Design and Synthesis of Benzopyranopyrimidinyl Phosphonates as Cytotoxic and Antioxidant Agents

Author(s): Sarva Santhisudha, Gundluru Mohan, Tenkayala Sobha Rani, Peddaiahgari Vasu Govardhana Reddy, Cirandur Suresh Reddy*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: A concatenation of bioactive diethyl(2-hydroxyphenylsubstituted) benzopyrano pyrimidinyl phosphonates were synthesized under eco-friendly green conditions in the presence of palladium doped graphitic carbon nitride (Pd@g-C3N4) as catalyst.

Methods: The title compounds were evaluated for cytotoxic activity against MCF-7, SW-480, HeLa and HL-7702 cell lines and in-vitro antioxidant activity by DPPH, NO and H2O2 methods.

Results: The synthesized compounds manifested robust cytotoxic and antioxidant activities.

Conclusion: Some of them showed much higher bioactivity than the standards.

Keywords: Benzopyranopyrimidinyl phosphonates, one-pot, green synthesis, Pd@g-C3N4, anticancer activity, SRB assay, antioxidant activity, in vitro.

World Cancer Report, World Health Organization. 2014. pp. Chapter 1.1. ISBN 9283204298Y, 2014.
Priya, P.V.; Rao, A.S. Evaluation of anticancer activity of mazus pumilus leaf extracts on selected human cancerous cell lines. Int. J. Pharm. Sci. Rev. Res., 2016, 37, 185-189.
Efferth, T.; Fu, Y-Y.; Zu, Y-G.; Schwarz, G.; Konkimalla, V.S.B.; Wink, M. Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine. Curr. Med. Chem., 2007, 14, 2024-2032.
Pham-Huy, L.A.; Hua, H.; Pham-Huy, C. Free radicals, antioxidants in disease and health. Int. J. Biomed. Sci., 2008, 4, 89-96.
Baylis, E.K.; Campbell, C.D.; Dingwall, J.G. 1-Aminoalkylphosphonous Acids. Part 1. Isosters of the protein amino acids. J. Chem. Soc. Perkin Trans., 1984, 1, 2845-2853.
Atherton, F.R.; Hassall, C.H.; Lambert, R.W. Synthesis and structure-activity relationships of antibacterial phosphonopeptides incorporating (1-aminoethyl) phosphonic acid and (aminome-thyl)phosphonic acid. J. Med. Chem., 1986, 29, 29-40.
Patel, D.V.; Rielly-Gauvin, K.; Ryono, D.E. Preparation of peptidic α-hydroxyphosphonates a new class of transition state analog renin inhibitors. Tetrahedron Lett., 1990, 31, 5587-5590.
Stowasser, B.; Budt, K.H.; Li, J.Q.; Peyman, A.; Ruppert, D. New hybrid transition state analog inhibitors of HIV protease with pe-ripheral C2-symmetry. Tetrahedron Lett., 1992, 33, 6625-6628.
Allen, M.C.; Fuhrer, W.; Tuck, B.; Wade, R. Wood, J.M. Renin inhibitors. Synthesis of transition-state analogue inhibitors containing phosphorus acid derivatives at the scissile bond. J. Med. Chem., 1989, 32, 1652-1661.
Kafarski, P.; LeJczak, B. Biological activity of aminophosphonic acids. Phosphorus Sulfur Silicon, 1991, 63, 193-215.
Enders, D.; Dizier, A.S.; Lannou, M.I.; Lenzen, A. The phospha-michael addition in organic synthesis. Eur. J. Org. Chem., 2006, 1, 29-49.
Iacobucci, G.A.; Sweeny, J.G. The chemistry of anthocyanins, anthocyanidins and related flavylium salts. Tetrahedron, 1983, 39, 3005-3038.
Khafagy, M.M.; El-Wahas, A.H.; Eid, F.A.; El-Agrody, A.M. Synthesis of halogen derivatives of benzo[h]chromene and benzo[a]anthracene with promising antimicrobial activities. Farmaco, 2002, 57, 715-722.
Smith, P.W.; Sollis, S.L.; Howes, P.D.; Cherry, P.C.; Starkey, I.D.; Cobley, K.N.; Weston, H.; Scicinski, J.; Merritt, A.; Whittington, A.; Wyatt, P.; Taylor, N.; Green, D.; Bethell, R.; Madar, S.; Fenton, R.J.; Morley, P.J.; Pateman, T.; Beresford, A. Dihydropyrancarboxamides related to zanamivir: A new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino-4h-pyran-6-carboxamides. J. Med. Chem., 1998, 41, 787-797.
(a)Moon, D.O.; Choi, Y.H.; Kim, N.D.; Park, Y.M.; Kim, G.Y. Anti-inflammatory effects of β-lapachone in lipopolysaccharide-stimulated BV2 microglia. Int. Immunopharmacol., 2007, 7, 506-514. (b) De Andrade-Neto, V.F.; Goulart, M.O.F.; Da Silva Filho, J.F.; Da Silva, M.J.; Pinto, M.D.C.F.R.; Pinto, A.V.; Zalis, M.G.; Carvalho, L.H.; Krettli, A.U. Antimalarial activity of phenazines from lapachol, β-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Bioorg. Med. Chem. Lett., 2004, 14, 1145-1149. (c) Elisa, P.S.; Ana, E.B.; Ravelo, A.G.; Yapu, D.J.; Turba, A.G. Antiplasmodial activity of naphthoquinones related to lapachol and β-lapachone. Chem. Biodivers., 2005, 2, 264-274.
Mohr, S.J.; Chirigios, M.A.; Fuhrman, F.S.; Pryor, J.W. Pyran copolymer as an effective adjuvant to chemotherapy against a murine leukemia and solid tumor. Cancer Res., 1975, 35, 3750-3754.
Bianchi, G.; Tava, A. Synthesis of (2R)-(+)-2,3-dihydro-2,6-dimethyl-4h-pyran-4-one, a homologue of pheromone of a species in the hepialidae family. Agric. Biol. Chem., 1987, 51, 2001-2002.
Anderson, D.R.; Hegde, S.; Reinhard, E.; Gomez, L.; Vernier, W.F.; Lee, L.; Liu, S.; Sambandam, A.; Sinder, P.A.; Masih, L. Aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg. Med. Chem. Lett., 2005, 15, 1587-1590.
Ellis, G.P. In Weissberger, A.; Taylor, E. C.; Eds; The Chemistry of Heterocyclic Compounds. Chromenes, Harmones, and Chromones John Wiley: New York, 1977, 31, 11-139.
Hafez, E.A.A.; Elnagdi, M.H.; Elagamey, A.G.A.; El-Taweel, F.M.A.A. Nitriles in heterocyclic synthesis: Novel synthesis of benzo[c]coumarin and of benzo[c]pyrano [3,2-c]quinoline derivatives. Heterocycles, 1987, 26, 903-907.
Juby, P.F.; Hudyma, T.W.; Brown, M.; Essery, J.M.; Partyka, R.A. Antiallergy agents. 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylic acids and esters. J. Med. Chem., 1979, 22, 263-269.
Gupta, K.S.; Kayath, H.P.; Singh, A.; Sharma, G.; Mishra, K.C. Anticonvulsant activity of pyrimidine thiols. Int. J. Pharmacol., 1994, 26, 227-228.
Lee, H.W.; Bok, Y.K.; Joong, B.A. Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione. Eur. J. Med. Chem., 2005, 40, 862-874.
Rahaman, S.A.; Pasad, Y.R.; Kumar, P.; Kumar, B. Synthesis and anti-histaminic activity of some novel pyrimidines. Saudi Pharm. J., 2009, 17, 255-258.
Hannah, D.R.; Stevens, M.F.G. Structural studies on bioactive compounds-part 38.1: Reactions of 5-aminoimidazole-4-carboxamide: Synthesis of imidazo [1,5-a]quinazoline-3-carboxamides. J. Chem. Res., 2003, 7, 398-401.
Abu-Hashem, A.A.; Youssef, M.M.; Hussein, H.A.R. Synthesis, antioxidant, antituomer activities of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolopyrrolothiazolopyrimidines derivatives. J. Chin. Chem. Soc., 2011, 58, 41-48.
Abu-Hashem, A.A.; El-Shehry, M.F.; Badria, F.A. Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents. Acta Pharm., 2010, 60, 311-323.
Balzarini, J.; McGuigan, C. Bicyclic pyrimidine nucleoside analogues (BCNAs) as highly selective and potent inhibitors of varicella-zoster virus replication. J. Antimicrob. Chemother., 2002, 50, 5-9.
Paola, D.; Daniela, F.; Giovanni, S.; Ildebrando, M.; Maura, F.; Pier, A.B.; Luisa, M.; Laura, S.; Paola, F.; Fulvia, O.; Franco, B.; Gabriella, B. Synthesis and cardiotonic activity of novel pyrimidine derivatives: Crystallographic and quantum chemical studies. J. Med. Chem., 1996, 39, 3671-3683.
Nezu, Y.; Miyazaki, M.; Sugiyama, K.; Kajiwara, I. Dimethoxypyrimidine as novel herbicides-part 1: Synthesis and herbicidal activity of dimethoxyphenoxypyrimidines and analogues. Pestic. Sci., 1996, 47, 103-113.
Kumar, B.; Kaur, B.; Kaur, J.; Parmar, A.; Anand, R.D. Kumar, H. Thermal/ microwave assisted synthesis of substituted tetrahydropyrimidines as potent calcium channel blockers. Indian J. Chem. B., 2002, 41, 1526-1530.
Tani, J.; Yamada, Y.; Oine, T.; Ochiai, T.; Ishida, R.; Inoue, I. Studies on biologically active halogenated compounds. 1. Synthesis and central nervous system depressant activity of 2-(fluoromethyl)-3-aryl-4(3H)-quinazolinone derivatives. J. Med. Chem., 1979, 22, 95-99.
Zhang, L.G.; Chen, X.F.; Guan, J.; Jiang, Y.J.; Hou, T.G.; Mu, X.D. Facile synthesis of phosphorus doped graphitic carbon nitride polymers with enhanced visible-light photocatalytic activity. Mater. Res. Bull., 2013, 48, 3485-3491.
Chen, X.F.; Zhang, J.S.; Fu, X.Z.; Antonietti, M.; Wang, X.C. Fe-g-C3N4- catalyzed oxidation of benzene to phenol using hydrogen peroxide and visible light. J. Am. Chem. Soc., 2009, 131, 11658-11659.
Wang, Y.; Yao, J.; Li, H.R.; Su, D.S.; Antonietti, M. Highly selective hydrogenation of phenol and derivatives over a Pd@carbon nitride catalyst in aqueous media. J. Am. Chem. Soc., 2011, 133, 2362-2365.
Gong, Y.T.; Zhang, P.F.; Xu, X.; Li, Y.; Li, H.R.; Wang, Y. A novel catalyst Pd@ompg-C3N4 for highly chemoselective hydrogenationof quinoline under mild conditions. J. Catal., 2013, 297, 272-280.
Xiangyang, S.; Ajayan, V.; Salem, S.A.; Lin, Z. Highly uniform Pd nanoparticles supported on g-C3N4 for efficiently catalytic Suzuki Miyaura reactions. Catal. Lett., 2015, 145, 1388-1395.
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, I.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxic assay for anticancer drug screening J. Nat. Cancer Inst., 1990, 82, 1107-1112.
Choi, C.W.; Kim, S.C.; Hwang, S.S.; Choi, B.K.; Ahn, H.J.; Lee, M.Y.; Park, S.H.; Kim, S.K. Antioxidant activity and free radical scavenging capacity between Korean medicinal plants and flavonoids by assay-guided comparison. Plant Sci., 2002, 163, 1161-1168.
Shirwaikar, A.N.; Sirwaikar, A.R.; Rajendrar, K.; Punitha, I.S.R. in vitro antioxidant studies on the benzyl tetra isoquinoline alkaloid. Biol. Pharm. Bull., 2006, 29, 1906-1910.
Yen, G.C.; Chen, H.Y.J. Antioxidant activity of various tea extracts in relation to their anti-mutagenicity. Agri. Food Chem., 1995, 43, 27-32.
Kalla, R.M.N.; Jin-Seok, C.; Jin-Wook, Y.; Seong, J.B.; Min, S.H.; Kim, I. Synthesis of 2-amino-3-cyano-4H-chromen-4-ylphosphonates and their anticancer properties. Eur. J. Med. Chem., 2014, 76, 61-66.
Santhisudha, S.; Sreekanth, T.; Murali, S.; Devi, M.A.; Reddy, C.S. Ultrasound promoted synthesis and anticoagulant activity of 2-amino-4h-chromen-4yl phosphonates. Cardiovasc. Hematol. Agents Med. Chem., 2016, 14, 167-174.
Reddy, K.M.K.; Santhisudha, S.; Mohan, G.; Peddanna, K.; Rao, C.A.; Reddy, C.S. Nano Gd2O3 catalyzed synthesis and anti-oxidant activity of new α-aminophosphonates. Phosphorus Sulfur Silicon, 2016, 191, 933-938.
Mohan, G.; Santhisudha, S.; Murali, S.; Reddy, N.B.; Sravya, G.; Grigory, Z.V.; Reddy, C.S. One-pot green synthesis and bio-assay of pyrazolylphosphonates. Res. Chem. Int., 2018, 44, 3475-3491.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [721 - 733]
Pages: 13
DOI: 10.2174/1570180815666180606083418
Price: $58

Article Metrics

PDF: 24