Development of pyridine dicoumarols as potent anti HIV-1 leads, targeting HIV-1 associated topoisomeraseIIβ kinase
Abstract
Aim: A structural study of a series of pyridine dicoumarol derivatives with potential activity against a novel Topoisomerase IIβ kinase which was identified in the HIV-1 viral lysate, compounds were designed and synthesized based on a 3D-QSAR study. Materials & methods: Based on QSAR model we have designed and synthesized a series of pyridine dicoumarol derivatives and characterized by spectral studies, all the molecules are biologically evaluated by kinase assay, cytotoxicity assay, ELISA and PCR method. Result: We demonstrated the achievement of water soluble disodium pyridine dicoumarate derivatives showing high anti-HIV-1 activity (IC50 <25 nM) which provides a crucial point for further development of pyridine dicoumarol series as HIV-1-associated topoisomerase IIβ kinase inhibitors for clinical application against AIDS. Conclusion: A new class of anti-HIV-1 lead compounds have been designed and tested. Further studies would result in development of novel and potential drugs.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Maraviroc. Nat. Rev. Drug Discov. 7, 15–16 (2008).
- 2 . Antisense-mediated repression of DNA topoisomerase II expression leads to an impairment of HIV-1 replicative cycle. J. Mol. Biol. 285, 945–54 (1999).
- 3 . A study of the topoisomerase II activity in HIV-1 replication using the ferrocene derivatives as probes. Arch. Biochem. Biophys. 450, 123–132 (2006).
- 4 . Involvement of human topoisomerase II isoforms in HIV-1 reverse transcription. Arch. Biochem. Biophys. 532(2), 91–102 (2013).
- 5 . TopoisomeraseIIβ in HIV-1 transactivation. Arch. Biochem. Biophys. 593, 90–97 (2016).
- 6 . Regulation of topoisomerase II by phosphorylation: a role for casein kinase II. J. Cell Sci. 104, 219–225 (1993).
- 7 . Biochemical analysis of topoisomerase IIα and β kinase activity found in HIV-1 infected cells and virus. Arch. Biochem. Biophys. 441, 41–55 (2005). • The antiviral activity of the viral lysate was identified first in this study.
- 8 . HIV-1 associated topoisomerase IIβ kinase: a potential pharmacological target for viral replication. Curr. Pharm. Design. 19, 4776–4786 (2013). • The 3D-QSAR model and the design of the molecules are based on this study.
- 9 . The partial structure of novobiocin (streptonivicin). J. Am. Chem. Soc. 78, 1072–1074 (1956).
- 10 . Geiparvarin analogues: synthesis and anticancer evaluation of α-methylidene-γ-butyrolactone-bearing coumarins. Helv. Chim. Acta 82, 191–197 (1999).
- 11 . Hydrophobic acceleration of Diels–Alder reactions. J. Am. Chem. Soc. 102, 7816–7817 (1980).
- 12 . Hydrophobic effects on simple organic reactions in water. Acc. Chem. Res. 24, 159–164 (1991).
- 13 . A new variant of the Claisen rearrangement capable of creating the bond between two quaternary centers. J. Org. Chem. 48, 3866–3868 (1983).
- 14 . Evidence for a dipolar transition state. J. Am. Chem. Soc. 109, 1160–1170 (1987).
- 15 . Reformatsky-type reactions in aqueous media. Use of bronometryl-acrylic acid for the synthesis of α-methylene-γ-butyrolactones. Tetrahedron Lett. 26, 5697–5698 (1985).
- 16 . A new approach for the synthesis of alpha-methylene-gammabutyrolactones from alpha-bromomethylacrylicacids (or esters). Synth. Commun. 22, 481–487 (2006).
- 17 . A new sonochemical carbonyl cross-coupling reaction. J. Chem. Soc. Chem. Commun. 7, 398–399 (1989).
- 18 . Catalyst-free synthesis of α,α-bis(4-hydroxycoumarin-3-yl)toluene in aqueous media under microwave irradiation. Synth. Comm. 39(3), 497–505 (2009).
- 19 . Long-chain 3-acyl-4-hydroxycoumarins: structure and antibacterial activity. Arch. Pharm. Life Sci. 339, 129–132 (2006).
- 20 . P2O5/SiO2 as a new, efficient and reusable catalyst for preparation of 4,41-epoxydicoumarins under solvent-free conditions. E-J. Chem. 8(4), 1626–1631 (2011).
- 21 . Synthesis and anticoagulant activities of substituted 2,4-diketochromans, biscoumarins, and chromanocoumarins. Arch. Pharm. Chem. Life Sci. 339, 319–326 (2006).
- 22 . Cytotoxic activity of new lanthanum (III) complexes of bis-coumarins. Eur. J. Med. Chem. 40, 542–551 (2005). •• Water-soluble compounds were synthesized based on this study.
- 23 . Coumarin: chemical and pharmacological profile. J. App. Pharm. Sci. 2(6), 236–240 (2012).
- 24 Coumarin-based inhibitors of HIV integrase. J. Med. Chem. 40(2), 242–249 (1997). •• Coumarin moiety was selected based on this study.
- 25 New biscoumarin derivatives: synthesis, crystal structure, theoretical study and antibacterial activity against Staphylococcus aureus. Molecules 19, 19868–19879 (2014).
