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One-pot multicomponent synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives

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Abstract

A simple, facile, and efficient green methodology has been developed for the synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives by the one-pot four-component reaction of cinnamaldehyde/crotonaldehyde, 2-hydroxy-1,4-naphthoquinone, 1,3-dimethyl-6-amino uracil, and o-phenylenediamine in ethanol medium under reflux conditions using p-TSA as a catalyst. In this environmentally benign methodology, three C–N and two C–C bonds are formed in one pot. The hybrid products have three bioactive moieties such as benzophenazine, tetrahydropyridine, and pyrimidine. Operational simplicity, metal-free conditions, wide substrate scope, readily available starting materials, moderate to good yields of the desired products, presence of pharmaceutically active moieties, and easy purification process are the notable features of this methodology.

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References

  1. Siri P (2021) Novel Hybrid molecules based on triazole-β–lactam as potential biological agents. Mini Rev Med Chem 21:536–553. https://doi.org/10.2174/1389557520666201027160436

    Article  CAS  Google Scholar 

  2. Mashayekh K, Shiri P (2019) An overview of recent advances in the applications of click chemistry in the synthesis of bioconjugates with anticancer activities. ChemistrySelect 4:13459–13478. https://doi.org/10.1002/slct.201902362

    Article  CAS  Google Scholar 

  3. Bailly C (2004) Lamellarins, from A to Z: a family of anticancer marine pyrrole alkaloids. Curr Med Chem Anti-Cancer Agents 4:363–378. https://doi.org/10.2174/1568011043352939

    Article  CAS  Google Scholar 

  4. Yao B, Prinsep MR, Nicholson BK, Gordon DP (2003) The pterocellins, novel bioactive alkaloids from the marine bryozoan pterocella vesiculosa. J Nat Prod 66:1074–1077. https://doi.org/10.1021/np030104y

    Article  CAS  Google Scholar 

  5. Cimmino A, Evidente A, Mathieu V, Andolfi A, Lefranc F, Kornienko A, Kiss R (2012) Phenazines and cancer. Nat Prod Rep 29:487–501. https://doi.org/10.1039/C2NP00079B

    Article  CAS  Google Scholar 

  6. Laursen JB, Nielsen J (2004) Phenazine natural products: biosynthesis, synthetic analogues, and biological activity. Chem Rev 104:1663–1686. https://doi.org/10.1021/cr020473j

    Article  CAS  Google Scholar 

  7. Schiessl KT, Hu F, Jo J, Nazia SZ, Wang B, Price-Whelan A, Min W, Dietrich LEP (2019) Phenazine production promotes antibiotic tolerance and metabolic heterogeneity in pseudomonas aeruginosa biofilms. Nat Comm 10:762. https://doi.org/10.1038/s41467-019-08733-w

    Article  CAS  Google Scholar 

  8. Hussain H, Specht S, Sarite SR, Saeftel M, Hoerauf A, Schulz B, Krohn K (2011) A new class of phenazines with activity against a chloroquine resistant plasmodium falciparum strain and antimicrobial activity. J Med Chem 54:4913–4917. https://doi.org/10.1021/jm200302d

    Article  CAS  Google Scholar 

  9. Andrade-Neto VF, Goulart MOF, da Filho JFS, Mjda Silva, Pinto Mdo CFR, Pinto AV, Zalis MG, Carvalho LH, Krettli AU (2004) 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 14:1145–1149. https://doi.org/10.1016/j.bmcl.2003.12.069

    Article  CAS  Google Scholar 

  10. Gamage SA, Spicer JA, Rewcastle GW, Milton J, Sohal S, Dangerfield W, Mistry P, Vicker N, Charlton PA, Denny WA (2002) Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents. J Med Chem 45:740–743. https://doi.org/10.1021/jm010330+

    Article  CAS  Google Scholar 

  11. Ligon JM, Hill DS, Hammer PE, Torkewitz NR, Hofmann D, Kempf HJ, van Pée KH (2000) Natural products with antifungal activity from Pseudomonas biocontrol bacteria. Pest Manag Sci 56:688–695. https://doi.org/10.1002/1526-4998(200008)56:8%3c688::AID-PS186%3e3.0.CO;2-V

    Article  CAS  Google Scholar 

  12. Muller M, Sorrell TC (1995) Inhibition of the human platelet cyclooxygenase response by the naturally occurring phenazine derivative, 1-hydroxyphenazine. Prostaglandins 50:301–311. https://doi.org/10.1016/0090-6980(95)00133-6

    Article  CAS  Google Scholar 

  13. Kandhasamy S, Ramanathan G, Muthukumar T, Thyagarajan SL, Umamaheshwari N, Santhanakrishnan VP, Sivagnanam UT, Perumal PT (2017) Nanofibrous matrixes with biologically active hydroxybenzophenazine pyrazolone compound for cancer theranostics. Mater Sci Eng C 74:70–85. https://doi.org/10.1016/j.msec.2017.01.001

    Article  CAS  Google Scholar 

  14. Gao J, Chen M, Tong X, Zhu H, Yan H, Liu D, Li W, Qi S, Xiao D, Wang Y, Lu Y, Jiang F (2015) Synthesis, antitumor activity, and structure-activity relationship of some benzo[a]pyrano[2,3-c]phenazine derivatives. Comb Chem High Throughput Screen 18:960–974. https://doi.org/10.2174/1386207318666150915113549

    Article  CAS  Google Scholar 

  15. Imato K, Ohira K, Yamaguchi M, Enoki T, Ooyama Y (2020) Phenazine-based photosensitizers for singlet oxygen generation. Mater Chem Front 4:589–596. https://doi.org/10.1039/C9QM00685K

    Article  CAS  Google Scholar 

  16. Xie FM, Li HZ, Dai GL, Li YQ, Cheng T, Xie M, Tag JX, Zhao X (2019) Rational molecular design of dibenzo[a, c]phenazine-based thermally activated delayed fluorescence emitters for orange-red OLEDs wih EQE up to 22.0%. ACS Appl Mater Interfaces 11:26144–26151. https://doi.org/10.1021/acsami.9b06401

    Article  CAS  Google Scholar 

  17. Pauliukaite R, Ghica ME, Barsan MM, Brett CMA (2010) Phenazines and polyphenazines in electrochemical sensors and biosensors. Anal Lett 43:1588–1608. https://doi.org/10.1080/00032711003653791

    Article  CAS  Google Scholar 

  18. Lin R, Johnson SG, Connolly PJ, Wetter SK, Binnun E, Hughes TV, Murray WV, Pandey NB, Moreno-Mazza SJ, Adams M, Fuentes-Pesquera AR, Middleton SA (2009) Synthesis and evaluation of 2,7-diamino-thiazolo[4,5-d]pyrimidine analogues as anti-tumor epidermal growth factor receptor (EGFR) tyrosine Kinase inhibitors. Bioorg Med Chem Lett 19:2333–2337. https://doi.org/10.1016/j.bmcl.2009.02.067

    Article  CAS  Google Scholar 

  19. Falcão EPdS, Melo SJd, Srivastava RM, Catanho MTJdA, Nascimento SCD (2006) Synthesis and anti-inflammatory activity of 4-amino-2-aryl-5-cyano-6-{3-and 4-(N-phthalimidophenyl)} pyrimidines. Eur J Med Chem 41:276–282. https://doi.org/10.1016/j.ejmech.2005.09.009

    Article  CAS  Google Scholar 

  20. Kantha SR, Reddy GV, Kishore KH, Rao PS, Narsaiaha B, Murthy USN (2006) Convenient synthesis of novel 4-substitutedamino-5-trifluoromethyl-2,7-disubstituted pyrido[2,3-d]pyrimidines and their antibacterial activity. Eur J Med Chem 41:1011–1016. https://doi.org/10.1016/j.ejmech.2006.03.028

    Article  CAS  Google Scholar 

  21. Fares M, Abou-Seri SM, Abdel-Aziz H, Abbas SES, Youssef MM, Eladwy RA (2014) Synthesis and antitumor activity of pyrido[2,3-d]pyrimidine and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest. Eur J Med Chem 83:155–166. https://doi.org/10.1016/j.ejmech.2014.06.027

    Article  CAS  Google Scholar 

  22. Kurumurthy C, Rao PS, Swamy BV, Kumar GS, Rao PS, Narsaiah B, Velatooru LR, Pamanji R, Rao JV (2011) Synthesis of novel alkyltriazole tagged pyrido[2,3-d]pyrimidine derivatives and their anticancer activity. Eur J Med Chem 46:3462–3468. https://doi.org/10.1016/j.ejmech.2011.05.011

    Article  CAS  Google Scholar 

  23. Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD (2012) Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia. Bioorg Med Chem Lett 22:5903–5908. https://doi.org/10.1016/j.bmcl.2012.07.072

    Article  CAS  Google Scholar 

  24. Fell JB, Fischer JP, Baer BR, Ballard J, Blake JF, Bouhana K, Brandhuber BJ, Briere DM, Burgess LE, Burkard MR, Chiang H, Chicarelli MJ, Davidson K, Gaudino JJ, Hallin J, Hanson L, Hee K, Hicken EJ, Hinklin RJ, Marx MA, Mejia MJ, Olson P, Savechenkov P, Sudhakar N, Tang TP, Vigers GP, Zecca H, Christensen JG (2018) Discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. ACS Med Chem Lett 9:1230–1234. https://doi.org/10.1021/acsmedchemlett.8b00382

    Article  CAS  Google Scholar 

  25. John SE, Gulati S, Shankaraiah N (2021) Recent advances in multi-component reactions and their mechanistic insights: a triennium review. Org Chem Front 8:4237–4287. https://doi.org/10.1039/D0QO01480J

    Article  CAS  Google Scholar 

  26. Dömling A, Wang W, Wang K (2012) Chemistry and biology of multicomponent reactions. Chem Rev 112:3083–3135. https://doi.org/10.1021/cr100233r

    Article  CAS  Google Scholar 

  27. Shiri P, Amani AM, Aboonajmi J (2021) Supported Cu(II)-Schiff base: novel heterogeneous catalyst with extremely high activity for eco-friendly, one-pot and multi-component C–S bond-forming reaction toward a wide range of thioethers as biologically active cores. Mol Divers. https://doi.org/10.1007/s11030-021-10227-1

    Article  Google Scholar 

  28. Abdolmohammadi S (2013) ZnO nanoparticles-catalyzed cyclocondensation reaction of arylmethylidenepyruvic acids with 6-Aminouracils. Comb Chem High Throughput Screen 16:32–36. https://doi.org/10.2174/1386207311316010005

    Article  CAS  Google Scholar 

  29. Abdolmohammadi S, Mohammadnejad M, Shafei F (2013) TiO2 Nanoparticles as an efficient catalyst for the one-pot preparation of tetrahydrobenzo[c]acridines in aqueous media. Z Naturforsch B 68:362–366. https://doi.org/10.5560/znb.2013-2323

    Article  CAS  Google Scholar 

  30. Abdolmohammadi S, Afsharpour M, Keshavarz-Fatideh S (2014) An efficient green synthesis of 3-amino-1H-chromenes catalyzed by Zno nanoparticles thin-film. S Afr J Chem 67:203–210

    Google Scholar 

  31. Abdolmohammadi S, Aghaei-Meybodi Z (2015) Simple and efficient route toward ambient preparation of pyrimido[b]quinolinetriones using copper (I) iodide nanoparticles in aqueous media. Comb Chem High Throughput Screen 18:911–916. https://doi.org/10.2174/1386207318666150525094234

    Article  CAS  Google Scholar 

  32. Abdolmohammadi S, Dahi-Azar S, Mohammadnejad M, Hosseinian A (2017) A simple and efficient synthesis of 4-arylacridinediones and 6-aryldiindeno[1,2-b:2,1-e] pyridinediones using CuI nanoparticles as catalyst under solvent-free conditions. Comb Chem High Throughput Screen 20:773–780. https://doi.org/10.2174/1386207320666171002123027

    Article  CAS  Google Scholar 

  33. Abdolmohammadi S, Mirza B, Vessally E (2019) Immobilized TiO2 nanoparticles on carbon nanotubes: an efficient heterogeneous catalyst for the synthesis of chromeno[b]pyridine derivatives under ultrasonic irradiation. RSC Adv 9:41868–41876. https://doi.org/10.1039/C9RA09031B

    Article  CAS  Google Scholar 

  34. Ghavidel H, Mirza B, Soleimani-Amiri S, Manafi M (2020) New insight into experimental and theoretical mechanistic study on a green synthesis of functionalized 4H-chromenes using magnetic nanoparticle catalyst. J Chin Chem Soc 67:1856–1876. https://doi.org/10.1002/jccs.201900554

    Article  CAS  Google Scholar 

  35. Kamalzare P, Mirza B, Soleimani-Amiri S (2021) Chitosan magnetic nanocomposite: a magnetically reusable nanocatalyst for green synthesis of Hantzsch 1,4-dihydropyridines under solvent-free conditions. J Nanostruct Chem 11:229–243. https://doi.org/10.1007/s40097-020-00361-x

    Article  CAS  Google Scholar 

  36. El-Remaily MAEAAA (2015) Bismuth triflate: a highly efficient catalyst for the synthesis of bio-active coumarin compounds via one-pot multi-component reaction. Chinese J Catal 36:1124–1130. https://doi.org/10.1016/S1872-2067(14)60308-9

    Article  CAS  Google Scholar 

  37. El-Remaily MAEAAA, Hamad HA, Soliman AMM, Elhady OM (2021) Boosting the catalytic performance of manganese (III)-porphyrin complex MnTSPP for facile one-pot green synthesis of 1,4-dihydropyridine derivatives under mild conditions. Appl Organomet Chem 35:e6238. https://doi.org/10.1002/aoc.6238

    Article  CAS  Google Scholar 

  38. El-Remaily MAEAAA, Elhady OM (2020) Green bio-organic and recoverable catalyst taurine (2-aminoethanesulfonic acid) for synthesis of bio-active compounds 3, 4-dihydropyrimidin derivatives in aqueous medium. ChemistrySelect 5:12098–12102. https://doi.org/10.1002/slct.202002575

    Article  CAS  Google Scholar 

  39. El-Remaily MAEAAA, Elhady OM (2019) Iron (III)-porphyrin complex FeTSPP as an efficient catalyst for synthesis of tetrazole derivatives via [2 + 3] cycloaddition reaction in aqueous medium. Appl Organomet Chem 33:e4989. https://doi.org/10.1002/aoc.4989

    Article  CAS  Google Scholar 

  40. El-Remaily MAEAAA, El-Dabea T, Alsawat M, Mahmoud MHH, Alfi AA, El-Metwaly N, Abu-Dief AM (2021) Development of new thiazole complexes as powerful catalysts for synthesis of pyrazole-4-carbonitrile derivatives under ultrasonic irradiation condition supported by DFT studies. ACS Omega 6:21071–21086. https://doi.org/10.1021/acsomega.1c02811

    Article  CAS  Google Scholar 

  41. El-Remaily MAEAAA, Soliman AMM, Khalifa ME, El-Metwaly NM, Alsoliemy A, El-Dabea T, Abu-Dief AM (2021) Rapidly, highly yielded and green synthesis of dihydrotetrazolo[1,5-a] pyrimidine derivatives in aqueous media using recoverable Pd (II) thiazole catalyst accelerated by ultrasonic: computational studies. Appl Organomet Chem 36:e6320. https://doi.org/10.1002/aoc.6320

    Article  CAS  Google Scholar 

  42. Yadav R, Parvin T, Panday AK, Choudhury LH (2021) Synthesis of styryl linked fused dihydropyridines by catalyst-free multicomponent reactions. Mol Divers 25:2161–2169. https://doi.org/10.1007/s11030-021-10216-4

    Article  CAS  Google Scholar 

  43. Yadav R, Darakshan B, Bhaumick P, Choudhury LH, Parvin T (2022) Synthesis of pentacyclic pyran fused pyrazolo benzo[h]quinolines by multicomponent reaction and their photophysical studies. ChemistrySelect 7:e202104124. https://doi.org/10.1002/slct.202104124

    Article  CAS  Google Scholar 

  44. Kumari P, Yadav R, Bharti R, Parvin T (2020) Regioselective synthesis of pyrimidine fused tetrahydropyridines and pyridines by microwave-assisted one-pot reaction. Mol Divers 24:107–117. https://doi.org/10.1007/s11030-019-09929-4

    Article  CAS  Google Scholar 

  45. Yadav R, Parvin T (2021) Multicomponent synthesis of styryl linked benzo[h]pyrazolo[3,4-b] quinoline-5,6(10 H)-diones by liquid assisted grinding. New J Chem 45:10388–10395. https://doi.org/10.1039/D1NJ00770J

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to NIT Patna for the general research facilities. Darakshan is thankful to NIT Patna for her fellowship. The authors are also thankful to the Dept. of Chemistry, IIT Patna, and SAIF IIT Patna for providing analytical facilities.

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  1. Department of Chemistry, National Institute of Technology Patna, Ashok Rajpath, Patna, 800 005, India

    Darakshan & Tasneem Parvin

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Darakshan, Parvin, T. One-pot multicomponent synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives. Mol Divers 27, 313–322 (2023). https://doi.org/10.1007/s11030-022-10426-4

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