Design, synthesis and structure-activity relationships of novel non-ketolides: 9-Oxime clarithromycin featured with seven-to thirteen-atom-length diamine linkers at 3-OH.

We report here on the structure-activity relationships of hybrids combining 3-descladinosyl clarithromycin with quinolones linked by extended diamine connectors. Several hybrids, exemplified by 23Bc, 23Be, 23Bf, 26Be, and 30Bc, not only restored potency against inducibly resistant pathogens but also exhibited significantly enhanced activities against constitutively resistant strains of Staphylococcus pneumoniae and Staphylococcus pyogenes, which express high-level resistance independent of clarithromycin or erythromycin induction. Additionally, the novel hybrids showed susceptibility against Gram-negative Haemophilus influenzae. Notably, hybrid 23Be demonstrated dual modes of action by inhibiting both protein synthesis and DNA replication in vitro and in vivo. Given these promising characteristics, 23Be emerges as a potential candidate for the treatment of community-acquired bacterial pneumonia.

The construction of a near-infrared fluorescent probe with dual advantages for imaging carbon monoxide in cells and in vivo.

As a kind of toxic gas, carbon monoxide (CO) can hinder uptake of oxygen in humans. However, more and more studies have shown that CO is an important gaseous messenger in the body and playing an indispensable role in intracellular signaling pathways. So, it is necessary to develop an analytical method to study CO in living organisms. Although there are many CO-responsive probes, most of them have the disadvantages of a small Stokes shift or short emission wavelength. In order to address the above issue, a novel probe (FDX-CO) with a large Stokes shift (190 nm) and long emission wavelength (770 nm) was firstly synthesized to detect CO. The probe shows high sensitivity and superior selectivity toward CO. Moreover, the probe was successfully used for visualizing exogenous and endogenous CO in cells by fluorescence imaging, 3D quantification analysis and flow cytometric analysis. More importantly, FDX-CO could excellently detect CO in mice, which suggests that this probe has the potential ability to image CO in vivo. This probe can be viewed as a useful tool in the research of CO.

Synthesis and structure-bactericidal activity relationships of non-ketolides: 9-Oxime clarithromycin 11,12-cyclic carbonate featured with three-to eight-atom-length spacers at 3-OH.

In general, potent non-ketolide versions of erythromycin possessed conformationally constricted two- or three-atom-length sidechains at 3-OH. Novel 14-membered non-ketolides possessing long spacers beyond three-atom length were evaluated for antibacterial activity. The most potent one is 34a, featuring a five-atom-length flexible linker from of a pyridine ring to the aglycone. Conversion of the pyridine of 34a to other aryl groups, changing the linker's length of 34a to longer or shorter ones, and variation of the linker flexibility to a rigid olefin or alkyne led to decreased antibacterial activity. The hybrids of macrolides and quinolones 28b, 31 and 34b possessing various sidechains, unlike their 15-membered counterparts, were ineffective compared to 34a. Similar to the marketed ketolide telithromycin, the non-ketolide 34a proved to be a time-dependent bactericidal agent, but it exhibited superior in vivo pharmacokinetic properties such as longer half-life, higher plasma concentration, lower clearance and shorter time to reach the highest drug concentration relative to telithromycin. Molecular docking suggested 34a might π - π interact with the bacterial ribosomal RNA base G2505Ec. This study suggested that the bacteriostatic agent erythromycin can be structurally modified to afford a new bactericidal chemotype that targets the ribosome and is superior to ciprofloxacin with regard to its minimum bactericidal concentration.

Discovery of efficient stimulators for adult hippocampal neurogenesis based on scaffolds in dragon's blood.

Reduction of hippocampal neurogenesis caused by aging and neurological disorders would impair neural circuits and result in memory loss. A new lead compound (N-trans-3',4'-methylenedioxystilben-4-yl acetamide 27) has been discovered to efficiently stimulate adult rats' neurogenesis. In-depth structure-activity relationship studies proved the necessity of a stilbene scaffold that is absent in highly cytotoxic analogs such as chalcones and heteroaryl rings and inactive analogs such as diphenyl acetylene and diphenyl ethane, and validated the importance of an NH in the carboxamide and a methylenedioxy substituent on the benzene ring. Immunohistochemical staining and biochemical analysis indicate, in contrast to previously reported neuroprotective chemicals, N-stilbenyl carboxamides have extra capacity for neuroproliferation-type neurogenesis, thereby providing a foundation for improving the plasticity of the adult mammalian brain.

[Photosynthetic activity of Gloiopeltis furcata (intertidal red macroalga) in response to desiccation].

In this study, the diurnal change of photosynthesis activity in response to various tidal patterns, the relationship between photosynthetic activity and tissue water content, and the interactive effect of desiccation and irradiance on photosynthetic activity in Gloiopeltis furcata were investigated by using portable pulse amplitude modulated (PAM) fluorometer. Results showed that Fv/Fm decreased more rapidly during the noon low tide than during the morning- or evening low tide. F/Fm decreased slowly at the beginning of desiccation during the morning low tide, but decreased rapidly throughout the evening low tide. Fv/Fm recovered to the initial values on the same day no matter when the low tide occurred, suggesting the occurrence of dynamic photoinhibition. These features endowed G. furcata with an ability to adapt to the periodic desiccation on high intertidal rocks. The maximum (Fv/Fm) and effective (Phi(PSII)) quantum yield declined with the decrease of tissue water content (TWC). However, photosynthetic activity could recover completely when TWC exceeded 6%, showing a strong ability of G. furcata to tolerate desiccation. The relationships between TWC and Fv/Fm and Phi (PS II) as were as follows: F/Fm = 0.68 + (0.44-0.68)/[1 +(TWC/ 66.96)]5 , R2 = 0.99; Phi(PSII) = 0.585 + (0.004-0.585)/[1+(TWC/73)10], R2 = 0.99. ANOVA result further showed that the interactive effect of irradiance and desiccation on photosynthetic activity was significant, and that the photoinhibition degree increased with elevation of irradiation and duration of desiccation. The extreme condition (6 h desiccation at 1000 micromol photons x m(-2) x s(-1)) resulted in a serious photoinhibition, with the longest period of complete recovery for photosynthesis activity.

[Spatiotemporal variation and related affecting factors of Gloiopeltis furcata biomass and length around Xiaoheishan Island, Shandong of China].

Gloiopeltis furcata, an important economic red macroalga, has been severely depleted due to human disturbances. Taking the natural G. furcata populations around the Xiaoheishan Island of Shandong, China as test objects, this paper studied the spatiotemporal variation pattern of their biomass and length and related affecting factors. The two-way ANCOVA showed that at island scale, both the subbottom and the Baardseth index had significant effects on the G. furcata biomass and length. The steady subbottom and the high Baardseth index were beneficial to the G. furcata growth. At micerohabitat scale, wave action and tidal level had significant effects on the G. furcata biomass and length. Wave wash and moderate tidal level promoted the G. furcata growth. The one-way repeated measurements ANOVA showed there existed seasonal variation of G. furcat biomass and length. The optimal growth period of G. furcata was from March to April, with the peak values of biomass and length appeared in late spring and early summer.