Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Research Article

Design, Synthesis and In Vitro Evaluation of 2-Oxo-N-substituted Phenyl- 2H-chromene-3-carboxamide Derivatives as HIV Integrase Strand Transfer Inhibitors

Author(s): Pankaj Wadhwa*, Priti Jain and Hemant R. Jadhav

Volume 17, Issue 4, 2020

Page: [418 - 427] Pages: 10

DOI: 10.2174/1570180816666190617150803

Price: $65

Abstract

Background: A series of eighteen 2-Oxo-N-substituted phenyl- 2H-chromene-3- carboxamide analogues has been evaluated for HIV-1 integrase (IN) inhibition.

Methods: The derivatives were synthesized via a two-step pathway commencing with 2- hydroxybenzaldehyde and diethyl malonate followed by hydrolysis of ester and coupling with various aromatic amines. The HIV-1 IN inhibitory potential of these compounds has been studied relative to dolutegravir, a known HIV-1 IN inhibitor using a standard available kit.

Results: Six molecules (compounds 13h, 13i, 13l, 13p to 13r) showed significant inhibition of HIV- 1 integrase 3′-strand transfer with IC50 values less than 1.7 μM. The presence of chromene-3- carboxamide motif was shown to be crucial for the enzymatic activity. In addition, molecular modelling studies were also done to justify the IN inhibition and in vitro-in silico correlation was drawn.

Conclusion: However, these compounds did not show HIV-1 and HIV-2 inhibition below their cytotoxic concentration indicating that these compounds cannot be taken further for anti-HIV activity as such and require structural modification.

Keywords: HIV-1 integrase, strand transfer, chromene-3-carboxamide, HIV-1 inhibition, cytotoxicity, Acquired immune deficiency syndrome (AIDS).

« Previous Next »
Graphical Abstract

[1]
Wilen, C.B.; Tilton, J.C.; Doms, R.W. Molecular mechanisms of HIV entry. Adv. Exp. Med. Biol., 2012, 726, 223-242.
[http://dx.doi.org/10.1007/978-1-4614-0980-9_10] [PMID: 22297516]
[2]
Chiu, T.K.; Davies, D.R. Structure and function of HIV-1 integrase. Curr. Top. Med. Chem., 2004, 4(9), 965-977.
[http://dx.doi.org/10.2174/1568026043388547] [PMID: 15134551]
[3]
Nair, V.; Chi, G. HIV integrase inhibitors as therapeutic agents in AIDS. Rev. Med. Virol., 2007, 17(4), 277-295.
[http://dx.doi.org/10.1002/rmv.539 ] [PMID: 17503547]
[4]
Pace, P.; Rowley, M. Integrase inhibitors for the treatment of HIV infection. Curr. Opin. Drug Discov. Devel., 2008, 11(4), 471-479.
[PMID: 18600564]
[5]
Su, M.; Tan, J.; Lin, C.Y. Development of HIV-1 integrase inhibitors: Recent molecular modeling perspectives. Drug Discov. Today, 2015, 20(11), 1337-1348.
[http://dx.doi.org/10.1016/j.drudis.2015.07.012] [PMID: 26220090]
[6]
Wadhwa, P.; Jain, P.; Rudrawar, S.; Jadhav, H.R.A. quinoline, coumarin and other heterocyclic analogs based hiv-1 integrase inhibitors. Curr. Drug Discov. Technol., 2018, 15(1), 2-19.
[http://dx.doi.org/10.2174/1570163814666170531115452] [PMID: 28558629]
[7]
Venugopala, K.N.; Rashmi, V.; Odhav, B. Review on natural coumarin lead compounds for their pharmacological activity. BioMed Res. Int., 2013. 2013963248
[http://dx.doi.org/10.1155/2013/963248] [PMID: 23586066]
[8]
Kontogiorgis, C.; Detsi, A.; Hadjipavlou-Litina, D. Coumarin-based drugs: A patent review (2008 -- present). Expert Opin. Ther. Pat., 2012, 22(4), 437-454.
[http://dx.doi.org/10.1517/13543776.2012.678835] [PMID: 22475457]
[9]
Leal, L.K.; Ferreira, A.A.; Bezerra, G.A.; Matos, F.J.; Viana, G.S. Antinociceptive, anti-inflammatory and bronchodilator activities of Brazilian medicinal plants containing coumarin: A comparative study. J. Ethnopharmacol., 2000, 70(2), 151-159.
[http://dx.doi.org/10.1016/S0378-8741(99)00165-8] [PMID: 10771205]
[10]
Riveiro, M.E.; De Kimpe, N.; Moglioni, A.; Vázquez, R.; Monczor, F.; Shayo, C.; Davio, C. Coumarins: Old compounds with novel promising therapeutic perspectives. Curr. Med. Chem., 2010, 17(13), 1325-1338.
[http://dx.doi.org/10.2174/092986710790936284] [PMID: 20166938]
[11]
Jain, S.V.; Sonawane, L.V.; Patil, R.R.; Bari, S.B. Pharmacophore modeling of some novel indole β-diketo acid and coumarin-based derivatives as HIV integrase inhibitors. Med. Chem. Res., 2012, 21, 165-173.
[http://dx.doi.org/10.1007/s00044-010-9520-1]
[12]
Kim, H.K.; Lee, H.K.; Shin, C.G.; Huh, H. HIV integrase inhibitory activity of Agastache rugosa. Arch. Pharm. Res., 1999, 22(5), 520-523.
[http://dx.doi.org/10.1007/BF02979163] [PMID: 10549582]
[13]
Mao, P.C.; Mouscadet, J.F.; Leh, H.; Auclair, C.; Hsu, L.Y. Chemical modification of coumarin dimer and HIV-1 integrase inhibitory activity. Chem. Pharm. Bull. (Tokyo), 2002, 50(12), 1634-1637.
[http://dx.doi.org/10.1248/cpb.50.1634] [PMID: 12499608]
[14]
Bailly, F.; Queffelec, C.; Mbemba, G.; Mouscadet, J.F.; Cotelle, P. Synthesis and HIV-1 integrase inhibitory activities of caffeic acid dimers derived from Salvia officinalis. Bioorg. Med. Chem. Lett., 2005, 15(22), 5053-5056.
[http://dx.doi.org/10.1016/j.bmcl.2005.07.091] [PMID: 16183277]
[15]
Debyser, Z.; Cherepanov, P.; Pluymers, W.; De Clercq, E. Assays for the evaluation of HIV-1 integrase inhibitors. Methods Mol. Biol., 2001, 160, 139-155.
[http://dx.doi.org/10.1385/1-59259-233-3:139] [PMID: 11265279]
[16]
Goldgur, Y.; Craigie, R.; Cohen, G.H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T.; Murai, H.; Davies, D.R. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design. Proc. Natl. Acad. Sci. USA, 1999, 96(23), 13040-13043.
[http://dx.doi.org/10.1073/pnas.96.23.13040] [PMID: 10557269]
[17]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]

Rights & Permissions Print Cite
Article Metrics
8
© 2025 Bentham Science Publishers | Privacy Policy