Skip to content
2000
image of A Comprehensive Analysis of the Therapeutic Potential of N-substituted Phenothiazine Derivatives in Medicinal Chemistry

Abstract

Phenothiazine and its -substituted derivatives are pivotal in heterocyclic chemistry, and serves as potential building blocks in chemical and pharmaceutical sciences. Over the past decade, extensive research has focused on the medicinal potentials of these compounds, exploring their anticancer, analgesic, anti-tumor, anti-inflammatory, and antibacterial properties. Due to their distinctive chemical compositions, phenothiazine and its -substituted derivatives have facilitated the development of novel substitutions. This paper reviews recent advancements in the synthesis of phenothiazine and its -substituted derivatives, with an emphasis on their potential biological roles. Numerous investigations have identified various types of phenothiazine and its -substituted derivatives that exhibit compelling biological characteristics. It discusses the impact of different functional groups on phenothiazine at the -substitution, specifically Cl, CF, OH, N(CH), and (CH)CH. Furthermore, the relationship between the biological activities and the structural characteristics of the compounds is examined, identifying the chemical groups and structural alterations that enhance bioactivity, reduce toxicity, and improve handling.

Loading

Article metrics loading...

/content/journals/mrmc/10.2174/0113895575400761251007165058
2025-10-30
2025-12-28
Loading full text...

Full text loading...

References

  1. Mitchell S. Phenothiazine: The parent molecule. Curr. Drug Targets 2006 7 9 1181 1189 10.2174/138945006778226552 17017893
    [Google Scholar]
  2. Pluta K. Morak-Młodawska B. Jeleń M. Recent progress in biological activities of synthesized phenothiazines. Eur. J. Med. Chem. 2011 46 8 3179 3189 10.1016/j.ejmech.2011.05.013 21620536
    [Google Scholar]
  3. Ohlow M.J. Moosmann B. Phenothiazine: The seven lives of pharmacology’s first lead structure. Drug Discov. Today 2011 16 3-4 119 131 10.1016/j.drudis.2011.01.001 21237283
    [Google Scholar]
  4. Massie S.P. The chemistry of phenothiazine. Chem. Rev. 1954 54 5 797 833 10.1021/cr60171a003
    [Google Scholar]
  5. Jaszczyszyn A. Gąsiorowski K. Świątek P. Malinka W. Cieślik-Boczula K. Petrus J. Czarnik-Matusewicz B. Chemical structure of phenothiazines and their biological activity. Pharmacol. Rep. 2012 64 1 16 23 10.1016/S1734‑1140(12)70726‑0 22580516
    [Google Scholar]
  6. Martinez A. Gil C. Heterocycles containing nitrogen and sulfur as potent biologically active scaffolds. Drug Discovery 2015 50 231 261 10.1039/9781782622246‑00231
    [Google Scholar]
  7. Vara J. Gualdesi M.S. Aiassa V. Ortiz C.S. Evaluation of physicochemical properties and bacterial photoinactivation of phenothiazine photosensitizers. Photochem. Photobiol. Sci. 2019 18 6 1576 1586 10.1039/c8pp00584b 31066390
    [Google Scholar]
  8. Ronco T. Juul M. Reynier Z. Christensen J.B. Svenningsen S. Olsen R.H. Phenothiazine derivatives: The importance of stereoisomerism in the tolerance and efficacy of antimicrobials. Indian J. Microbiol. 2024 64 2 743 748 10.1007/s12088‑024‑01309‑3 39010999
    [Google Scholar]
  9. Balouiri M. Sadiki M. Ibnsouda S.K. Methods for in vitro evaluating antimicrobial activity: A review. J. Pharm. Anal. 2016 6 2 71 79 10.1016/j.jpha.2015.11.005 29403965
    [Google Scholar]
  10. Hershon H.I. Kennedy P.F. Mcguire R.J. Persistence of extra-pyramidal disorders and psychiatric relapse after withdrawal of long-term phenothiazine therapy. Br. J. Psychiatry 1972 120 554 41 50 10.1192/bjp.120.554.41 4557435
    [Google Scholar]
  11. González-González A. Vazquez-Jimenez L.K. Paz-González A.D. Bolognesi M.L. Rivera G. Recent advances in the medicinal chemistry of phenothiazines, new anticancer and antiprotozoal agents. Curr. Med. Chem. 2021 28 38 7910 7936 10.2174/0929867328666210405120330 33820509
    [Google Scholar]
  12. Sadhu C. Mitra A.K. Synthetic, biological and optoelectronic properties of phenoxazine and its derivatives: A state of the art review. Mol. Divers. 2024 28 2 965 1007 10.1007/s11030‑023‑10619‑5 36757655
    [Google Scholar]
  13. Stępnicki P. Kondej M. Koszła O. Żuk J. Kaczor A.A. Multi-targeted drug design strategies for the treatment of schizophrenia. Expert Opin. Drug Discov. 2021 16 1 101 114 10.1080/17460441.2020.1816962 32915109
    [Google Scholar]
  14. Mosnaim A.D. Ranade V.V. Wolf M.E. Puente J. Antonieta Valenzuela M. Phenothiazine molecule provides the basic chemical structure for various classes of pharmacotherapeutic agents. Am. J. Ther. 2006 13 3 261 273 10.1097/01.mjt.0000212897.20458.63 16772768
    [Google Scholar]
  15. Kisla M.M. Yaman M. Zengin-Karadayi F. Korkmaz B. Bayazeid O. Kumar A. Peravali R. Gunes D. Tiryaki R.S. Gelinci E. Cakan-Akdogan G. Ates-Alagoz Z. Konu O. Synthesis and structure of novel phenothiazine derivatives, and compound prioritization via in silico target search and screening for cytotoxic and cholinesterase modulatory activities in liver cancer cells and in vivo in Zebrafish. ACS Omega 2024 9 28 30594 30614 10.1021/acsomega.3c06532 39035947
    [Google Scholar]
  16. Hu W. Zhang S. Method for the synthesis of phenothiazines via a domino iron-catalyzed C–S/C–N cross-coupling reaction. J. Org. Chem. 2015 80 12 6128 6132 10.1021/acs.joc.5b00568 26028127
    [Google Scholar]
  17. Naik N. Kumar H.V. Veena V. Novel phenothiazine analogous: Synthesis and a new perceptivity into their antioxidant potential. Pharm. Lett. 2012 4 3 786 794
    [Google Scholar]
  18. Zhao Y. Zhang J. Zhang J. Zhang Z. Liu R. Iodine-catalyzed cyclization of o-nitrothiophenols with cyclohexanones to phenothiazines. J. Org. Chem. 2024 89 11 7478 7484 10.1021/acs.joc.4c00039 38773694
    [Google Scholar]
  19. Dai C. Sun X. Tu X. Wu L. Zhan D. Zeng Q. Synthesis of phenothiazines via ligand-free CuI-catalyzed cascade C–S and C–N coupling of aryl ortho-dihalides and ortho-aminobenzenethiols. Chem. Commun. 2012 48 43 5367 5369 10.1039/c2cc30814b 22525793
    [Google Scholar]
  20. Madrid P.B. Polgar W.E. Toll L. Tanga M.J. Synthesis and antitubercular activity of phenothiazines with reduced binding to dopamine and serotonin receptors. Bioorg. Med. Chem. Lett. 2007 17 11 3014 3017 10.1016/j.bmcl.2007.03.064 17407813
    [Google Scholar]
  21. Huang M. Huang D. Zhu X. Wan Y. Copper‐catalyzed domino reactions for the synthesis of phenothiazines. Eur. J. Org. Chem. 2015 2015 22 4835 4839 10.1002/ejoc.201500667
    [Google Scholar]
  22. Liao Y. Jiang P. Chen S. Xiao F. Deng G.J. Synthesis of phenothiazines from cyclohexanones and 2-aminobenzenethiols under transition-metal-free conditions. RSC Advances 2013 3 40 18605 18608 10.1039/c3ra43989e
    [Google Scholar]
  23. Wu S. Hu W.Y. Zhang S.L. Potassium carbonate-mediated tandem C–S and C–N coupling reaction for the synthesis of phenothiazines under transition-metal-free and ligand-free conditions. RSC Advances 2016 6 29 24257 24260 10.1039/C6RA01295G
    [Google Scholar]
  24. Rui X. Wang C. Si D. Hui X. Li K. Wen H. Li W. Liu J. One-pot tandem access to phenothiazine derivatives from acetanilide and 2-bromothiophenol via rhodium-catalyzed C–H thiolation and copper-catalyzed C–N amination. J. Org. Chem. 2021 86 9 6622 6632 10.1021/acs.joc.1c00403 33881319
    [Google Scholar]
  25. Chen J. Li G. Xie Y. Liao Y. Xiao F. Deng G.J. Four-component approach to N -substituted phenothiazines under transition-metal-free conditions. Org. Lett. 2015 17 23 5870 5873 10.1021/acs.orglett.5b03058 26593334
    [Google Scholar]
  26. Zhou Y. Zeng Q. Zhang L. Transition-metal-free synthesis of phenothiazines from S-2-acetamidophenyl ethanethioate and ortho -dihaloarenes. Synth. Commun. 2017 47 7 710 715 10.1080/00397911.2017.1281959
    [Google Scholar]
  27. Omoruyi S.I. Ekpo O.E. Semenya D.M. Jardine A. Prince S. Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma. Apoptosis 2020 25 3-4 261 274 10.1007/s10495‑020‑01594‑5 32036474
    [Google Scholar]
  28. Sarhan M.O. Haffez H. Elsayed N.A. El-Haggar R.S. Zaghary W.A. New phenothiazine conjugates as apoptosis inducing agents: Design, synthesis, in-vitro anti-cancer screening and 131I-radiolabeling for in-vivo evaluation. Bioorg. Chem. 2023 141 106924 10.1016/j.bioorg.2023.106924 37871390
    [Google Scholar]
  29. Slodek A. Zych D. Maroń A. Gawecki R. Mrozek-Wilczkiewicz A. Malarz K. Musioł R. Phenothiazine derivatives - Synthesis, characterization, and theoretical studies with an emphasis on the solvatochromic properties. J. Mol. Liq. 2019 285 515 525 10.1016/j.molliq.2019.04.102
    [Google Scholar]
  30. Morak-Młodawska B. Pluta K. Latocha M. Jeleń M. Kuśmierz D. Synthesis, anticancer activity, and apoptosis induction of novel 3,6-diazaphenothiazines. Molecules 2019 24 2 267 10.3390/molecules24020267 30642021
    [Google Scholar]
  31. Krishnan K.G. Kumar C.U. Lim W.M. Mai C.W. Thanikachalam P.V. Ramalingan C. Novel cyanoacetamide integrated phenothiazines: Synthesis, characterization, computational studies and in vitro antioxidant and anticancer evaluations. J. Mol. Struct. 2020 1199 127037 10.1016/j.molstruc.2019.127037
    [Google Scholar]
  32. Luan Y. Liu J. Gao J. Wang J. The design and synthesis of novel phenothiazine derivatives as potential cytotoxic agents. Lett. Drug Des. Discov. 2019 17 1 57 67 10.2174/1570180816666181115112236
    [Google Scholar]
  33. Montoya M.C. DiDone L. Heier R.F. Meyers M.J. Krysan D.J. Antifungal phenothiazines: Optimization, characterization of mechanism, and modulation of neuroreceptor activity. ACS Infect. Dis. 2018 4 4 499 507 10.1021/acsinfecdis.7b00157 29058407
    [Google Scholar]
  34. Oliva C.R. Zhang W. Langford C. Suto M.J. Griguer C.E. Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit. Oncotarget 2017 8 23 37568 37583 10.18632/oncotarget.17247 28455961
    [Google Scholar]
  35. Vanneste M. Venzke A. Guin S. Fuller A.J. Jezewski A.J. Beattie S.R. Krysan D.J. Meyers M.J. Henry M.D. The anti-cancer efficacy of a novel phenothiazine derivative is independent of dopamine and serotonin receptor inhibition. Front. Oncol. 2023 13 1295185 10.3389/fonc.2023.1295185 37909019
    [Google Scholar]
  36. Wainwright M. McLean A. Rational design of phenothiazinium derivatives and photoantimicrobial drug discovery. Dyes Pigments 2017 136 590 600 10.1016/j.dyepig.2016.09.015
    [Google Scholar]
  37. Lorente-Torres B. Llano-Verdeja J. Castañera P. Ferrero H.Á. Fernández-Martínez S. Javadimarand F. Mateos L.M. Letek M. Mourenza Á. Innovative strategies in drug repurposing to tackle intracellular bacterial pathogens. Antibiotics 2024 13 9 834 10.3390/antibiotics13090834 39335008
    [Google Scholar]
  38. Guguloth V. Thirukovela N.S. Paidakula S. Vadde R. One-pot regioselective synthesis of some novel isoxazole-phenothiazine hybrids and their antibacterial activity. Russ. J. Gen. Chem. 2020 90 3 470 475 10.1134/S1070363220030214
    [Google Scholar]
  39. Monteiro K.L.C. Silva O.N. dos Santos Nascimento I.J. Mendonça Júnior F.J.B. Aquino P.G.V. da Silva-Júnior E.F. de Aquino T.M. Medicinal chemistry of inhibitors targeting resistant bacteria. Curr. Top. Med. Chem. 2022 22 24 1983 2028 10.2174/1568026622666220321124452 35319372
    [Google Scholar]
  40. Babalola B.A. Malik M. Sharma L. Olowokere O. Folajimi O. Exploring the therapeutic potential of phenothiazine derivatives in medicinal chemistry. Results Chem. 2024 8 101565 10.1016/j.rechem.2024.101565
    [Google Scholar]
  41. Nehra B. Kumar M. Singh S. Chawla V.A. Chawla P. Grover P. Recent developments in the antimicrobial potential of some nitrogenous heterocycles and their SAR studies: A review. Curr. Med. Chem. 2024 31 10.2174/0109298673301266240506083014 38797910
    [Google Scholar]
  42. Pandhurnekar C.P. Pandhurnekar H.C. Mungole A.J. Butoliya S.S. Yadao B.G. A review of recent synthetic strategies and biological activities of isoxazole. J. Heterocycl. Chem. 2023 60 4 537 565 10.1002/jhet.4586
    [Google Scholar]
  43. Amaral L. Viveiros M. Molnar J. Antimicrobial activity of phenothiazines. In Vivo 2004 18 6 725 731 15646813
    [Google Scholar]
  44. Vitale R.G. Afeltra J. Meis J.F.G.M. Verweij P.E. Activity and post antifungal effect of chlorpromazine and trifluopherazine against Aspergillus, Scedosporium and zygomycetes. Mycoses 2007 50 4 270 276 10.1111/j.1439‑0507.2007.01371.x 17576318
    [Google Scholar]
  45. Galgóczy L. Papp T. Kovács L. Ördögh L. Vágvölgyi C. In vitro activity of phenothiazines and their combinations with amphotericin B against Zygomycetes causing rhinocerebral zygomycosis. Med. Mycol. 2009 47 3 331 335 10.1080/13693780802378853 18798117
    [Google Scholar]
  46. Darvesh S. McDonald R.S. Penwell A. Conrad S. Darvesh K.V. Mataija D. Gomez G. Caines A. Walsh R. Martin E. Structure–activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives. Bioorg. Med. Chem. 2005 13 1 211 222 10.1016/j.bmc.2004.09.059 15582466
    [Google Scholar]
  47. Aref M.A. El-Guindy T.A. Pipothiazine palmitate in the long-term treatment of schizophrenia. J. Int. Med. Res. 1980 8 4 293 294 10.1177/030006058000800409 6105981
    [Google Scholar]
  48. Raval J.P. Desai K.G. Desai K.R. Microwave synthesis, characterization and antimicrobial study of new pyrazolyl-oxopropyl-quinazolin-4(3H)-one derivatives. J. Saudi Chem. Soc. 2012 16 4 387 393 10.1016/j.jscs.2011.02.003
    [Google Scholar]
  49. Sarmiento G.P. Vitale R.G. Afeltra J. Moltrasio G.Y. Moglioni A.G. Synthesis and antifungal activity of some substituted phenothiazines and related compounds. Eur. J. Med. Chem. 2011 46 1 101 105 10.1016/j.ejmech.2010.10.019 21093111
    [Google Scholar]
  50. Nyamu S.N. Ombaka L. Masika E. Ng’ang’a M. Antimicrobial photodynamic activity of phthalocyanine derivatives. Adv. Chem. 2018 2018 1 1 8 10.1155/2018/2598062
    [Google Scholar]
  51. Balestri L.J.I. Synthesis of antifungal compounds. Doctor of Philosophy. Università di Siena 2022 10.25434/BALESTRI‑LORENZO‑JACOPO‑ILIC_PHD2022
    [Google Scholar]
  52. Manzur M.E. Brandán, S.A. S(-) and R(+) species derived from antihistaminic promethazine agent: Structural and vibrational studies. Heliyon 2019 5 9 e02322 10.1016/j.heliyon.2019.e02322 31535039
    [Google Scholar]
  53. Blanco P. Sanz-García F. Hernando-Amado S. Martínez J.L. Alcalde-Rico M. The development of efflux pump inhibitors to treat Gram-negative infections. Expert Opin. Drug Discov. 2018 13 10 919 931 10.1080/17460441.2018.1514386 30198793
    [Google Scholar]
  54. Chamoun-Emanuelli A.M. Pecheur E.I. Simeon R.L. Huang D. Cremer P.S. Chen Z. Phenothiazines inhibit hepatitis C virus entry, likely by increasing the fluidity of cholesterol-rich membranes. Antimicrob. Agents Chemother. 2013 57 6 2571 2581 10.1128/AAC.02593‑12 23529728
    [Google Scholar]
  55. Dyall J. Coleman C.M. Hart B.J. Venkataraman T. Holbrook M.R. Kindrachuk J. Johnson R.F. Olinger G.G. Jahrling P.B. Laidlaw M. Johansen L.M. Lear-Rooney C.M. Glass P.J. Hensley L.E. Frieman M.B. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob. Agents Chemother. 2014 58 8 4885 4893 10.1128/AAC.03036‑14 24841273
    [Google Scholar]
  56. Kitamura K. Fujitani K. Takahashi K. Tanaka Y. Hirako S. Kotani C. Hashimoto T. Takegami S. Synthesis of [N-13CH3] drugs (chlorpromazine, triflupromazine and promazine). J. Labelled Comp. Radiopharm. 2000 43 9 865 872 10.1002/1099‑1344(200008)43:9<865:AID‑JLCR370>3.0.CO;2‑E
    [Google Scholar]
  57. Beignon A.S. McKenna K. Skoberne M. Manches O. DaSilva I. Kavanagh D.G. Larsson M. Gorelick R.J. Lifson J.D. Bhardwaj N. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via toll-like receptor- viral RNA interactions. J. Clin. Invest. 2005 115 11 3265 3275 10.1172/JCI26032 16224540
    [Google Scholar]
  58. Bhattacharyya S. Warfield K.L. Ruthel G. Bavari S. Aman M.J. Hope T.J. Ebola virus uses clathrin-mediated endocytosis as an entry pathway. Virology 2010 401 1 18 28 10.1016/j.virol.2010.02.015 20202662
    [Google Scholar]
  59. Wei X. She G. Wu T. Xue C. Cao Y. PEDV enters cells through clathrin-, caveolae-, and lipid raft-mediated endocytosis and traffics via the endo-/lysosome pathway. Vet. Res. 2020 51 1 10 10.1186/s13567‑020‑0739‑7 32041637
    [Google Scholar]
  60. Florey K. Fluphenazine hydrochloride. Analytical Profiles of Drug Substances 1973 2 263 294 10.1016/S0099‑5428(08)60043‑X
    [Google Scholar]
  61. Dyall J. Gross R. Kindrachuk J. Johnson R.F. Olinger G.G. Hensley L.E. Frieman M.B. Jahrling P.B. Middle East respiratory syndrome and severe acute respiratory syndrome: Current therapeutic options and potential targets for novel therapies. Drugs 2017 77 18 1935 1966 10.1007/s40265‑017‑0830‑1 29143192
    [Google Scholar]
  62. Pillaiyar T. Meenakshisundaram S. Manickam M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov. Today 2020 25 4 668 688 10.1016/j.drudis.2020.01.015 32006468
    [Google Scholar]
  63. Liu Q. Xia S. Sun Z. Wang Q. Du L. Lu L. Jiang S. Testing of Middle East respiratory syndrome coronavirus replication inhibitors for the ability to block viral entry. Antimicrob. Agents Chemother. 2015 59 1 742 744 10.1128/AAC.03977‑14 25331705
    [Google Scholar]
  64. Otręba M. Kośmider L. Rzepecka-Stojko A. Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review. Eur. J. Pharmacol. 2020 887 173553 10.1016/j.ejphar.2020.173553 32949606
    [Google Scholar]
  65. Bhatnagar A. Pemawat G. Recent developments of antipsychotic drugs with phenothiazine hybrids: A review. Chem. Biol. INTERFACE 2022 12 4 77 87
    [Google Scholar]
  66. Lee N. Shum D. König A. Kim H. Heo J. Min S. Lee J. Ko Y. Choi I. Lee H. Radu C. Hoenen T. Min J.Y. Windisch M.P. High-throughput drug screening using the Ebola virus transcription- and replication-competent virus-like particle system. Antiviral Res. 2018 158 226 237 10.1016/j.antiviral.2018.08.013 30149038
    [Google Scholar]
  67. Pohjala L. Utt A. Varjak M. Lulla A. Merits A. Ahola T. Tammela P. Inhibitors of alphavirus entry and replication identified with a stable Chikungunya replicon cell line and virus-based assays. PLoS One 2011 6 12 e28923 10.1371/journal.pone.0028923 22205980
    [Google Scholar]
  68. Filone C.M. Hanna S.L. Caino M.C. Bambina S. Doms R.W. Cherry S. Rift valley fever virus infection of human cells and insect hosts is promoted by protein kinase C epsilon. PLoS One 2010 5 11 e15483 10.1371/journal.pone.0015483 21124804
    [Google Scholar]
  69. Hashizume M. Takashima A. Ono C. Okamoto T. Iwasaki M. Phenothiazines inhibit SARS-CoV-2 cell entry via a blockade of spike protein binding to neuropilin-1. Antiviral Res. 2023 209 105481 10.1016/j.antiviral.2022.105481 36481388
    [Google Scholar]
  70. Liang T. Xiao S. Wu Z. Lv X. Liu S. Hu M. Li G. Li P. Ma X. Phenothiazines inhibit SARS-CoV-2 entry through targeting spike protein. Viruses 2023 15 8 1666 10.3390/v15081666 37632009
    [Google Scholar]
  71. Varga B. Csonka Á. Csonka A. Molnár J. Amaral L. Spengler G. Possible biological and clinical applications of phenothiazines. Anticancer Res. 2017 37 11 5983 5993 10.21873/anticanres.12045 29061777
    [Google Scholar]
  72. Singh S. Gangopadhyay A.D.S. Chakravarty M. Phenothiazine-linked glutamic acid dendrons: An easy access and a new class of SARS-CoV-2 main protease inhibitors. R. Soc. Open Sci. 2025 12 4 241628 10.1098/rsos.241628 40177100
    [Google Scholar]
  73. Barnard D.L. Day C.W. Bailey K. Heiner M. Montgomery R. Lauridsen L. Jung K.H. Li J.K.K. Chan P.K.S. Sidwell R.W. Is the anti-psychotic, 10-(3-(dimethylamino)propyl) phenothiazine (promazine), a potential drug with which to treat SARS infections? Antiviral Res. 2008 79 2 105 113 10.1016/j.antiviral.2007.12.005 18423639
    [Google Scholar]
  74. Plaze M. Attali D. Prot M. Petit A.C. Blatzer M. Vinckier F. Levillayer L. Chiaravalli J. Perin-Dureau F. Cachia A. Friedlander G. Chrétien F. Simon-Loriere E. Gaillard R. Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine. Int. J. Antimicrob. Agents 2021 57 3 106274 10.1016/j.ijantimicag.2020.106274 33387629
    [Google Scholar]
  75. Forrestall K.L. Burley D.E. Cash M.K. Pottie I.R. Darvesh S. Forrestall K.L. Burley D.E. Cash M.K. Pottie I.R. Darvesh S. Phenothiazines as dual inhibitors of SARS-CoV-2 main protease and COVID-19 inflammation. Can. J. Chem. 2021 99 10 801 811 10.1139/cjc‑2021‑0139
    [Google Scholar]
  76. Forrestall K. Pringle E.S. Sands D. Duguay B.A. Farewell B. Woldemariam T. Falzarano D. Pottie I. Mccormick C. Dual inhibition of Coronavirus Mpro and PLpro enzymes by phenothiazines and their antiviral activity. Biorxiv 2023 10.1101/2023.09.11.557219
    [Google Scholar]
  77. Saklani P. Khan H. Singh T.G. Gupta S. Grewal A.K. Demethyleneberberine, a potential therapeutic agent in neurodegenerative disorders: A proposed mechanistic insight. Mol. Biol. Rep. 2022 49 10 10101 10113 10.1007/s11033‑022‑07594‑9 35657450
    [Google Scholar]
  78. Aggarwal M. Patra A. Awasthi I. George A. Gagneja S. Gupta V. Capalash N. Sharma P. Drug repurposing against antibiotic resistant bacterial pathogens. Eur. J. Med. Chem. 2024 279 116833 10.1016/j.ejmech.2024.116833 39243454
    [Google Scholar]
  79. Mathur A. Parihar A.S. Modi S. Kalra A. Photodynamic therapy for ESKAPE pathogens: An emerging approach to combat antimicrobial resistance (AMR). Microb. Pathog. 2023 183 106307 10.1016/j.micpath.2023.106307 37604213
    [Google Scholar]
  80. Tsakovska I. Pajeva I. Phenothiazines and structurally related compounds as modulators of cancer multidrug resistance. Curr. Drug Targets 2006 7 9 1123 1134 10.2174/138945006778226660 17017890
    [Google Scholar]
  81. Mohiuddin S.G. Nguyen T.V. Orman M.A. Pleiotropic actions of phenothiazine drugs are detrimental to gram-negative bacterial persister cells. Commun. Biol. 2022 5 1 217 10.1038/s42003‑022‑03172‑8 35264714
    [Google Scholar]
  82. Mishra R. Sareen S. Sharma B. Goyal S. Kaur G. Bhardwaj S. Siddiqui A.A. Husain A. Singla R.K. Rashid M. Kumar D. Sati B. Shalmali N. Kumar R. Phenothiazines and related drugs as multi drug resistance reversal agents in cancer chemotherapy mediated by p-glycoprotein. Curr. Cancer Ther. Rev. 2017 13 1 28 42 10.2174/1573394713666170524122904
    [Google Scholar]
  83. Guan J. Kyle D.E. Gerena L. Zhang Q. Milhous W.K. Lin A.J. Design, synthesis, and evaluation of new chemosensitizers in multi-drug-resistant Plasmodium falciparum. J. Med. Chem. 2002 45 13 2741 2748 10.1021/jm010549o 12061877
    [Google Scholar]
  84. Bisi A. Meli M. Gobbi S. Rampa A. Tolomeo M. Dusonchet L. Multidrug resistance reverting activity and antitumor profile of new phenothiazine derivatives. Bioorg. Med. Chem. 2008 16 13 6474 6482 10.1016/j.bmc.2008.05.040 18522868
    [Google Scholar]
  85. Lasoń W. Chlebicka M. Rejdak K. Research advances in basic mechanisms of seizures and antiepileptic drug action. Pharmacol. Rep. 2013 65 4 787 801 10.1016/S1734‑1140(13)71060‑0 24145073
    [Google Scholar]
  86. Trivedi A.R. Siddiqui A.B. Shah V.H. Design, synthesis, characterization and antitubercular activity of some 2-heterocycle-substituted phenothiazines. ARKIVOC 2008 2 210 217 10.3998/ark.5550190.0009.223
    [Google Scholar]
  87. Upadhyay R.K. Upadhyay M.S. Jain S. Synthesis and antimicrobial activity of 1-[2-(10-p-chlorobenzyl) phenothiazinyl]-3-(substituted aryl)-2-propen-1-ones. J. Chem. 2009 6 Suppl. 1 S254 S258 10.1155/2009/901646
    [Google Scholar]
  88. Dighe N.S. Bankar A.A. Musmade D.S. Nirmal S.A. Research on synthesis and anti convulsant activity of novel oxadiazole substituted phenothiazine derivatives. Curr. Adv. Chem. Biochem. 2021 4 54 60 10.9734/bpi/cacb/v4/1783F
    [Google Scholar]
  89. Wang J. Zhou Y. Zhang H. Hu L. Liu J. Wang L. Wang T. Zhang H. Cong L. Wang Q. Pathogenesis of allergic diseases and implications for therapeutic interventions. Signal Transduct. Target. Ther. 2023 8 1 138 10.1038/s41392‑023‑01344‑4 36964157
    [Google Scholar]
  90. Watts A.M. Cripps A.W. West N.P. Cox A.J. Modulation of allergic inflammation in the nasal mucosa of allergic rhinitis sufferers with topical pharmaceutical agents. Front. Pharmacol. 2019 10 MAR 294 10.3389/fphar.2019.00294 31001114
    [Google Scholar]
  91. Stojković N. Cekić S. Ristov M. Ristić M. Đukić D. Binić M. Virijević D. Histamine and Antihistamines / Histamin i antihistamini Sci. J. Fac Med. Niš 2015 32 1 7 22 10.1515/afmnai‑2015‑0001
    [Google Scholar]
  92. Tobe M. Isobe Y. Goto Y. Obara F. Tsuchiya M. Matsui J. Hirota K. Hayashi H. Synthesis and biological evaluation of CX-659S and its related compounds for their inhibitory effects on the delayed-type hypersensitivity reaction. Bioorg. Med. Chem. 2000 8 8 2037 2047 10.1016/S0968‑0896(00)00126‑7 11003148
    [Google Scholar]
  93. Nishikawa S. Inoue Y. Hori Y. Miyajima C. Morishita D. Ohoka N. Hida S. Makino T. Hayashi H. Anti-inflammatory activity of kurarinone involves induction of HO-1 via the KEAP1/Nrf2 pathway. Antioxidants 2020 9 9 842 10.3390/antiox9090842 32916869
    [Google Scholar]
  94. Kubota K. Kurebayashi H. Miyachi H. Tobe M. Onishi M. Isobe Y. Synthesis and structure–activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H1 antagonists. Bioorg. Med. Chem. Lett. 2009 19 10 2766 2771 10.1016/j.bmcl.2009.03.124 19362477
    [Google Scholar]
  95. Tasaka K. Pharmacology of newly developed H1 antagonists: Antiallergic profile of H1 antagonists. In: New Advances in Histamine Research. Tokyo Springer 1994 293 324 10.1007/978‑4‑431‑68263‑9_9
    [Google Scholar]
  96. Atta E.M. Mohamed N.H. Abdelgawad A.A.M. Antioxidants: An overview on the natural and synthetic types. Eur. Chem. Bull. 2017 6 8 365 10.17628/ecb.2017.6.365‑375
    [Google Scholar]
  97. Pathania S. Narang R.K. Rawal R.K. Role of sulphur-heterocycles in medicinal chemistry: An update. Eur. J. Med. Chem. 2019 180 486 508 10.1016/j.ejmech.2019.07.043 31330449
    [Google Scholar]
  98. Maddila S. Momin M. Gorle S. Palakondu L. Jonnalagadda S.B. Synthesis and antioxidant evaluation of novel phenothiazine linked substitutedbenzylideneamino-1,2,4-triazole derivatives. J. Chil. Chem. Soc. 2015 60 2 2919 2923 10.4067/S0717‑97072015000200012
    [Google Scholar]
  99. Al Zahrani N.A. El-Shishtawy R.M. Elaasser M.M. Asiri A.M. Synthesis of novel chalcone-based phenothiazine derivatives as antioxidant and anticancer agents. Molecules 2020 25 19 4566 10.3390/molecules25194566 33036301
    [Google Scholar]
  100. Hamama W.S. Gouda M.A. Kamal El-din, H.A.; Zoorob, H.H. Synthesis and antioxidant activity of some new binary pyrazoles containing core phenothiazine moiety. J. Heterocycl. Chem. 2017 54 2 1369 1377 10.1002/jhet.2716
    [Google Scholar]
  101. Antolovich M. Prenzler P.D. Patsalides E. McDonald S. Robards K. Methods for testing antioxidant activity. Analyst 2002 127 1 183 198 10.1039/b009171p 11827390
    [Google Scholar]
  102. Kaushik I. Ramachandran S. Prasad S. Srivastava S.K. Drug rechanneling: A novel paradigm for cancer treatment. Semin. Cancer Biol. 2021 68 279 290 10.1016/j.semcancer.2020.03.011 32437876
    [Google Scholar]
  103. Gopi C. Dhanaraju M.D. Recent progress in synthesis, structure and biological activities of phenothiazine derivatives. Rev. J. Chem. 2019 9 2 95 126 10.1134/S2079978019020018
    [Google Scholar]
  104. Raslan M.A. Raslan S.A. Shehata E.M. Mahmoud A.S. Sabri N.A. Advances in the applications of bioinformatics and chemoinformatics. Pharmaceuticals 2023 16 7 1050 10.3390/ph16071050 37513961
    [Google Scholar]
  105. Otręba M. Kośmider L. In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review. J. Appl. Toxicol. 2021 41 1 82 94 10.1002/jat.4046 32852120
    [Google Scholar]
  106. Dasgupta A. Dastidar S.G. Shirataki Y. Motohashi N. Antibacterial activity of artificial phenothiazines and isoflavones from plants. Top. Heterocycl. Chem. 2008 15 67 132 10.1007/7081_2007_108
    [Google Scholar]
  107. Huang C.L. Mir G.M. Yeh J.Z. Distribution, excretion, and metabolism of 14C-labeled quaternary ammonium salt of perphenazine in rats. J. Pharm. Sci. 1970 59 7 976 979 10.1002/jps.2600590712 5428092
    [Google Scholar]
  108. Lange I.E.S. Pral E.M.F. Magdaleno A. Silber A.M. Evaluation of the anti-trypanosoma cruzi effects of the antipsychotic drug Levomepromazine. Int. J. Clin. Med. 2012 3 5 344 351 10.4236/ijcm.2012.35067
    [Google Scholar]
  109. Alsaad N. Wilffert B. van Altena R. de Lange W.C.M. van der Werf T.S. Kosterink J.G.W. Alffenaar J.W.C. Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis. Eur. Respir. J. 2014 43 3 884 897 10.1183/09031936.00113713 23988774
    [Google Scholar]
  110. Szerencsés B. Mülbacher A. Vágvölgyi C. Pfeiffer I. Acta biologica szegediensis. Acta Biol. Szeged. 2019 63 2 181 184 10.14232/abs.2019.2.181‑184
    [Google Scholar]
  111. Rani Basu L. Mazumdar K. Kumar Dutta N. Karak P. Dastidar S.G. Antibacterial property of the antipsychotic agent prochlorperazine, and its synergism with methdilazine. Microbiol. Res. 2005 160 1 95 100 10.1016/j.micres.2004.10.002 15782943
    [Google Scholar]
  112. Kushwaha K. Kaushik N.K. Kaushik N. Chand M. Kaushik R. Choi E. Jain S.C. Novel aminoalkylated azaphenothiazines as potential inhibitors of T98G, H460 and SNU80 cancer cell lines in vitro. Bioorg. Med. Chem. Lett. 2016 26 9 2237 2244 10.1016/j.bmcl.2016.03.056 27017112
    [Google Scholar]
  113. Jain A. Chaudhary J. Khaira H. Chopra B. Dhingra A. Piperazine: A promising scaffold with analgesic and anti-inflammatory potential. Drug Res. 2021 71 2 62 72 10.1055/a‑1323‑2813 33336346
    [Google Scholar]
  114. Raikar P. Gurupadayya B. Koganti V.S. Recent Advances in chiral separation of antihistamine drugs: Analytical and bioanalytical methods. Curr. Drug Deliv. 2018 15 10 1393 1410 10.2174/1567201815666180830100015 30160212
    [Google Scholar]
  115. Morak-Młodawska B. Pluta K. Latocha M. Jeleń M. Kuśmierz D. Suwińska K. Shkurenko A. Czuba Z. Jurzak M. 10 H -1,9-diazaphenothiazine and its 10-derivatives: Synthesis, characterisation and biological evaluation as potential anticancer agents. J. Enzyme Inhib. Med. Chem. 2019 34 1 1298 1306 10.1080/14756366.2019.1639695 31307242
    [Google Scholar]
  116. Trnavský K. Kopecký Š. The influence of some anti-inflammatory drugs on the inflammatory reaction to Sodium Urate. Pharmacology 1966 15 3 322 327 10.1159/000135884
    [Google Scholar]
  117. Schaller-Clostre F. Dunant Y. Antipsychotic drugs depress acetylcholine release in the Torpedo electric organ, a purely cholinergic system. Eur. J. Pharmacol. 1985 112 1 27 37 10.1016/0014‑2999(85)90235‑3 2862052
    [Google Scholar]
  118. Hohl C.M. Stenekes S. Harlos M.S. Shepherd E. McClement S. Chochinov H.M. Methotrimeprazine for the management of end-of-life symptoms in infants and children. J. Palliat. Care 2013 29 3 178 185 10.1177/082585971302900307 24380217
    [Google Scholar]
  119. Désaméricq G. Schürhoff F. Macquin-Mavier I. Bachoud-Lévi A.C. Maison P. Use of antipsychotics: A study from the French national insurance healthcare system database Pharmacol. Pharm 2015 6 8 411 419 10.4236/pp.2015.68042
    [Google Scholar]
/content/journals/mrmc/10.2174/0113895575400761251007165058
Loading
/content/journals/mrmc/10.2174/0113895575400761251007165058
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test