fish biogeography. Under stepwise regression analysis, river discharge was found to be the most influential factor in determining richness, followed by population size and net primary productivity. The higher level of fish endemicity and sensitivity to environmental change led to the identification of Southwest China and the higher areas of Qinghai‐Tibetan Plateau as the primary areas to be considered for fish conservation and potential natural reserves.

Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.