Generic placeholder image

Anti-Infective Agents


ISSN (Print): 2211-3525
ISSN (Online): 2211-3533

Research Article

Phosphonate Derivatives of 3,5-bis(arylidene)-4-piperidone: Synthesis and Biological Evaluation

Author(s): Shweta Mishra, Debashree Das, Adarsh Sahu, Shailendra Patil, Ram Kishore Agrawal and Asmita Gajbhiye*

Volume 18, Issue 3, 2020

Page: [245 - 254] Pages: 10

DOI: 10.2174/2211352517666190820143735


Background: 3,5-Bis(arylidene)-4-piperidinones (BAP) belong to a wide class of cross conjugated dienones. The 1,5-diaryl-3-oxo-1,4-pentadienyl fragment of the BAP moiety is responsible for the molecule's anti-tumor, antioxidant, antimicrobial and anti-inflammatory manifestations. In the present study, we present combinations of phosphonate and 3,5-bis(arylidene)-4- piperidone pharmacophores. The anti-inflammatory, anti-oxidant potential, anti-proliferative, cytotoxic potential and antimicrobial of the title compounds were evaluated in in-vitro bioassay paradigms.

Methods: A novel class of phosphonate linked 3,5-Bis(aryl methylene)-4-piperidone derivatives were synthesized from simple, versitalie and efficient synthetic methodology. All of the synthesized compounds were screened for their in vitro anti-inflammatory, in vitro anti-oxidant potential, in vitro anti-proliferative, in vitro cytotoxic potential and in vitro antimicrobial activity. Amongst all the synthesized compounds in series, phosphonate derivatives of 3,5-Bis(arylmethylene)-4- piperidone containing 4-hydroxy-3-methoxyphenyl curcumin like prototype were more active than phenyl substituted compounds.

Results: The results of the screening revealed that compounds 5e, 5f, 5g, 5h were more active candidates as compared to 5a, 5b, 5c and 5d, however 5d can be readily endorsed as the most active compound of the series. Structure- activity relationship of the synthesized series suggested that structural resemblance of the synthesized compounds with that of curcumin was enormously accountable for the compounds anti-inflammatory, antioxidant and cytotoxic potential activity.

Conclusion: The in-vitro biological spectrum indicated that the substitution of groups at third and fourth position and alkyl phosphonates substitution potentiates the activity as compared to curcumin.

Keywords: 4-Piperidonone, curcumin, Phosphonates, 3, 5-bis(arylidene)-4-piperidone, anti-inflammatory activity, antioxidant activity.

Graphical Abstract
Aggarwal, B.B.; Sundaram, C.; Malani, N.; Ichikawa, H. Curcumin: the Indian solid gold. Adv. Exp. Med. Biol., 2007, 595, 1-75.
[] [PMID: 17569205]
Esatbeyoglu, T.; Huebbe, P.; Ernst, I.M.; Chin, D.; Wagner, A.E.; Rimbach, G. Curcumin--from molecule to biological function. Angew. Chem. Int. Ed. Engl., 2012, 51(22), 5308-5332.
[] [PMID: 22566109]
Maheshwari, R.K.; Singh, A.K.; Gaddipati, J.; Srimal, R.C. Multiple biological activities of curcumin: a short review. Life Sci., 2006, 78(18), 2081-2087.
[] [PMID: 16413584]
Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: problems and promises. Mol. Pharm., 2007, 4(6), 807-818.
[] [PMID: 17999464]
Bandgar, B.P.; Jalde, S.S.; Korbad, B.L.; Patil, S.A.; Chavan, H.V.; Kinkar, S.N.; Adsul, L.K.; Shringare, S.N.; Nile, S.H. Synthesis and antioxidant, cytotoxicity and antimicrobial activities of novel curcumin mimics. J. Enzyme Inhib. Med. Chem., 2012, 27(2), 267-274.
[] [PMID: 21679049]
Bykhovskaya, O.V.; Aladzheva, I.M.; Makarov, M.V.; Rybalkina, E.Y.; Klemenkova, Z.S.; Brel, V.K. Synthesis and study of antitumor activity of 4H-pyrano [3, 2-c] pyridines based on N-(2-azidoethyl)-and N-propargy 3, 5-bis(arylidene) piperidin-4-ones. Russ. Chem. Bull., 2017, 66(1), 104-110.
Rathore, S.; Mishra, S.; Mahapatra, D.K.; Patil, S.; Patil, A.G. Thoughtful insights into the therapeutic armamentarium of chalcones: 10 years of glorious journey. Curr. Bioact. Compd., 2019, •••, 1-60.
Hatcher, H.; Planalp, R.; Cho, J.; Torti, F.M.; Torti, S.V. Curcumin: from ancient medicine to current clinical trials. Cell. Mol. Life Sci., 2008, 65(11), 1631-1652.
[] [PMID: 18324353]
Zhou, H.; Beevers, C.S.; Huang, S. The targets of curcumin. Curr. Drug Targets, 2011, 12(3), 332-347.
[] [PMID: 20955148]
Rao, R.N.; Mm, B.; Maiti, B.; Thakuria, R.; Chanda, K. Efficient access to imidazo[1,2- a]pyridines/pyrazines/pyrimidines via catalyst-free annulation reaction under microwave irradiation in green solvent. ACS Comb. Sci., 2018, 20(3), 164-171.
[] [PMID: 29373013]
Montchamp, J.L. Phosphinate chemistry in the 21st century: a viable alternative to the use of phosphorus trichloride in organophosphorus synthesis. Acc. Chem. Res., 2014, 47(1), 77-87.
[] [PMID: 23909275]
Demmer, C.S.; Krogsgaard-Larsen, N.; Bunch, L. Review on modern advances of chemical methods for the introduction of a phosphonic acid group. Chem. Rev., 2011, 111(12), 7981-8006.
[] [PMID: 22010799]
Kolodiazhnyi, O.I. Asymmetric Synthesis in Organophosphorus Chemistry: Synthetic Methods, Catalysis, and Applications, 1st ed; Wiley VCH, 2017.
Sahu, A.; Mishra, S.; Gajbhiye, A.; Agrawal, R.K. Magnesium perchlorate catalyzed phospha-michael addition of dialkyl phosphite to chalcone. Curr. Org. Synth., 2018, 15(7), 1020-1023.
Kálai, T.; Kuppusamy, M.L.; Balog, M.; Selvendiran, K.; Rivera, B.K.; Kuppusamy, P.; Hideg, K. Synthesis of N-substituted 3,5-bis(arylidene)-4-piperidones with high antitumor and antioxidant activity. J. Med. Chem., 2011, 54(15), 5414-5421.
[] [PMID: 21702507]
Thakur, A.; Manohar, S.; Gerena, C.E.V.; Zayas, B.; Kumar, V.; Malhotra, S.V.; Rawat, D.S. Novel 3, 5-bis (arylidiene)-4-piperidone based monocarbonyl analogs of curcumin: anticancer activity evaluation and mode of action study. MedChemComm, 2014, 5(5), 576-586.
Makarov, M.V.; Rybalkina, E.Y.; Röschenthaler, G.V.; Short, K.W.; Timofeeva, T.V.; Odinets, I.L. Design, cytotoxic and fluorescent properties of novel N-phosphorylalkyl substituted E,E-3,5-bis(arylidene)piperid-4-ones. Eur. J. Med. Chem., 2009, 44(5), 2135-2144.
[] [PMID: 19046794]
Makarov, M.V.; Rybalkina, E.Y.; Khrustalev, V.N.; Röschenthaler, G.V. Modification of 3, 5-bis (arylidene)-4-piperidone pharmacophore by phosphonate group using 1, 2, 3-triazole cycle as a linker for the synthesis of new cytostatics. Med. Chem. Res., 2015, 24(4), 1753-1762.
Ezzat, S.M.; Ezzat, M.I.; Okba, M.M.; Menze, E.T.; Abdel-Naim, A.B. The hidden mechanism beyond ginger (Zingiber officinale Rosc.) potent in vivo and in vitro anti-inflammatory activity. J. Ethnopharmacol., 2018, 214, 113-123.
[] [PMID: 29253614]
Cui, W.; Qin, H.; Zhou, Y.; Du, J. Determination of the activity of hydrogen peroxide scavenging by using blue-emitting glucose oxidase–stabilized gold nanoclusters as fluorescent nanoprobes and a Fenton reaction that induces fluorescence quenching. Mikrochim. Acta, 2017, 184(4), 1103-1108.
Khan, N.; Afaq, F.; Mukhtar, H. Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid. Redox Signal., 2008, 10(3), 475-510.
[] [PMID: 18154485]
Lee, D.; Park, S.; Bae, S.; Jeong, D.; Park, M.; Kang, C.; Yoo, W.; Samad, M.A.; Ke, Q.; Khang, G.; Kang, P.M. Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury. Sci. Rep., 2015, 5, 16592.
[] [PMID: 26563741]
Jain, P.K.; Kharya, M.; Gajbhiye, A. Pharmacological evaluation of mangiferin herbosomes for antioxidant and hepatoprotection potential against ethanol induced hepatic damage. Drug Dev. Ind. Pharm., 2013, 39(11), 1840-1850.
[] [PMID: 23167243]
Abraham, R.; Prakash, P.; Mahendran, K.; Ramanathan, M. A novel series of N-acyl substituted indole-linked benzimidazoles and naphthoimidazoles as potential anti inflammatory, anti biofilm and anti microbial agents. Microb. Pathog., 2018, 114, 409-413.
[] [PMID: 29233780]
Eleftheriou, E.P.; Adamakis, I.D.S.; Melissa, P. Effects of hexavalent chromium on microtubule organization, ER distribution and callose deposition in root tip cells of Allium cepa L. Protoplasma, 2012, 249(2), 401-416.
[] [PMID: 21633932]
Rauf, A.; Uddin, G.; Khan, H.; Raza, M.; Zafar, M.; Tokuda, H. Anti-tumour-promoting and thermal-induced protein denaturation inhibitory activities of β-sitosterol and lupeol isolated from Diospyros lotus L. Nat. Prod. Res., 2016, 30(10), 1205-1207.
[] [PMID: 26134930]

© 2022 Bentham Science Publishers | Privacy Policy