ABSTRACT
In the search for new anti-influenza virus (IV) compounds, we have identified the 1,2,4-triazolo[1,5-a]pyrimidine (TZP) as a very suitable scaffold to obtain compounds able to disrupt IV RNA-dependent RNA polymerase (RdRP) PA-PB1 subunits heterodimerization. In this work, in order to acquire further SAR insights for this class of compounds and identify more potent derivatives, we designed and synthesized additional series of analogues to investigate the role of the substituents around the TZP core. To this aim, we developed four facile and efficient one-step procedures for the synthesis of 5-phenyl-, 6-phenyl- and 7-phenyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines, and 2-amino-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol. Two analogues having the ethyl carboxylate moiety at the C-2 position of the TZP were also prepared in good yields. Then, the scaffolds herein synthesized and two previous scaffolds were functionalized and evaluated for their anti-IAV activity, leading to the identification of compound 22 that showed both anti-PA-PB1 (IC50 = 19.5 µM) and anti-IAV activity (EC50 = 16 µM) at non-toxic concentrations, thus resulting among the most active TZP derivatives reported to date by us. A selection of the synthesized compounds, along with a set of in-house available analogues, was also tested against SARS-CoV-2. The most promising compound 49 from this series displayed an EC50 value of 34.47 µM, highlighting the potential of the TPZ scaffold in the search for anti-CoV agents.
Subject(s)
Antiviral Agents/pharmacology , Protein Multimerization/drug effects , Pyrimidines/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Triazoles/pharmacology , Viral Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Chlorocebus aethiops , Dogs , Drug Design , HEK293 Cells , Humans , Influenza A virus/drug effects , Madin Darby Canine Kidney Cells , Microbial Sensitivity Tests , Pyrimidines/chemical synthesis , SARS-CoV-2/drug effects , Triazoles/chemical synthesis , Vero CellsABSTRACT
At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quinoline conjugates (10a-l, 11a-c, and 12a-e) by incorporating 1,2,3-triazole were synthesized via a modified microwave-assisted click chemistry technique. Among the synthesized conjugates, 4-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the reference drugs.