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


  • Jun-Fei Zhang Department of Infectious Disease, 105th Hospital, Affiliated with Anhui Medical University, Hefei, 230031
  • Bo Liu Department of Infectious Disease, 105th Hospital, Affiliated with Anhui Medical University, Hefei, 230031
  • Cong-Xin Chen Department of Infectious Disease, 105th Hospital, Affiliated with Anhui Medical University, Hefei, 230031




Anti-HBV, Dihydroisoindolo[2, 1-a]quinazoline-5, 11-dione, HBV DNA replication, Lamivudine


The construction of dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives (4a4m), 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.




Download data is not yet available.


Arnesto D, Horspool WM, Martin N, Ramos A, Seaone C. Synthesis of cyclobutenes by the novel photochemical ring contraction of 4-substituted 2-amino-3,5-dicyano-6-phenyl-4H-pyrans. J Org Chem. 1989; 54: 3069-72.

Bonsignore L, Loy G, Secci D, Calignano A. Synthesis and pharmacological activity of 2-oxo-(2H) 1-benzopyran-3-carboxamide derivatives. Eur J Med Chem. 1993; 28: 517-20.

Breiner B, Schlatterer JC, Kovalenko SV, Greenbaum NL, Alabugin IV. DNA damage-site recognition by lysine conjugates. Proc Natl Acad Sci USA. 2007; 104: 13016-21.

Breiner B, Schlatterer JC, Kovalenko SV, Greenbaum NL, Alabugin IV. Protected 32P-Labels in Deoxyribonucleotides: Investigation of sequence selectivity of DNA photocleavage by enediyne, fulvene, and acetylenelysine conjugates. Angew Chem Int Ed. 2006; 45: 3666-70.

Dény P, Zoulim F. Hepatitis B virus: From diagnosis to treatment. Pathol Biol. 2010; 58: 245-53.

Ellis GP. In: The chemistry of heterocyclic compounds: Chro-menes, chromanes and chromones. Weissberger A, Taylor EC (eds). New York, John Wiley, 1977, p 11.

Fattovich G, Brollo L, Alberti A, Pontisso P, Giustina G, Realdi G. Long-term follow-up of anti-HBe positive chronic active hepatitis B. Hepatology 1998; 8; 1651-54.

Foye WO. Principidi chemico farmaceutica; Piccin, Padora, Italy, 1991, p 416.

Furumi K, Fujioka T, Fujii H, Okabe H, Nakano Y, Matsunaga H, Katano M, Mori M, Mihashi K. Novel antiproliferative falcarindiol furanocoumarin ethers from the root of Angelica japonica. Bioorg Med Chem Lett. 1998; 8: 93-96.

Hyodo S, Fujita K, Kasuyaa O, Takahashia I, Uzawab J, Koshino H. Structures of phospholipase A2 inhibitors, ergo-philones A and B. Tetrahedron 1995; 51: 6717-24.

Kortylewicz ZP, Nearman J, Baranowska-Kortylewicz J. Radiolabeled 5-Iodo-3?-O-(17?-succinyl-5?-androstan-3-one)-2?-deoxyuridine and Its 5?-monophosphate for imaging and therapy of androgen receptor-positive cancers: Synthesis and biological evaluation. J Med Chem. 2009; 52; 5124-43.

Kovalenko SV, Alabugin IV. Lysineenediyne conjugates as photochemically triggered DNA double-strand cleavage agents. Chem Commun. 2005; 1444-46.

Korba BE, Gerin JL. Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication. Antiviral Res. 1992; 19: 55-70.

Locarnini S, Mason WS. Cellular and virological mechanisms of HBV drug resistance. J Hepatol 2006; 44; 422-31.

Oaksmith JM, Ganem B. Synthesis of a COMCestradiol conjugate for targeted, tissue-selective cancer chemotherapy. Tetrahedron Lett. 2009; 50; 3497-98.

Sato K, Mori M. Current and novel therapies for hepatitis B virus infection. Mini Rev Med Chem. 2010; 10; 20-31.

Siva Kumar K, Mahesh Kumar P, Anil Kumar K, Sreenivasulu M, Ahamed AJ, Rambabu D, Rama Krishna G, Malla Reddy C, Ravikumar K, Shivakumar K, Krishna Priya K, Kishore VLP, Pal M. A new three-component reaction: Green synthesis of novel isoindolo[2,1-a]quinazoline derivatives as potent inhibitors of TNF-?. Chem Commun. 2011; 47; 5010-12.

Stray SJ, Bourne CR, Punna S, Lewis WG, Finn MG, Zlotnick A. A heteroaryl dihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly. Proc Natl Acad Sci USA. 2005; 102: 8138-43.

Vasilevsky SF, Govdi AI, Sorokina IV, Tolstikova TG, Baev DS, Tolstikov, GA, Mamatuyk, VI, Alabugin IV. Rapid access to new bioconjugates of betulonic acid via click chemistry. Bioorg Med Chem Lett. 2011; 21: 62-65.

Wong DKH, Cheung AM, Orourke K, Naylor CD, Detsky AS. Effect of alpha-interferon treatment in patients with heap-titis B e antigen-positive chronic hepatitis B: A meta-analysis. Ann Intern Med. 1993; 119: 312-23.

Yang WY, Breiner B, Kovalenko SV, Ben C.; Singh M, Le Grand SN, Sang QX, Strouse GF, Copland JA, Alabugin IV. C-Lysine conjugates: pH-controlled light-activated reagents for efficient double-stranded DNA cleavage with implica-tions for cancer therapy. J Am Chem Soc. 2009; 131; 11458-70.

Yang WY, Marrone SA, Minors N, Zorio DAR, Alabugin IV. Fine-tuning alkyne cyclo additions: Insights into photochemistry responsible for the double-strand DNA cleavage via structural perturbations in diaryl alkyne conjugates. Beilstein J Org Chem. 2011; 7; 813-23.




How to Cite

Zhang, J.-F., B. Liu, and C.-X. Chen. “Dihydroisoindolo[2,1-a]quinazoline-5,11-Dione Derivatives As Potent and Selective Inhibitors Targeting Hepatitis B Virus”. Bangladesh Journal of Pharmacology, vol. 10, no. 3, July 2015, pp. 612-20, doi:10.3329/bjp.v10i3.23264.



Research Articles