{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T23:21:29Z","timestamp":1774999289188,"version":"3.50.1"},"reference-count":89,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/00709\/2020; UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020; UIDP\/00709\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.<\/jats:p>","DOI":"10.3390\/molecules27010276","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T03:46:27Z","timestamp":1641527187000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Marina C.","family":"Posso","sequence":"first","affiliation":[{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Fernanda C.","family":"Domingues","sequence":"additional","affiliation":[{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8308-2862","authenticated-orcid":false,"given":"Susana","family":"Ferreira","sequence":"additional","affiliation":[{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4297-5108","authenticated-orcid":false,"given":"Samuel","family":"Silvestre","sequence":"additional","affiliation":[{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3390\/ijerph5010004","article-title":"Gene-Environment Interactions in the Development of Complex Disease Phenotypes","volume":"5","author":"Ramos","year":"2008","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.2147\/DDDT.S257494","article-title":"Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases","volume":"14","author":"Makhoba","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1111\/jcmm.12930","article-title":"Combination Therapeutics in Complex Diseases","volume":"20","author":"He","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ejmech.2018.03.057","article-title":"Success Stories of Natural Product-based Hybrid Molecules for Multi-factorial Diseases","volume":"151","author":"Choudhary","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/0960-894X(96)00072-8","article-title":"Imino 1,2,3,4-tetrahydrocyclopent[b]indole carbamates as Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase","volume":"6","author":"Fink","year":"1996","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1517\/17460441.2016.1135125","article-title":"An Overview of Molecular Hybrids in Drug Discovery","volume":"11","year":"2016","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ejmech.2016.08.039","article-title":"Hybrid Molecules: The Privileged Scaffolds for Various Pharmaceuticals","volume":"124","author":"Shaveta","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.drudis.2011.01.001","article-title":"Phenothiazine: The Seven Lives of Pharmacology\u2019s First Lead Structure","volume":"16","author":"Ohlow","year":"2011","journal-title":"Drug Discov. Today"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Berneth, H. (2008). Azine Dyes. Ullmann\u2019s Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co. KGaA.","DOI":"10.1002\/14356007.a03_213.pub3"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6128","DOI":"10.1021\/acs.joc.5b00568","article-title":"Method for the Synthesis of Phenothiazines via a Domino Iron-Catalyzed C\u2013S\/C\u2013N Cross-Coupling Reaction","volume":"80","author":"Hu","year":"2015","journal-title":"J. Org. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"173553","DOI":"10.1016\/j.ejphar.2020.173553","article-title":"Antiviral Activity of Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, and Thioridazine Towards RNA-Viruses. A Review","volume":"887","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ejphar.2010.08.045","article-title":"Multiple Non-psychiatric Effects of Phenothiazines: A Review","volume":"648","author":"Sudeshna","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","unstructured":"Ferlay, J., Ervik, M., Lam, F., Colombet, M., Mery, L., and Pi\u00f1eros, M. (2021, October 28). The Global Cancer Observatory-All cancers. Available online: https:\/\/gco.iarc.fr\/today\/home."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.canep.2016.06.013","article-title":"The Fractions of Cancer Attributable to Modifiable Factors: A Global Review","volume":"44","author":"Whiteman","year":"2016","journal-title":"Cancer Epidemiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41568-021-00378-6","article-title":"Cancer Metabolism: Looking Forward","volume":"21","author":"Chandel","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, X., Zhang, H., and Chen, X. (2019). Drug Resistance and Combating Drug Resistance in Cancer. Cancer Drug Resist.","DOI":"10.20517\/cdr.2019.10"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00280-003-0738-1","article-title":"Phenothiazines Suppress Proliferation and Induce Apoptosis in Cultured Leukemic Cells Without Any Influence on the Viability of Normal Lymphocytes","volume":"53","author":"Zhelev","year":"2004","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1124\/mol.114.096941","article-title":"Repurposing the Antipsychotic Trifluoperazine as an Antimetastasis Agent","volume":"87","author":"Li","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"114403","DOI":"10.1016\/j.bcp.2020.114403","article-title":"Chlorpromazine, an Antipsychotic Agent, Induces G2\/M Phase Arrest and Apoptosis Via Regulation of the PI3K\/AKT\/mTOR-mediated Autophagy Pathways in Human Oral Cancer","volume":"184","author":"Jhou","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"27540","DOI":"10.1038\/srep27540","article-title":"Pharmacological Exploitation of the Phenothiazine Antipsychotics to Develop Novel Antitumor Agents\u2013A Drug Repurposing Strategy","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12701","DOI":"10.1002\/slct.201903203","article-title":"Design, Synthesis and Characterisation of Novel Phenothiazine-Based Triazolopyridine Derivatives: Evaluation of Anti-Breast Cancer Activity on Human Breast Carcinoma","volume":"4","author":"Sachdeva","year":"2019","journal-title":"ChemistrySelect"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.jmb.2017.01.001","article-title":"Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures","volume":"429","author":"Kellogg","year":"2017","journal-title":"J. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"357","DOI":"10.2174\/1568009616666160928110818","article-title":"Mechanisms of Tubulin Binding Ligands to Target Cancer Cells: Updates on their Therapeutic Potential and Clinical Trials","volume":"17","author":"Kumar","year":"2017","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1007\/s10637-018-0682-x","article-title":"Antitumor Evaluation of Novel Phenothiazine Derivatives that Inhibit Migration and Tubulin Polymerization Against Gastric Cancer MGC-803 cells","volume":"37","author":"Liu","year":"2019","journal-title":"Investig. New Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"696","DOI":"10.3184\/174751917X15122516000140","article-title":"Design, Synthesis and Antiproliferative Activity of Novel Phenothiazine-1,2,3-Triazole Analogues","volume":"41","author":"Ma","year":"2017","journal-title":"J. Chem. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhang, J.-X., Guo, J.-M., Zhang, T.-T., Lin, H.-J., Qi, N.-S., Li, Z.-G., Zhou, J.-C., and Zhang, Z.-Z. (2018). Antiproliferative Phenothiazine Hybrids as Novel Apoptosis Inducers Against MCF-7 Breast Cancer. Molecules, 23.","DOI":"10.3390\/molecules23061288"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Morak-M\u0142odawska, B., Pluta, K., Latocha, M., Jele\u0144, M., and Ku\u015bmierz, D. (2019). Design, Synthesis, and Structural Characterization of Novel Diazaphenothiazines with 1,2,3-Triazole Substituents as Promising Antiproliferative Agents. Molecules, 24.","DOI":"10.3390\/molecules24234388"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1016\/j.bmc.2013.04.034","article-title":"Synthesis and Pharmacological Investigation of New N-hydroxyalkyl-2-aminophenothiazines Exhibiting Marked MDR Inhibitory Effect","volume":"21","author":"Egyed","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_29","first-page":"3245","article-title":"Reversal of ABCB1-related Multidrug Resistance of Colonic Adenocarcinoma Cells by Phenothiazines","volume":"35","author":"Csonka","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/bs.acr.2020.05.002","article-title":"Biology, pathology, and therapeutic targeting of RAS","volume":"148","author":"Rhett","year":"2020","journal-title":"Adv Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/d41573-021-00168-7","article-title":"The FDA Approves a First Farnesyltransferase Inhibitor","volume":"20","author":"Mullard","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4517","DOI":"10.1016\/j.bmcl.2012.06.007","article-title":"New farnesyltransferase inhibitors in the phenothiazine series","volume":"22","author":"Belei","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104184","DOI":"10.1016\/j.bioorg.2020.104184","article-title":"Indolizine-phenothiazine Hybrids as the First Dual Inhibitors of Tubulin Polymerization and Farnesyltransferase with Synergistic Antitumor Activity","volume":"103","author":"Moise","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6896","DOI":"10.1016\/j.bmcl.2012.09.030","article-title":"Synthesis and Biological Evaluation of New Phenothiazine Derivatives Bearing a Pyrazole Unit as Protein Farnesyltransferase Inhibitors","volume":"22","author":"Ghinet","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1111\/febs.15612","article-title":"Cell-Permeable CaaX-Peptides Affect K-Ras Downstream Signaling and Promote Cell Death in Cancer Cells","volume":"288","author":"Klimpel","year":"2021","journal-title":"FEBS J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1016\/j.bmcl.2015.09.008","article-title":"Phenothiazine-based CaaX Competitive Inhibitors of Human Farnesyltransferase Bearing a Cysteine, Methionine, Serine or Valine Moiety as a New Family of Antitumoral Compounds","volume":"25","author":"Dumitriu","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Al Zahrani, N.A., El-Shishtawy, R.M., Elaasser, M.M., and Asiri, A.M. (2020). Synthesis of Novel Chalcone-Based Phenothiazine Derivatives as Antioxidant and Anticancer Agents. Molecules, 25.","DOI":"10.3390\/molecules25194566"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Brem, B., Gal, E., G\u0103in\u0103, L., Silaghi-Dumitrescu, L., Fischer-Fodor, E., Tomuleasa, C.I., Grozav, A., Zaharia, V., Filip, L., and Cristea, C. (2017). Novel Thiazolo[5,4-b]phenothiazine Derivatives: Synthesis, Structural Characterization, and In Vitro Evaluation of Antiproliferative Activity against Human Leukaemia. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071365"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1002\/ardp.201100355","article-title":"Heterocycles 27. Microwave Assisted Synthesis and Antitumour Activity of Novel Phenothiazinyl-Thiazolyl-Hydrazine Derivatives","volume":"345","author":"Ignat","year":"2012","journal-title":"Arch. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, I.S., Liang, W.Z., Wang, J.L., Kuo, C.C., Hao, L.J., Chou, C.T., and Jan, C.R. (2020). Exploration of Thioridazine-Induced Ca2+ Signaling and Non-Ca2+-Triggered Cell Death in HepG2 Human Hepatocellular Carcinoma Cells. Chin. J. Physiol., 187\u2013194.","DOI":"10.4103\/CJP.CJP_45_20"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Karatoprak, G.\u015e., K\u00fcpeli Akkol, E., Gen\u00e7, Y., Bardakci, H., Y\u00fccel, \u00c7., and Sobarzo-S\u00e1nchez, E. (2020). Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications. Molecules, 25.","DOI":"10.3390\/molecules25112560"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.bmcl.2012.10.135","article-title":"Synthesis and anticancer activity of analogues of phenstatin, with a phenothiazine A-ring, as a new class of microtubule-targeting agents","volume":"23","author":"Abuhaie","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ejmech.2012.10.051","article-title":"Synthesis, antiproliferative activity and tubulin targeting effect of acridinone and dioxophenothiazine derivatives","volume":"59","author":"Verones","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1021\/acs.jmedchem.6b01591","article-title":"N-heterocyclic (4-phenylpiperazin-1-yl)methanones derived from phenoxazine and phenothiazine as highly potent inhibitors of tubulin polymerization","volume":"60","author":"Prinz","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4247","DOI":"10.1021\/jm200436t","article-title":"N-Benzoylated Phenoxazines and Phenothiazines: Synthesis, Antiproliferative Activity, and Inhibition of Tubulin Polymerization","volume":"54","author":"Prinz","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1016\/j.bmc.2016.04.001","article-title":"Studies on Phenothiazines: New Microtubule-interacting Compounds with Phenothiazine A-ring as Potent Antineoplastic Agents","volume":"24","author":"Ghinet","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1007\/s11030-017-9773-4","article-title":"Molecular Diversity of Phenothiazines: Design and Synthesis of Phenothiazine\u2013Dithiocarbamate Hybrids as Potential Cell Cycle Blockers","volume":"21","author":"Fu","year":"2017","journal-title":"Mol. Divers."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Chu, C.-W., Ko, H.-J., Chou, C.-H., Cheng, T.-S., Cheng, H.-W., Liang, Y.-H., Lai, Y.-L., Lin, C.-Y., Wang, C., and Loh, J.-K. (2019). Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt\/\u03b2-Catenin Signaling Pathway in Glioma Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030473"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"17046","DOI":"10.1039\/C9NJ03394G","article-title":"Phenothiazine and Amide-ornamented Novel Nitrogen Heterocyclic Hybrids: Synthesis, Biological and Molecular Docking Studies","volume":"43","author":"Sivaramakarthikeyan","year":"2019","journal-title":"New J. Chem."},{"key":"ref_50","first-page":"301","article-title":"Synthesis, Pro-apoptotic Activity and 2D-QSAR Studies of New Analogues of Fluphenazine","volume":"71","author":"Zyta","year":"2014","journal-title":"Acta Pol. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ejmech.2017.04.028","article-title":"Aromatase Inhibitors and Apoptotic Inducers: Design, Synthesis, Anticancer Activity and Molecular Modeling Studies of Novel Phenothiazine Derivatives Carrying Sulfonamide Moiety as Hybrid Molecules","volume":"134","author":"Ghorab","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1016\/j.bmcl.2019.07.023","article-title":"Design, Synthesis and Anticancer Activity of Constrained Sphingolipid-phenoxazine\/phenothiazine Hybrid Constructs Targeting Protein Phosphatase 2A","volume":"29","author":"Garsi","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1172\/JCI65093","article-title":"Phenothiazines Induce PP2A-Mediated Apoptosis in T Cell Acute Lymphoblastic Leukemia","volume":"124","author":"Gutierrez","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National Institute on Aging\u2013Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: A practical approach","volume":"123","author":"Montine","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"779","DOI":"10.3233\/JAD-180766","article-title":"Treatment Combinations for Alzheimer\u2019s Disease: Current and Future Pharmacotherapy Options","volume":"67","author":"Cummings","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1007\/s00044-014-0931-2","article-title":"Design and Synthesis of Tacrine-phenothiazine Hybrids as Multitarget Drugs for Alzheimer\u2019s Disease","volume":"23","author":"Hui","year":"2014","journal-title":"Med. Chem. Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Frenzel, D., Gl\u00fcck, J.M., Brener, O., Oesterhelt, F., Nagel-Steger, L., and Willbold, D. (2014). Immobilization of Homogeneous Monomeric, Oligomeric and Fibrillar A\u03b2 Species for Reliable SPR Measurements. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089490"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1016\/j.ejmech.2011.03.003","article-title":"N-Acylaminophenothiazines: Neuroprotective Agents Displaying Multifunctional Activities for a Potential Treatment of Alzheimer\u2019s Disease","volume":"46","author":"Arce","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6152","DOI":"10.1016\/j.ejmech.2010.09.039","article-title":"Old Phenothiazine and Dibenzothiadiazepine Derivatives for Tomorrow\u2019s Neuroprotective Therapies Against Neurodegenerative Diseases","volume":"45","author":"Arce","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1016\/j.bmcl.2013.04.082","article-title":"Selectivity of Phenothiazine Cholinesterase Inhibitors for Neurotransmitter Systems","volume":"23","author":"Darvesh","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2332\/allergolint.13-RA-0675","article-title":"The Role of Histamine H1 and H4 Receptors in Atopic Dermatitis: From Basic Research to Clinical Study","volume":"63","author":"Ohsawa","year":"2014","journal-title":"Allergol. Int."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1016\/j.bmcl.2009.03.124","article-title":"Synthesis and Structure\u2013activity Relationships of Phenothiazine Carboxylic Acids Having Pyrimidine-dione as Novel Histamine H1 Antagonists","volume":"19","author":"Kubota","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/nrmicro.2017.103","article-title":"Diagnosing Antimicrobial Resistance","volume":"15","author":"Burnham","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1093\/femsre\/fuz017","article-title":"V Do Phenothiazines Possess Antimicrobial and Efflux Inhibitory Properties?","volume":"43","author":"Grimsey","year":"2019","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Grimsey, E.M., Fais, C., Marshall, R.L., Ricci, V., Ciusa, M.L., Stone, J.W., Ivens, A., Malloci, G., Ruggerone, P., and Vargiu, A.V. (2020). Chlorpromazine and Amitriptyline Are Substrates and Inhibitors of the AcrB Multidrug Efflux Pump. MBio, 11.","DOI":"10.1128\/mBio.00465-20"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.1128\/AAC.00006-08","article-title":"Inhibitors of bacterial multidrug efflux pumps potentiate antimicrobial photoinactivation","volume":"52","author":"Tegos","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1128\/AAC.50.1.196-203.2006","article-title":"Phenothiazinium Antimicrobial Photosensitizers Are Substrates of Bacterial Multidrug Resistance Pumps","volume":"50","author":"Tegos","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1021\/acsinfecdis.7b00095","article-title":"Attaching the NorA Efflux Pump Inhibitor INF55 to Methylene Blue Enhances Antimicrobial Photodynamic Inactivation of Methicillin-Resistant Staphylococcus aureus in Vitro and in Vivo","volume":"3","author":"Rineh","year":"2017","journal-title":"ACS Infect. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1016\/j.bmcl.2018.02.041","article-title":"Attaching NorA Efflux Pump Inhibitors to Methylene Blue Enhances Antimicrobial Photodynamic Inactivation of Escherichia coli and Acinetobacter baumannii In Vitro and In Vivo","volume":"28","author":"Rineh","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1134\/S1070363220030214","article-title":"One-Pot Regioselective Synthesis of Some Novel Isoxazole-Phenothiazine Hybrids and Their Antibacterial Activity","volume":"90","author":"Guguloth","year":"2020","journal-title":"Russ. J. Gen. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1021\/bi002162d","article-title":"A Structural Variation for MurB: X-ray Crystal Structure of Staphylococcus aureus UDP-N-acetylenolpyruvylglucosamine Reductase (MurB)","volume":"40","author":"Benson","year":"2001","journal-title":"Biochemistry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejmech.2015.10.035","article-title":"Design of New Phenothiazine-thiadiazole Hybrids Via Molecular Hybridization Approach for the Development of Potent Antitubercular Agents","volume":"106","author":"Ramprasad","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"101574","DOI":"10.1016\/j.cimid.2020.101574","article-title":"Drug Resistant Tuberculosis: A Review","volume":"74","author":"Khawbung","year":"2021","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.bbabio.2014.03.017","article-title":"Characterization of the Type 2 NADH: Menaquinone Oxidoreductases from Staphylococcus aureus and the Bactericidal Action of Phenothiazines","volume":"1837","author":"Yano","year":"2014","journal-title":"Biochim. Biophys. Acta-Bioenerg."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.bmcl.2013.11.031","article-title":"Rational Design, Synthesis and Antitubercular Evaluation of Novel 2-(trifluoromethyl)phenothiazine-[1,2,3]triazole Hybrids","volume":"24","author":"Addla","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1021\/acsinfecdis.6b00111","article-title":"Design, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis","volume":"2","author":"Kumar","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5320","DOI":"10.1016\/j.bmc.2014.07.050","article-title":"Incorporation of Triphenylphosphonium Functionality Improves the Inhibitory Properties of Phenothiazine Derivatives in Mycobacterium tuberculosis","volume":"22","author":"Dunn","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_79","first-page":"556","article-title":"Microwave Assisted Synthesis and SAR Studies of Novel Hybrid Phenothiazine Analogs as Potential Antitubercular Agents","volume":"57","author":"Pemmadi","year":"2018","journal-title":"INDIAN J. Chem. Sect. B-Org. Chem. Incl. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.ejmech.2019.02.010","article-title":"Molecular Hybridization Approach for Phenothiazine Incorporated 1,2,3-triazole Hybrids as Promising Antimicrobial Agents: Design, Synthesis, Molecular Docking and In Silico ADME Studies","volume":"168","author":"Reddyrajula","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/S0140-6736(18)30324-6","article-title":"Malaria","volume":"391","author":"Ashley","year":"2018","journal-title":"Lancet"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1021\/jm010549o","article-title":"Design, Synthesis, and Evaluation of New Chemosensitizers in Multi-Drug-Resistant Plasmodium falciparum","volume":"45","author":"Guan","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1093\/mmy\/myz140","article-title":"Antifungal Activity of Promethazine and Chlorpromazine Against Planktonic Cells and Biofilms of Cryptococcus neoformans\/Cryptococcus gattii Complex Species","volume":"58","author":"Brilhante","year":"2020","journal-title":"Med. Mycol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1021\/acsinfecdis.7b00157","article-title":"Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity","volume":"4","author":"Montoya","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.1172\/JCI83626","article-title":"Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages","volume":"127","author":"Mancini","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1124\/pr.58.3.2","article-title":"The Endocannabinoid System as an Emerging Target of Pharmacotherapy","volume":"58","author":"Pacher","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1038\/s41598-018-20078-w","article-title":"New Role of Phenothiazine Derivatives as Peripherally Acting CB1 Receptor Antagonizing Anti-obesity Agents","volume":"8","author":"Sharma","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0014-2999(03)01856-9","article-title":"Cannabinoid Pharmacological Properties Common to Other Centrally Acting Drugs","volume":"471","author":"Wiley","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1016\/j.bmc.2004.04.009","article-title":"New Class of Potent Antinociceptive and Antiplatelet 10H-phenothiazine-1-acylhydrazone Derivatives","volume":"12","author":"Silva","year":"2004","journal-title":"Bioorg. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/1\/276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:59:58Z","timestamp":1760363998000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/1\/276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,3]]},"references-count":89,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["molecules27010276"],"URL":"https:\/\/doi.org\/10.3390\/molecules27010276","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,3]]}}}