Dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives as potent and selective inhibitors targeting hepatitis B virus

Jun-Fei Zhang,Bo Liu,Cong-Xin Chen

doi:10.3329/bjp.v10i3.23264

Jun-Fei Zhang, Bo Liu + Show 1 more

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https://doi.org/10.3329/bjp.v10i3.23264

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Abstract

The construction of dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives (4a–4m), by the condensation isatoic anhydride, appropriate amines and 2-formylbenzoic acid by using silica sulfuric acid as catalyst was reported. These dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives (DIQ) were identified as potent inhibitors of HBV capsid assembly. The newly synthesized dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives 4a-4m were characterized by 1H NMR, 13C NMR, and Mass spectrum and evaluated for their anti-HBV activity. Majority of the synthesized compounds inhibited the expression of viral antigens at low concentration. But five compounds, 4a, 4b, 4c, 4f, and 4m were shown potent inhibition of HBV DNA replication at submicromolar range. Of these compounds, compound 4a was the most active when compared with lamivudine.

Highlights

Worldwide hepatitis B virus (HBV) becomes serious problem which is causing disease for more than 2 billion people
Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates and visualized under UV light. 1H NMR spectra were recorded with Varian Mercury Plus 400 MHz instrument.13C NMR spectra were recorded with a Varian Gemini 100 MHz instrument
In the initial studies we investigated the cylclization reaction of 2-formylbenzoic acid (3) with isatoic anhydride (1) and 2,4-difluoro aniline (2a) using SSA as catalyst in ethanol under reflux (Scheme-1) for 2 hours which yielded the required compound 4a in 89% (Table I, entry 1)

Summary

Introduction

Worldwide hepatitis B virus (HBV) becomes serious problem which is causing disease for more than 2 billion people. It is important to explore novel classes of drugs with different antiviral targets and mechanisms for anti-HBV purposes. On the other hand Hybrid molecules which can form by combining two heterocyclic cores of different nature often possess improved biological activities (Hyodo et al, 1995; Furumi et al, 1998). There are several literature precedence for the biologically active hybrids in the literature such as steroid-antibiotic (Oaksmith and Ganem, 2009), steroid-nucleoside, (Kortylewicz et al, 2009) triterpenoid-peptide (Vasilevsky et al, 2011) and DNA-cleaving agent- amino acid (Breiner et al, 2007; Breiner et al, 2006; Kovalenko and Alabugin, 2005; Yang et al, 2011) etc

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