Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors.

Pei-Tzu Huang,Shirit Einav,Christopher R M Asquith,Sirle Saul

doi:10.3390/molecules26237338

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.

Highlights

Mosquito-borne viral infections, including those caused by the flavivirus dengue (DENV) and the alphavirus Venezuelan Equine Encephalitis virus (VEEV), represent a major public health concern [1,2,3,4]
There are no approved antiviral therapies for dengue virus (DENV) infection, and the development of an effective and safe DENV vaccine has been challenged by the need to generate a balanced protective immunity against the four distinct DENV serotypes
We have previously demonstrated that the 4-anilinoquinoline/quinazoline scaffold is active on both DENV and VEEV [32,33]

Summary

Introduction

Mosquito-borne viral infections, including those caused by the flavivirus dengue (DENV) and the alphavirus Venezuelan Equine Encephalitis virus (VEEV), represent a major public health concern [1,2,3,4]. The methanolic substitution 10, was 2fold Wweeatkheernwscirteherneesdpeacstetroie5s aonf dm8a-tfcohleddwpiathir rmesetpae-mcte4t.hoxy and meta-hydroxy analogues (11–18), changing the 6-position of the quinoline ring (Table 2) [48]. 3-fold decrease in activity against DENV, while the hydroxy analogue 14 showed no activity at the top concentration tested. Switching to the electron donating 6-methoxyquinoline methoxy analogue 15 was 5-fold less potent with respect to 4, while the hydroxy analogue was inactive (EC50 = >10 μM). >co1m0 μpMou)n.0dT.8hw2eitshubasptiotutetniotnanotfivthireaal ma>c1itn0ivei2ty0 with a profile (EC50 = 50.24 μM), but thOisHappeared to be in p2a.7rt driven by toxicity (C>C1500 = 5.3 μM) with a 226-fold selectivityNinOd2ex window This to>x1ic0ity interference appeare>d10more likely consider7ing 19 and 20 wNerHe2inactive, as was th5e.9dimethyl analogue 22. Molecules 2021, 26, 7338 hours following infection with DENV2 via luciferase assays and calculated the half-maximal effective concentration (EC50) relative to DMSO treated cells.

H CH2OCH2

Extension Screening of Lead Compounds

Findings

Materials and Methods