Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

Abstract

Emerging viral infections, including those caused by dengue virus (DENV) and Venezuelan Equine Encephalitis virus (VEEV), pose a significant global health challenge. Here, we report the preparation and screening of a series of 4-anilinoquinoline libraries targeting DENV and VEEV. This effort generated a series of lead compounds, each occupying a distinct chemical space, including 3-((6-bromoquinolin-4-yl)amino)phenol (12), 6-bromo-N-(5-fluoro-1H-indazol-6-yl)quinolin-4-amine (50) and 6-((6-bromoquinolin-4-yl)amino)isoindolin-1-one (52), with EC50 values of 0.63–0.69 µM for DENV infection. These compound libraries demonstrated very limited toxicity with CC50 values greater than 10 µM in almost all cases. Additionally, the lead compounds were screened for activity against VEEV and demonstrated activity in the low single-digit micromolar range, with 50 and 52 demonstrating EC50s of 2.3 µM and 3.6 µM, respectively. The promising results presented here highlight the potential to further refine this series in order to develop a clinical compound against DENV, VEEV, and potentially other emerging viral threats.

Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies

“…Beyond viral entry, the time-of-addition experiments provide evidence that NAKs are also involved in regulating later stage(s) of the viral life cycle, likely assembly and/or egress, but not viral RNA replication. This is in agreement with our prior findings involving their roles in unrelated RNA viral infections such as DENV, EBOV, and VEEV ( Neveu et al, 2015 ; Bekerman et al, 2017 ; Pu et al, 2020 ; Saul et al, 2020 , 2021a , 2021b ; Huang et al, 2021 ). Together, these findings provide evidence that NAKs regulate temporally distinct stages of the SARS-CoV-2 life cycle and represent candidate targets for the development of anti-SARS-CoV-2 approaches.…”

Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for therapy

“…Beyond viral entry, the time-of-addition experiments provide evidence that NAKs are also involved in regulating later stage(s) of the viral life cycle, likely assembly and/or egress, but not viral RNA replication. This is in agreement with our prior findings involving their roles in unrelated RNA viral infections such as DENV, EBOV, and VEEV (Neveu et al, 2015; Bekerman et al, 2017; Pu et al, 2020; Saul et al, 2020; Huang et al, 2021; Saul et al, 2021; Saul et al, 2021). Together, these findings provide evidence that NAKs regulate temporally distinct stages of the SARS-CoV-2 life cycle and represent candidate targets for anti-SARS-CoV-2 treatment.…”

Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses

“…Following a systematic SAR effort, quinoline 27 and quinazoline 54 ( Figure 12 , Table 4 ) showed activity in human U87MG astrocytes infected with VEEV TC83 (EC 50 = 0.50–0.60 µM, CC 50 > 10 µM). In a separate study, structurally related compounds that more deeply assessed substitutions of the 4-aminoaryl substituent were assessed against these viruses [ 185 ], resulting in several analogs with single digit TC83 micromolar activity.…”