Enteroviral replication inhibition by N-Alkyl triazolopyrimidinone derivatives through a non-capsid binding mode.

Small-molecule inhibitors exhibiting broad-spectrum enteroviral inhibition by targeting viral replication proteins are highly desirable in antiviral drug discovery. We used the previously identified antiviral compound 1 as the starting material to develop a novel compound series with high efficacy against human rhinovirus (hRV). Further optimization of N-substituted triazolopyrimidinone derivatives revealed that the N-alkyl triazolopyrimidinone derivatives (2) had more potent antiviral activity against hRVs than compound 1. The new compounds showed improved selectivity index values, and compound 2c (KR-25210) displayed broad anti-hRV activity, with half-maximal effective concentration values ≤ 2 µM against all tested hRVs. In addition, 2c showed notable activity against other enteroviruses. Drug-likeness elucidation showed that 2c exhibited reasonable human and rat liver microsomal phase-I stability and safe CYP inhibition. Replication studies revealed that 2c is not a capsid inhibitor, and a time-of-addition assay indicated that 2c targets the virus replication stages.

Novel tacrine-pyridinium hybrid reactivators of organophosphorus-inhibited acetylcholinesterase: Synthesis, molecular docking, and in vitro reactivation study.

First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine-pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2-C7) were prepared (Scheme 1, 5a-f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1 µM concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1 µM concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (n = 2-5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1 µM concentrations. Molecular docking simulation showed that the most stable binding free energy was observed in 5c at 73.79 kcal⋅mol-1, and the binding mode of 5c is acceptable for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited eel AChE model structure.

Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.

Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85µM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6µM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.

Flow Synthesis of L-α-Glycerylphosphorylcholine: Studies on Synthetic Routes Applicable to a Flow Reactor and Optimization of Reaction Conditions.

L-α-Glycerylphosphorylcholine (L-α-GPC) has mainly been produced by two methods: extraction from plants rich in phosphatidylcholine and chemical synthesis. However, production through extraction involves difficult processes, such as fermentation, extractions and ripening, and conventional chemical synthesis methods with high-cost reactants and a batch reactor. These methods are not ideal for large-quantity production. Thus, it is important to develop a simple production method of L-α-GPC, which is suitable for mass production without the need for expensive reactants. Here, we studied synthetic L-α-GPC methods that are applicable to a flow synthesis system, which can provide selectivity, reproducibility, scalability, and a high yield in short reaction time using inexpensive starting materials. We developed a two-step synthetic route to produce L-α-GPC, including the synthesis of phosphoryl choline using choline chloride and phosphoryl oxychloride (POCl3) as a first step and synthesis of L-α-GPC by reacting phosphoryl choline with (R)-(-)-3-chloro-1,2-propanediol (CPD) as a second step under basic conditions. Both steps were separately performed in a customized flow reactor, and reaction conditions were optimized. Finally, phosphoryl choline and L-α-GPC, the products first and second reactions, were successfully synthesized with high conversion yields of 97% and 79%, respectively.

Multicomponent Oxidative Trifluoromethylation of Alkynes with Photoredox Catalysis: Synthesis of α-Trifluoromethyl Ketones.

The direct oxidative addition of CF3 and H2O to alkynes was achieved with photoredox catalysis to obtain α-trifluoromethyl ketones via rapid enol-keto tautomerization. The reaction exhibits high functional group tolerance and regioselectivity. Heterocycles of various sizes containing CF3 were synthesized from the α-CF3-substituted diketones obtained through the protocol, thereby demonstrating the versatile applicability of the method. Mechanistic studies of the reaction with isotopes provided insight into the reaction pathway.

Vicinal difunctionalization of alkenes: chlorotrifluoromethylation with CF3SO2Cl by photoredox catalysis.

Photoredox-catalyzed vicinal chlorotrifluoromethylation of alkene is described. In the presence of Ru(Phen)3Cl2, CF3SO2Cl was used as a source for the CF3 radical and chloride ion under visible light irradiation. Various terminal and internal alkenes were transformed to their vicinal chlorotrifluoromethylated derivatives. Biologically active compounds were applied under the condition to obtain desired products, suggesting that the method could be feasible for late-stage modification in drug discovery.