ABSTRACT
In this work, a series of novel substituted polycyclic pyridone derivatives were designed and synthesized as potent anti-influenza agents. The cytopathic effect (CPE) assay and cytotoxicity assay indicated that all of the compounds possessed potent anti-influenza virus activity and relatively low cytotoxicity; some of them inhibited the replication of influenza A virus (IAV) at picomolar concentrations. Further studies revealed that, at a concentration of 3 nM, three compounds (10a, 10d, and 10g) could significantly reduce the M2 RNA amounts and M2 protein expression of IAV and inhibit the activity of RNA-dependent RNA polymerase (RdRp). Among them, (R)-12-(5H-dibenzo[a,d][7]annulen-5-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (10a) was found to be a promising anti-influenza drug candidate with good human liver microsomal stability, as well as with better selectivity index and oral bioavailability than Baloxavir.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Dibenzothiepins/chemistry , Influenza A virus/drug effects , Morpholines/chemistry , Pyridones/chemical synthesis , Pyridones/pharmacology , Triazines/chemistry , Animals , Cell Survival/drug effects , Cytopathogenic Effect, Viral/drug effects , Dogs , Humans , Madin Darby Canine Kidney Cells , Male , Pyridones/chemistry , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain ReactionABSTRACT
In order to prevent the further spread of the COVID-19 virus, enclosed management of gated communities is necessary. The implementation of contactless food distribution for closed gated communities is an urgent issue. This paper proposes a contactless joint distribution service to avoid contact between couriers. Then a multi-vehicle multi-trip routing problem for contactless joint distribution service is proposed, and a mathematical programming model for this problem is established. The goal of the model is to increase residents' satisfaction with food distribution services. To solve this model, a PEABCTS algorithm is developed, which is the enhanced artificial bee colony algorithm embedded with a tabu search operator, using a progressive method to form a solution of multi-vehicle distribution routings. Finally, a variety of numerical simulations were carried out for statistical research. Compared with the two distribution services of supportive supply and on-demand supply, the proposed contactless joint distribution service can not only improve residents' satisfaction with the distribution service but also reduce the contact frequency between couriers. In addition, compared with various algorithms, it is found that the PEABCTS algorithm has better performance.