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Abstract
A novel series of dihydropyrido[2,3-d]pyrimidine derivatives were synthesized by multicomponent domino cyclization via the one-pot three component reaction of 6-amino uracil, substituted aryl aldehydes and N-methyl-1-(methylthio)-2-nitroethenamine in the presence of PTSA 10 mol% as a catalyst. The structures of these synthesized compounds were characterized by spectral analysis. Further the synthesized compounds screened for in vitro antimicrobial activity. Among all the compounds, compound 4b containing flouro substitution exhibited good inhibition against the tested species.
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References
- E.K. Davison and J. Sperry, Natural Products with Heteroatom-Rich Ring Systems, J. Nat. Prod., 80, 3060 (2017); https://doi.org/10.1021/acs.jnatprod.7b00575
- Y. Ju and R.S. Varma, Aqueous N-Heterocyclization of Primary Amines and Hydrazines with Dihalides: Microwave-Assisted Syntheses of N-Azacycloalkanes, Isoindole, Pyrazole, Pyrazolidine, and Phthalazine Derivatives, J. Org. Chem., 71, 135 (2006); https://doi.org/10.1021/jo051878h
- S. Ravi Kanth, G. Venkat Reddy, K. Hara Kishore, P. Shanthan Rao, B. Narsaiah and U.S. Narayana Murthy, Convenient Synthesis of Novel 4-Substituted Amino-5-trifluoromethyl–2,7-disubstituted pyrido[2,3-d]- pyrimidines and their Antibacterial Activity, Eur. J. Med. Chem., 41, 1011 (2006); https://doi.org/10.1016/j.ejmech.2006.03.028
- I.I. Abbas, H.H. Hammud and H. Shamsaldeen, Calix[4]pyrrole Macrocycle: Extraction of Fluoride Anions from Aqueous Media, Eur. J. Chem., 3, 156 (2012); https://doi.org/10.5155/eurjchem.3.2.156-162.542
- L.R. Bennett, C.J. Blankley, R.W. Fleming, R.D. Smith and D.K. Tessman, Antihypertensive Activity of 6-Arylpyrido[2,3-d]pyrimidin-7-amine derivatives, J. Med. Chem., 24, 382 (1981); https://doi.org/10.1021/jm00136a006
- S. El-Kalyoubi and F. Agili, Synthesis, In Silico Prediction and in vitro Evaluation of Antitumor Activities of Novel Pyrido[2,3-d]pyrimidine, Xanthine and Lumazine Derivatives, Molecules, 25, 5205 (2020); https://doi.org/10.3390/molecules25215205
- H.N. Hafez, H.A.S. Abbas and A.R.B.A. El-Gazzar, Synthesis and Evaluation of Analgesic, Anti-inflammatory and Ulcerogenic Activities of Some Triazolo- and 2-Pyrazolyl-pyrido[2,3-d]pyrimidines, Acta Pharm., 58, 359 (2008); https://doi.org/10.2478/v10007-008-0024-1
- H.J. Zhang, S. Ben Wang, X. Wen, J.Z. Li and Z.S. Quan, Design, Synthesis, and Evaluation of the Anticonvulsant and Antidepressant Activities of Pyrido[2,3-d]pyrimidine Derivatives, Med. Chem. Res., 25, 1287 (2016); https://doi.org/10.1007/s00044-016-1559-1
- J.M. Quintela, C. Peinador, L. Botana, M. Estevez and R. Riguera, Synthesis and Antihistaminic Activity of 2-Guanadino-3-cyanopyridines and Pyrido[2,3-d]pyrimidines, Bioorg. Med. Chem., 5, 1543 (1997); https://doi.org/10.1016/S0968-0896(97)00108-9
- A. Agarwal, Ramesh, Ashutosh, N. Goyal, P.M.S. Chauhan and S. Gupta, Dihydropyrido[2,3-d]pyrimidines as a New Class of Antileishmanial Agents, Bioorg. Med. Chem., 13, 6678 (2005); https://doi.org/10.1016/j.bmc.2005.07.043
- N. Kammasud, C. Boonyarat, K. Sanphanya, M. Utsintong, S. Tsunoda, H. Sakurai, I. Saiki, I. Andre, D.S. Grierson and O. Vajragupta, 5-Substituted Pyrido[2,3-d]pyrimidine, An Inhibitor against Three Receptor Tyrosine Kinases, Bioorg. Med. Chem. Lett., 19, 745 (2009); https://doi.org/10.1016/j.bmcl.2008.12.023
- K. Wu, J. Ai, Q. Liu, T.T. Chen, A. Zhao, X. Peng, Y. Wang, Y. Ji, Q. Yao, Y. Xu, M. Geng and A. Zhang, Multisubstituted Quinoxalines and Pyrido[2,3-d]pyrimidines: Synthesis and SAR study as Tyrosine Kinase c-Met Inhibitors, Bioorg. Med. Chem. Lett., 22, 6368 (2012); https://doi.org/10.1016/j.bmcl.2012.08.075
- R. Edupuganti, Q. Wang, C.D.J. Tavares, C.A. Chitjian, J.L. Bachman, P. Ren, E.V. Anslyn and K.N. Dalby, Synthesis and Biological Evaluation of Pyrido[2,3-d]pyrimidine-2,4-dione Derivatives as eEF-2K Inhibitors, Bioorg. Med. Chem., 22, 4910 (2014); https://doi.org/10.1016/j.bmc.2014.06.050
- J.W. Ellingboe, M. Antane, T.T. Nguyen, M.D. Collini, S. Antane, R. Bender, D. Hartupee, V. White, J. McCallum, C. Hyung Park, A. Russo, M.B. Osier, A. Wojdan, J. Dinish, D.M. Ho and J.F. Bagl, Pyrido[2,3-d]-pyrimidine Angiotensin II Antagonists, J. Med. Chem., 37, 542 (1994); https://doi.org/10.1021/jm00030a013
- A. Pastor, R. Alajarin, J. J. Vaquero, J. Alvarez-Builla, M.F. de Casa-Juana, C. Sunkel, J.G. Priego, I. Fonseca and J. Sanz-Aparicio, Synthesis and Structure of New Pyrido[2,3-d]pyrimidine Derivatives with Calcium Channel Antagonist Activity, Tetrahedron, 50, 8085 (1994); https://doi.org/10.1016/S0040-4020(01)85291-1
- A. Palasz and D. Ciez, In Search of Uracil Derivatives as Bioactive Agents. Uracils and Fused Uracils: Synthesis, Biological Activity and Applications, Eur. J. Med. Chem., 97, 582 (2015); https://doi.org/10.1016/j.ejmech.2014.10.008
- A.J. Kraker, B.G. Hartl, A.M. Amar, M.R. Barvian, H.D.H. Showalter and C.W. Moore, Biochemical and Cellular Effects of c-Src Kinase-Selective Pyrido[2,3-d]pyrimidine Tyrosine Kinase Inhibitors, Biochem. Pharmacol., 60, 885 (2000); https://doi.org/10.1016/S0006-2952(00)00405-6
- J.F. Dorsey, R. Jove, A.J. Kraker and J. Wu, The Pyrido[2,3-d]pyrimidine Derivative PD180970 Inhibits p210Bcr-Abl Tyrosine Kinase and Induces Apoptosis of K562 Keukemic Cells, Cancer Res., 60, 3127 (2000).
- C.H. Lee, M. Jiang, M. Cowart, G. Gfesser, R. Perner, K.H. Kim, Y.G. Gu, M. Williams, M.F. Jarvis, E.A. Kowaluk, A.O. Stewart and S. Shripad, Discovery of 4-Amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine, An Orally Active, Non-Nucleoside Adenosine Kinase Inhibitor, J. Med. Chem., 44, 2133 (2001); https://doi.org/10.1021/jm000314x
- R.C. Cioc, E. Ruijter and R.V.A. Orru, Multicomponent Reactions: Advanced Tools for Sustainable Organic Synthesis, Green Chem., 16, 2958 (2014); https://doi.org/10.1039/C4GC00013G
- A. Dömling, W. Wang and K. Wang, Chemistry and Biology of Multicomponent Reactions, Chem. Rev., 112, 3083 (2012); https://doi.org/10.1021/cr100233r
- B.H. Rotstein, S. Zaretsky, V. Rai and A.K. Yudin, Small Heterocycles in Multicomponent Reactions, Chem. Rev., 114, 8323 (2014); https://doi.org/10.1021/cr400615v
- L.A. Wessjohann, B. Voigt and D.G. Rivera, Diversity Oriented One-Pot Synthesis of Complex Macrocycles: Very Large Steroid–Peptoid Hybrids from Multiple Multicomponent Reactions Including Bifunctional Building Blocks, Angew. Chem. Int. Ed., 44, 4785 (2005); https://doi.org/10.1002/anie.200500019
- C. Hulme and V. Gore, Multi-Component Reactions:Emerging Chemistry in Drug Discovery from Xylocain to Crixivan, Curr. Med. Chem., 10, 51 (2003); https://doi.org/10.2174/0929867033368600
- A. Dömling and I. Ugi, Multicomponent Reactions with Isocyanides, Angew. Chem. Int. Ed., 39, 3168 (2000); https://doi.org/10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U
- P. Padmaja, J.S. Anireddy and P.N. Reddy, Synthesis and Antiprolifera-tive Activity of Novel Pyranocarbazoles, Chem. Heterocycl. Compd., 54, 812 (2018); https://doi.org/10.1007/s10593-018-2354-3
- A. Parthiban, J. Muthukumaran, A. Moushumi Priya, S. Jayachandran, R. Krishna and H. Surya Prakash Rao, Design, Synthesis, Molecular Docking and Biological Evaluation of N-Methyl-3-nitro-4-(nitromethyl)-4H-chromen-2-amine Derivatives as Potential Anticancer Agents, Med. Chem. Res., 23, 642 (2014); https://doi.org/10.1007/s00044-013-0642-0
- Saigal, S. Khan, H. Rahman, S. Shafiullah and M.M. Khan, Nitroketene N,S-Acetals: Synergistic Building Blocks for the Synthesis of Heterocycles, RSC Adv., 9, 14477 (2019); https://doi.org/10.1039/C9RA00630C
- M. Kannan, P. Manivel, K. Geetha, J. Muthukumaran, H.S.P. Rao and R. Krishna, Synthesis and in silico Evaluation of 1N-Methyl-1S-methyl-2-nitroethylene (NMSM) Derivatives against Alzheimer Disease: To Understand their Interacting Mechanism with Acetylcholinesterase, J. Chem. Biol., 5, 151 (2012); https://doi.org/10.1007/s12154-012-0084-z
References
E.K. Davison and J. Sperry, Natural Products with Heteroatom-Rich Ring Systems, J. Nat. Prod., 80, 3060 (2017); https://doi.org/10.1021/acs.jnatprod.7b00575
Y. Ju and R.S. Varma, Aqueous N-Heterocyclization of Primary Amines and Hydrazines with Dihalides: Microwave-Assisted Syntheses of N-Azacycloalkanes, Isoindole, Pyrazole, Pyrazolidine, and Phthalazine Derivatives, J. Org. Chem., 71, 135 (2006); https://doi.org/10.1021/jo051878h
S. Ravi Kanth, G. Venkat Reddy, K. Hara Kishore, P. Shanthan Rao, B. Narsaiah and U.S. Narayana Murthy, Convenient Synthesis of Novel 4-Substituted Amino-5-trifluoromethyl–2,7-disubstituted pyrido[2,3-d]- pyrimidines and their Antibacterial Activity, Eur. J. Med. Chem., 41, 1011 (2006); https://doi.org/10.1016/j.ejmech.2006.03.028
I.I. Abbas, H.H. Hammud and H. Shamsaldeen, Calix[4]pyrrole Macrocycle: Extraction of Fluoride Anions from Aqueous Media, Eur. J. Chem., 3, 156 (2012); https://doi.org/10.5155/eurjchem.3.2.156-162.542
L.R. Bennett, C.J. Blankley, R.W. Fleming, R.D. Smith and D.K. Tessman, Antihypertensive Activity of 6-Arylpyrido[2,3-d]pyrimidin-7-amine derivatives, J. Med. Chem., 24, 382 (1981); https://doi.org/10.1021/jm00136a006
S. El-Kalyoubi and F. Agili, Synthesis, In Silico Prediction and in vitro Evaluation of Antitumor Activities of Novel Pyrido[2,3-d]pyrimidine, Xanthine and Lumazine Derivatives, Molecules, 25, 5205 (2020); https://doi.org/10.3390/molecules25215205
H.N. Hafez, H.A.S. Abbas and A.R.B.A. El-Gazzar, Synthesis and Evaluation of Analgesic, Anti-inflammatory and Ulcerogenic Activities of Some Triazolo- and 2-Pyrazolyl-pyrido[2,3-d]pyrimidines, Acta Pharm., 58, 359 (2008); https://doi.org/10.2478/v10007-008-0024-1
H.J. Zhang, S. Ben Wang, X. Wen, J.Z. Li and Z.S. Quan, Design, Synthesis, and Evaluation of the Anticonvulsant and Antidepressant Activities of Pyrido[2,3-d]pyrimidine Derivatives, Med. Chem. Res., 25, 1287 (2016); https://doi.org/10.1007/s00044-016-1559-1
J.M. Quintela, C. Peinador, L. Botana, M. Estevez and R. Riguera, Synthesis and Antihistaminic Activity of 2-Guanadino-3-cyanopyridines and Pyrido[2,3-d]pyrimidines, Bioorg. Med. Chem., 5, 1543 (1997); https://doi.org/10.1016/S0968-0896(97)00108-9
A. Agarwal, Ramesh, Ashutosh, N. Goyal, P.M.S. Chauhan and S. Gupta, Dihydropyrido[2,3-d]pyrimidines as a New Class of Antileishmanial Agents, Bioorg. Med. Chem., 13, 6678 (2005); https://doi.org/10.1016/j.bmc.2005.07.043
N. Kammasud, C. Boonyarat, K. Sanphanya, M. Utsintong, S. Tsunoda, H. Sakurai, I. Saiki, I. Andre, D.S. Grierson and O. Vajragupta, 5-Substituted Pyrido[2,3-d]pyrimidine, An Inhibitor against Three Receptor Tyrosine Kinases, Bioorg. Med. Chem. Lett., 19, 745 (2009); https://doi.org/10.1016/j.bmcl.2008.12.023
K. Wu, J. Ai, Q. Liu, T.T. Chen, A. Zhao, X. Peng, Y. Wang, Y. Ji, Q. Yao, Y. Xu, M. Geng and A. Zhang, Multisubstituted Quinoxalines and Pyrido[2,3-d]pyrimidines: Synthesis and SAR study as Tyrosine Kinase c-Met Inhibitors, Bioorg. Med. Chem. Lett., 22, 6368 (2012); https://doi.org/10.1016/j.bmcl.2012.08.075
R. Edupuganti, Q. Wang, C.D.J. Tavares, C.A. Chitjian, J.L. Bachman, P. Ren, E.V. Anslyn and K.N. Dalby, Synthesis and Biological Evaluation of Pyrido[2,3-d]pyrimidine-2,4-dione Derivatives as eEF-2K Inhibitors, Bioorg. Med. Chem., 22, 4910 (2014); https://doi.org/10.1016/j.bmc.2014.06.050
J.W. Ellingboe, M. Antane, T.T. Nguyen, M.D. Collini, S. Antane, R. Bender, D. Hartupee, V. White, J. McCallum, C. Hyung Park, A. Russo, M.B. Osier, A. Wojdan, J. Dinish, D.M. Ho and J.F. Bagl, Pyrido[2,3-d]-pyrimidine Angiotensin II Antagonists, J. Med. Chem., 37, 542 (1994); https://doi.org/10.1021/jm00030a013
A. Pastor, R. Alajarin, J. J. Vaquero, J. Alvarez-Builla, M.F. de Casa-Juana, C. Sunkel, J.G. Priego, I. Fonseca and J. Sanz-Aparicio, Synthesis and Structure of New Pyrido[2,3-d]pyrimidine Derivatives with Calcium Channel Antagonist Activity, Tetrahedron, 50, 8085 (1994); https://doi.org/10.1016/S0040-4020(01)85291-1
A. Palasz and D. Ciez, In Search of Uracil Derivatives as Bioactive Agents. Uracils and Fused Uracils: Synthesis, Biological Activity and Applications, Eur. J. Med. Chem., 97, 582 (2015); https://doi.org/10.1016/j.ejmech.2014.10.008
A.J. Kraker, B.G. Hartl, A.M. Amar, M.R. Barvian, H.D.H. Showalter and C.W. Moore, Biochemical and Cellular Effects of c-Src Kinase-Selective Pyrido[2,3-d]pyrimidine Tyrosine Kinase Inhibitors, Biochem. Pharmacol., 60, 885 (2000); https://doi.org/10.1016/S0006-2952(00)00405-6
J.F. Dorsey, R. Jove, A.J. Kraker and J. Wu, The Pyrido[2,3-d]pyrimidine Derivative PD180970 Inhibits p210Bcr-Abl Tyrosine Kinase and Induces Apoptosis of K562 Keukemic Cells, Cancer Res., 60, 3127 (2000).
C.H. Lee, M. Jiang, M. Cowart, G. Gfesser, R. Perner, K.H. Kim, Y.G. Gu, M. Williams, M.F. Jarvis, E.A. Kowaluk, A.O. Stewart and S. Shripad, Discovery of 4-Amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine, An Orally Active, Non-Nucleoside Adenosine Kinase Inhibitor, J. Med. Chem., 44, 2133 (2001); https://doi.org/10.1021/jm000314x
R.C. Cioc, E. Ruijter and R.V.A. Orru, Multicomponent Reactions: Advanced Tools for Sustainable Organic Synthesis, Green Chem., 16, 2958 (2014); https://doi.org/10.1039/C4GC00013G
A. Dömling, W. Wang and K. Wang, Chemistry and Biology of Multicomponent Reactions, Chem. Rev., 112, 3083 (2012); https://doi.org/10.1021/cr100233r
B.H. Rotstein, S. Zaretsky, V. Rai and A.K. Yudin, Small Heterocycles in Multicomponent Reactions, Chem. Rev., 114, 8323 (2014); https://doi.org/10.1021/cr400615v
L.A. Wessjohann, B. Voigt and D.G. Rivera, Diversity Oriented One-Pot Synthesis of Complex Macrocycles: Very Large Steroid–Peptoid Hybrids from Multiple Multicomponent Reactions Including Bifunctional Building Blocks, Angew. Chem. Int. Ed., 44, 4785 (2005); https://doi.org/10.1002/anie.200500019
C. Hulme and V. Gore, Multi-Component Reactions:Emerging Chemistry in Drug Discovery from Xylocain to Crixivan, Curr. Med. Chem., 10, 51 (2003); https://doi.org/10.2174/0929867033368600
A. Dömling and I. Ugi, Multicomponent Reactions with Isocyanides, Angew. Chem. Int. Ed., 39, 3168 (2000); https://doi.org/10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U
P. Padmaja, J.S. Anireddy and P.N. Reddy, Synthesis and Antiprolifera-tive Activity of Novel Pyranocarbazoles, Chem. Heterocycl. Compd., 54, 812 (2018); https://doi.org/10.1007/s10593-018-2354-3
A. Parthiban, J. Muthukumaran, A. Moushumi Priya, S. Jayachandran, R. Krishna and H. Surya Prakash Rao, Design, Synthesis, Molecular Docking and Biological Evaluation of N-Methyl-3-nitro-4-(nitromethyl)-4H-chromen-2-amine Derivatives as Potential Anticancer Agents, Med. Chem. Res., 23, 642 (2014); https://doi.org/10.1007/s00044-013-0642-0
Saigal, S. Khan, H. Rahman, S. Shafiullah and M.M. Khan, Nitroketene N,S-Acetals: Synergistic Building Blocks for the Synthesis of Heterocycles, RSC Adv., 9, 14477 (2019); https://doi.org/10.1039/C9RA00630C
M. Kannan, P. Manivel, K. Geetha, J. Muthukumaran, H.S.P. Rao and R. Krishna, Synthesis and in silico Evaluation of 1N-Methyl-1S-methyl-2-nitroethylene (NMSM) Derivatives against Alzheimer Disease: To Understand their Interacting Mechanism with Acetylcholinesterase, J. Chem. Biol., 5, 151 (2012); https://doi.org/10.1007/s12154-012-0084-z