Generic placeholder image

Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

Design, Synthesis, and Characterization of Novel Linomide Analogues and their Evaluation for Anticancer Activity

Author(s): Rudrax N.S. Priolkar, Sunil Shingade*, Mahesh Palkar and Shivalingrao M. Desai

Volume 17 , Issue 2 , 2020

Page: [203 - 212] Pages: 10

DOI: 10.2174/1570163815666181008151037

Price: $65

Abstract

Background: According to WHO, in 2017, about 90.5 million people suffered from cancer and about 8.8 million deaths occurred due to disease. Although the chemotherapeutic agents have decreased the mortality among the cancer patients but high toxicity and non-specific targets are still major drawbacks.

Many researchers have identified linomide, a 4-hydroxy-2-quinolone derivative, as a lead molecule for the development of anticancer agents. With this background, we thought of the following objective.

Objective: The objective of this research work involves the synthesis of a series of N-(2-(4- hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides IVa-d (1-3) by replacing the anilide moiety at the third position of linomide with sulfamoylacyl and also N-methyl by N-phenyl functionality. To perform in silico anticancer activity by using Molegro Virtual Docker (MVD-2013, 6.0) software and in vitro anticancer activity by MTT assay.

Methods: The starting material 4-hydroxy-1-phenylquinolin-2(1H)-one was treated with N-bromosuccinamide to yield compound II. Condensation of compound II with primary amines resulted in compounds IIIa-d, which, on coupling with substituted aromatic sulfonyl chlorides yield the title compounds IVa-d (1-3).

Results: All the synthesized compounds were satisfactorily characterized by spectral data. The results of docking revealed that the synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17). The MolDock Score of compound IVd-1 (-115.503) was the highest amongst those tested. The in vitro anticancer activity results showed that compound IVc-1 (R= - (CH2) 2-CH3 ; R′= -H) and IV d-1 (R= -CH2-C6H5; R′= -H) were found to be most potent against K562 cell line with an IC50 of 0.451 μM/ml and 0.455 μM/ml respectively. Compound IVd-1 also showed better potency against A549 cell line with IC50 value of 0.704 μM/ml.

Conclusion: The results of in silico and in vitro anticancer activity are in agreement with each other. Compound IV d-1 was found to be most active of the series.

Keywords: Linomide, quinolin-2-one, N-bromosuccinimide, sulfonamides, anticancer, docking.

Graphical Abstract
[1]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[3]
Tripathi KD. Essentials of Medical Pharmacology.sixth ed New Delhi: Jaypee Brothers Medical Publishers (P) Ltd. 2006; pp. pp. ((reprint 2010)):. 819-29.
[4]
Block JH, Beale JM. Wilson and Gisvold’s Medicinal and Pharmaceutical Chemistry. 12th ed. United States of America: Lippincott Williams and Wilkins 2011.
[5]
Thomas K. The pyrano route to 4-hydroxy-2-quinolones and 4-hydroxy-2-pyridones. IL Farmaco 1999; 54: 309-15.
[http://dx.doi.org/10.1016/S0014-827X(99)00030-0]
[6]
Zhang Q, Chen Y, Zheng YQ, et al. Synthesis and bioactivity of 4,10-dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid and its esters. Bioorg Med Chem 2003; 11(6): 1031-4.
[http://dx.doi.org/10.1016/S0968-0896(02)00526-6] [PMID: 12614889]
[7]
Ohashi T, Oguro Y, Tanaka T, et al. Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors. Bioorg Med Chem 2012; 20(18): 5496-506.
[http://dx.doi.org/10.1016/j.bmc.2012.07.039] [PMID: 22910224]
[8]
Afzal O, Kumar S, Haider MR, et al. A review on anticancer potential of bioactive heterocycle quinoline. Eur J Med Chem 2015; 97: 871-910.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.044] [PMID: 25073919]
[9]
Ogino K, Hobara T, Ishiyama H, et al. Antiulcer mechanism of action of rebamipide, a novel antiulcer compound, on diethyldithiocarbamate-induced antral gastric ulcers in rats. Eur J Pharmacol 1992; 212(1): 9-13.
[http://dx.doi.org/10.1016/0014-2999(92)90065-C] [PMID: 1313372]
[10]
Trinquand C, Romanet JP, Nordmann JP, Allaire C. [Efficacy and safety of long-acting carteolol 1% once daily. A double-masked, randomized study]. J Fr Ophtalmol 2003; 26(2): 131-6.
[PMID: 12660585]
[11]
De Fruyt J, Deschepper E, Audenaert K, et al. Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol (Oxford) 2012; 26(5): 603-17.
[http://dx.doi.org/10.1177/0269881111408461] [PMID: 21940761]
[12]
Maria GR, Shivlingrao MD, Soniya N, et al. Synthesis and evaluation of 2-(4-methoxy-2-oxo-1-phenyl/methyl-1,2-dihydroquinolin-3-yl)-2-methyl-3-(phenyl/substitutedphenylamino)thiazolidin-4-one as antibacterial and anticancer agents. Indian J Chem 2016; 55B: 1254-8.
[13]
Shi J, Xiao Z, Ihnat MA, et al. Structure-activity relationships studies of the anti-angiogenic activities of linomide. Bioorg Med Chem Lett 2003; 13(6): 1187-9.
[http://dx.doi.org/10.1016/S0960-894X(03)00047-7] [PMID: 12643940]
[14]
Li Q, Woods KW, Wang W, et al. Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors. Bioorg Med Chem Lett 2005; 15(8): 2033-9.
[http://dx.doi.org/10.1016/j.bmcl.2005.02.062] [PMID: 15808463]
[15]
Jochmans D. Novel HIV-1 reverse transcriptase inhibitors. Virus Res 2008; 134(1-2): 171-85.
[http://dx.doi.org/10.1016/j.virusres.2008.01.003] [PMID: 18308412]
[16]
Palkar MB, Singhai AS, Ronad PM, et al. Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents. Bioorg Med Chem 2014; 22(10): 2855-66.
[http://dx.doi.org/10.1016/j.bmc.2014.03.043] [PMID: 24751552]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy