Streptochlorin analogues as potential antifungal agents: Design, synthesis, antifungal activity and molecular docking study.

Streptochlorin is a small molecule of indole alkaloid isolated from marine Streptomyces sp., it is a promising lead compound due to its potent bioactivity in preventing many phytopathogens in our previous study, but further structural modifications are required to improve its antifungal activity. Our work in this paper focused on the replacement of oxazole ring in streptochlorin with the imidazole ring, to discover novel analogues. Based on this design strategy, three series of streptochlorin analogues were efficiently synthesized through sequential Vilsmeier-Haack reaction, Van Leusen imidazole synthesis and halogenation reaction. Some of the analogues displayed excellent activity in the primary assays, and this is highlighted by compounds 4g and 4i, the growth inhibition against Alternaria Leaf Spot and Rhizoctorzia solani under 50 µg/mL are 97.5% and 90.3%, respectively, even more active than those of streptochlorin, pimprinine and Osthole. Molecular docking models indicated that streptochlorin binds with Thermus thermophiles Leucyl-tRNA Synthetase in a similar mode to AN2690, offering a perspective on the mode of action study for antifungal activities of streptochlorin derivatives. Further study is still ongoing with the aim of discovering synthetic analogues, with improved antifungal activity and clear mode of action.

Biological evaluation and SAR analysis of novel covalent inhibitors against fructose-1,6-bisphosphatase.

Fructose-1,6-bisphosphatase (FBPase) is an attractive target for affecting the GNG pathway. In our previous study, the C128 site of FBPase has been identified as a new allosteric site, where several nitrovinyl compounds can bind to inhibit FBPase activity. Herein, a series of nitrostyrene derivatives were further synthesized, and their inhibitory activities against FBPase were investigated in vitro. Most of the prepared nitrostyrene compounds exhibit potent FBPase inhibition (IC50 < 10 µM). Specifically, when the substituents of F, Cl, OCH3, CF3, OH, COOH, or 2-nitrovinyl were installed at the R2 (meta-) position of the benzene ring, the FBPase inhibitory activities of the resulting compounds increased 4.5-55 folds compared to those compounds with the same groups at the R1 (para-) position. In addition, the preferred substituents at the R3 position were Cl or Br, thus compound HS36 exhibited the most potent inhibitory activity (IC50 = 0.15 µM). The molecular docking and site-directed mutation suggest that C128 and N125 are essential for the binding of HS36 and FBPase, which is consistent with the C128-N125-S123 allosteric inhibition mechanism. The reaction enthalpy calculations show that the order of the reactions of compounds with thiol groups at the R3 position is Cl > H > CH3. CoMSIA analysis is consistent with our proposed binding mode. The effect of compounds HS12 and HS36 on glucose production in primary mouse hepatocytes were further evaluated, showing that the inhibition was 71% and 41% at 100 µM, respectively.

Boronate-modified hollow molecularly imprinted polymers for selective enrichment of glycosides.

D-Glucose was used as a dummy template in a strategy to fabricate boronate-based hollow molecularly imprinted polymers (h-MIPs) for the recognition of glycosides. 3-Aminophenylboronic acid (APBA) was selected as the functional monomer to impart glycoside binding capability. A polystyrene core was synthesized via an emulsifier-free emulsion polymerization. It was then be corroded to form a hollow structure where the binding sites on the inner surface can be fully utilized. Adsorption studies indicate that the resulting h-MIPs can specifically recognize glycosides. The h-MIPs were applied as a sorbent for solid phase extraction of the glycosides (daidzin, glycitin, rutin, and genistin) in soy products. Following desorption with 1% TFA in acetonitrile-water (3:7, v/v), the glycosides were quantified by HPLC with UV detection. The detection limits for the glycosides range from 3.5 to 10.8 ng·mL-1. Graphical abstract Boronate-affinity hollow molecularly imprinted polymers using D-glucose as dummy template were prepared as solid phase extraction adsorbents for selective enrichment of glycosides in soy products prior to quantitation by HPLC-UV.

Vinylation of α-Aminoazoles with Triethylamine: A General Strategy to Construct Azolo[1,5-a]pyrimidines with a Nonsubstituted Ethylidene Fragment.

A new general synthesis of pharmaceutically important azolo[1,5-a]pyrimidines starting from widely available 3(5)-aminoazoles, aldehydes, and triethylamine is developed. The key is to enable the vinylation reaction that allows the in situ generation of elusive acyclic enamines and the subsequent annulation reaction to occur. This direct and practical strategy is capable of constructing a range of 5,6-unsubstituted pyrazolo[1,5-a]pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines. More importantly, this protocol provides a concise synthetic route to prepare the clinically used zaleplon.