In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds 23j, 24f, 25a, and 25b exhibited potent in vitro activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02–0.12 μg/mL) and drug-resistant (MIC = 0.031–0.24 μg/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC₅₀) = 0.2–0.9 μg/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-à-go-go related gene (hERG) channel. The representative compound 25a with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound 23j provides new insight into the discovery of novel antitubercular agents targeting DprE1.

The one-pot synthesis of quinazoline-2,4-diones was developed in the presence of 4-dimethylaminopyridine (DMAP) by metal-free catalysis. The commercially available (Boc)₂O acted as a key precursor in the construction of the 2-position carbonyl of quinazolinediones. The p-methoxybenzyl (PMB)-activated heterocyclization could smoothly proceed at room temperature instead of the microwave condition. This strategy is compatible with a variety of substrates with different functional groups. Furthermore, this protocol was utilized to smoothly prepare Zenarestat with a total yield of 70%.

Background: The impact of coronavirus diseases 2019 (COVID-19) related non-pharmaceutical interventions (NPIs) on influenza activity in the presence of other known seasonal driving factors is unclear, especially at the municipal scale. This study aimed to assess the impact of NPIs on outpatient influenza-like illness (ILI) consultations in Beijing and the Hong Kong Special Administrative Region (SAR) of China. Methods: We descriptively analyzed the temporal characteristics of the weekly ILI counts, nine NPI indicators, mean temperature, relative humidity, and absolute humidity from 2011 to 2021. Generalized additive models (GAM) using data in 2011–2019 were established to predict the weekly ILI counts under a counterfactual scenario of no COVID-19 interventions in Beijing and the Hong Kong SAR in 2020–2021, respectively. GAM models were further built to evaluate the potential impact of each individual or combined NPIs on weekly ILI counts in the presence of other seasonal driving factors in the above settings in 2020–2021. Results: The weekly ILI counts in Beijing and the Hong Kong SAR fluctuated across years and months in 2011–2019, with an obvious winter-spring seasonality in Beijing. During the 2020–2021 season, the observed weekly ILI counts in both Beijing and the Hong Kong SAR were much lower than those of the past 9 flu seasons, with a 47.5% [95% confidence interval (CI): 42.3%, 52.2%) and 60.0% (95% CI: 58.6%, 61.1%) reduction, respectively. The observed numbers for these two cities also accounted for only 40.2% (95% CI: 35.4%, 45.3%) and 58.0% (95% CI: 54.1%, 61.5%) of the GAM model estimates in the absence of COVID-19 NPIs, respectively. Our study revealed that, “Cancelling public events” and “Restrictions on internal travel” measures played an important role in the reduction of ILI in Beijing, while the “restrictions on international travel” was statistically most associated with ILI reductions in the Hong Kong SAR. Conclusions: Our study suggests that COVID-19 NPIs had been reducing outpatient ILI consultations in the presence of other seasonal driving factors in Beijing and the Hong Kong SAR from 2020 to 2021. In cities with varying local circumstances, some NPIs with appropriate stringency may be tailored to reduce the burden of ILI caused by severe influenza strains or other respiratory infections in future. Graphical