{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:29:48Z","timestamp":1772252988381,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,14]],"date-time":"2018-10-14T00:00:00Z","timestamp":1539475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001459","name":"Ministry of Education - Singapore","doi-asserted-by":"publisher","award":["MOE2012-TIF-1-T-051"],"award-info":[{"award-number":["MOE2012-TIF-1-T-051"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chloroquine was among the first of several effective drug treatments against malaria until the onset of chloroquine resistance. In light of diminished clinical efficacy of chloroquine as an antimalarial therapeutic, there is potential in efforts to adapt chloroquine for other clinical applications, such as in combination therapies and in diagnostics. In this context, we designed and synthesized a novel asymmetrical squaraine dye coupled with chloroquine (SQR1-CQ). In this study, SQR1-CQ was used to label live Plasmodium falciparum (P. falciparum) parasite cultures of varying sensitivities towards chloroquine. SQR1-CQ positively stained ring, mature trophozoite and schizont stages of both chloroquine\u2013sensitive and chloroquine\u2013resistant P. falciparum strains. In addition, SQR1-CQ exhibited significantly higher fluorescence, when compared to the commercial chloroquine-BODIPY (borondipyrromethene) conjugate CQ-BODIPY. We also achieved successful SQR1-CQ labelling of P. falciparum directly on thin blood smear preparations. Drug efficacy experiments measuring half-maximal inhibitory concentration (IC50) showed lower concentration of effective inhibition against resistant strain K1 by SQR1-CQ compared to conventional chloroquine. Taken together, the versatile and highly fluorescent labelling capability of SQR1-CQ and promising preliminary IC50 findings makes it a great candidate for further development as diagnostic tool with drug efficacy against chloroquine-resistant P. falciparum.<\/jats:p>","DOI":"10.3390\/molecules23102635","type":"journal-article","created":{"date-parts":[[2018,10,15]],"date-time":"2018-10-15T03:43:01Z","timestamp":1539574981000},"page":"2635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Near Infrared Fluorophore-Tagged Chloroquine in Plasmodium falciparum Diagnostic Imaging"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6778-7042","authenticated-orcid":false,"given":"Li Yan","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Technology, Innovation and Enterprise (TIE), Singapore Polytechnic, 500 Dover Road, Singapore 139651, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua Ding Wei","family":"Teo","sequence":"additional","affiliation":[{"name":"Department of Technology, Innovation and Enterprise (TIE), Singapore Polytechnic, 500 Dover Road, Singapore 139651, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin Shyong-Wei","family":"Tan","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, 5 Science Drive 2 Block MD4, Level 3, Singapore 117545, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5449-9084","authenticated-orcid":false,"given":"Keitaro","family":"Sou","sequence":"additional","affiliation":[{"name":"Research Institute for Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei Lek","family":"Kwan","sequence":"additional","affiliation":[{"name":"Engineering Product Development, Singapore University of Technology and Design, 8 Somapah Road, Singapore 487372, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Lik Ken","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Technology, Innovation and Enterprise (TIE), Singapore Polytechnic, 500 Dover Road, Singapore 139651, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Loh, C.C.Y., Suwanarusk, R., Lee, Y.Q., Chan, K.W.K., Choy, K.-Y., R\u00e9nia, L., Russell, B., Lear, M.J., Nosten, F.H., and Tan, K.S.W. (2014). Characterization of the commercially-available fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a marker for chloroquine resistance and uptake in a 96-Well plate assay. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110800"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5433","DOI":"10.1039\/C6CC10282D","article-title":"Novel glycoconjugated squaraine dyes for selective optical imaging of cancer cells","volume":"53","author":"Shimi","year":"2017","journal-title":"Chem. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0163-7258(93)90056-J","article-title":"Chloroquine: Mechanism of drug action and resistance in plasmodium falciparum","volume":"57","author":"Slater","year":"1993","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/235050a0","article-title":"Lysosomes, pH and the anti-malarial action of chloroquine","volume":"235","author":"Homewood","year":"1972","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1016\/0006-2952(74)90174-9","article-title":"Commentary. Lysosomotropic agents","volume":"23","author":"Poole","year":"1974","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Van Schalkwyk, D.A., Saliba, K.J., Biagini, G.A., Bray, P.G., and Kirk, K. (2013). Loss of pH Control in Plasmodium falciparum Parasites Subjected to Oxidative Stress. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058933"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Saliba, K.J., and Kirk, K. pH Regulation in the intracellular malaria parasite. J. Biol. Chem., Available online: http:\/\/www.jbc.org\/content\/274\/47\/33213.long.","DOI":"10.1074\/jbc.274.47.33213"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ejso.2010.10.006","article-title":"Near-infrared fluorescence (NIRF) imaging in breast conserving surgery: Assessing intraoperative techniques in tissue simulating breast phantoms","volume":"37","author":"Pleijhuis","year":"2011","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1016\/j.ejmech.2009.01.019","article-title":"An in vitro characterization study of new near infrared dyes for molecular imaging","volume":"44","author":"Pauli","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1118\/1.2919078","article-title":"Assessing the future of diffuse optical imaging technologies for breast cancer management","volume":"35","author":"Tromberg","year":"2008","journal-title":"Med. Phys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1002\/ijc.23780","article-title":"Highly sensitive detection of early-stage pancreatic cancer by multimodal nearinfrared molecular imaging in living mice","volume":"123","author":"Eser","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.amjsurg.2007.02.032","article-title":"Intraoperative identification of sentinel lymph nodes by near-infrared fluorescence imaging in patients with breast cancer","volume":"195","author":"Tagaya","year":"2008","journal-title":"Am. J. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5176","DOI":"10.1016\/j.bmc.2009.05.048","article-title":"Toward preparation of antibody-based imaging probe libraries for dual-modality positron emission tomography and fluorescence imaging","volume":"17","author":"Xu","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.cbpa.2009.10.022","article-title":"NIR dyes for bioimaging applications","volume":"14","author":"Escobedo","year":"2010","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5797","DOI":"10.1039\/C8TA00750K","article-title":"Central dicyanomethylene-substituted unsymmetrical squaraines and their application in organic solar cells","volume":"6","author":"Wu","year":"2018","journal-title":"J. Mater. Chem. A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1039\/C3CS60271K","article-title":"Recent progress in the development of near-infrared fluorescent probes for bioimaging applications","volume":"43","author":"Guo","year":"2014","journal-title":"Chem. Soc. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.cbpa.2009.09.029","article-title":"Near-infrared fluorescence: Application to in vivo molecular imaging","volume":"14","author":"Hilderbrand","year":"2010","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.crad.2010.03.011","article-title":"Molecular imaging: Current status and emerging strategies","volume":"65","author":"Pysz","year":"2010","journal-title":"Clin. Radiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.cbpa.2003.08.007","article-title":"In vivo near-infrared fluorescence imaging","volume":"7","author":"Frangioni","year":"2003","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106868","DOI":"10.1039\/C5RA18998E","article-title":"Development of asymmetrical near infrared squaraines with large Stokes shift","volume":"5","author":"Liu","year":"2015","journal-title":"RSC Adv."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9991","DOI":"10.1002\/chem.201402369","article-title":"Relationship between molecular stacking and optical properties of 9,10-bis((4-N,N-dialkylamino)styryl) anthracene crystals: The cooperation of excitonic and dipolar coupling","volume":"20","author":"Li","year":"2014","journal-title":"Chem. Eur. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6590","DOI":"10.1021\/ja0393776","article-title":"A Controlled supramolecular approach toward cation-specific chemosensors: Alkaline earth metal ion-driven exciton signaling in squaraine tethered podands","volume":"126","author":"Arunkumar","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1002\/anie.201008198","article-title":"Resettable, multi\u2013readout logic gates based on controllably reversible aggregation of gold nanoparticles","volume":"50","author":"Liu","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1016\/j.tetlet.2007.02.034","article-title":"Photovoltaic properties of new cyanine\u2013naphthalimide dyads synthesized by \u2018Click\u2019 chemistry","volume":"48","author":"Zhan","year":"2007","journal-title":"Tetrahedron Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1021\/acsanm.8b00084","article-title":"Far-red fluorescent liposomes for folate receptor-targeted bioimaging","volume":"1","author":"Dong","year":"2018","journal-title":"ACS Appl. Nano Mater."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1128\/AAC.02476-15","article-title":"Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel hybrid compounds","volume":"60","author":"Boudhar","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6720","DOI":"10.1039\/C7OB01346A","article-title":"Effect of spermine-derived AGEs on oxidative stress and polyamine metabolism","volume":"15","author":"Tsutsui","year":"2017","journal-title":"Org. Biomol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/j.bmcl.2018.03.016","article-title":"Design, synthesis, nuclear localization and biological activity of a fluorescent duocarmycin analog, HxTfA","volume":"28","author":"Kiakos","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7804","DOI":"10.1016\/j.bmc.2010.09.054","article-title":"Selective accumulation of a novel antimalarial rhodacyanine derivative, SSJ-127, in an organelle of Plasmodium berghei","volume":"18","author":"Arai","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_30","unstructured":"(2018, August 12). WHO Basic Malaria Microscopy\u2014Part I: Learner\u2019s Guide. Available online: http:\/\/www.who.int\/malaria\/publications\/atoz\/9241547820\/en\/."},{"key":"ref_31","first-page":"1424","article-title":"The malaria digestive vacuole","volume":"4","author":"Wunderlich","year":"2012","journal-title":"Front. Biosci. (Sch. Ed.)"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1002\/j.1460-2075.1984.tb02195.x","article-title":"Identification of the acidic compartment of Plasmodium falciparum-infected human erythrocytes as the target of the antimalarial drug chloroquine","volume":"3","author":"Yayon","year":"1984","journal-title":"EMBO J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17136","DOI":"10.1039\/C5CC06094J","article-title":"Bright fluorogenic squaraines with tuned cell entry for selective imaging of plasma membrane vs. endoplasmic reticulum","volume":"51","author":"Collot","year":"2015","journal-title":"Chem. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Esposito, A., Tiffert, T., Mauritz, J.M., Schlachter, S., Bannister, L.H., Kaminski, C.F., and Lew, V.L. (2008). FRET imaging of hemoglobin concentration in Plasmodium falciparum-infected red cells. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003780"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0021-9258(18)72329-6","article-title":"The absorption spectra of hemoglobin and its derivatives in the visible and near infra-red regions","volume":"148","author":"Horecker","year":"1943","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E2068","DOI":"10.1073\/pnas.1615195114","article-title":"Quantification of labile heme in live malaria parasites using a genetically encoded biosensor","volume":"114","author":"Abshire","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1186\/1475-2875-8-279","article-title":"Haemoglobin interference and increased sensitivity of fluorimetric assays for quantification of low-parasitaemia Plasmodium infected erythrocytes","volume":"8","author":"Moneriz","year":"2009","journal-title":"Malar. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1096\/fj.05-5122fje","article-title":"Hemoglobin degradation in malaria-infected erythrocytes determined from live cell magnetophoresis","volume":"20","author":"Moore","year":"2006","journal-title":"FASEB J."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Richards, S.N., Nash, M.N., Baker, E.S., Webster, M.W., Lehane, A.M., Shafik, S.H., and Martin, R.E. (2016). Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite\u2019s Chloroquine Resistance Transporter. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005725"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.jiph.2017.01.001","article-title":"LED fluorescence microscopy: Novel method for malaria diagnosis compared with routine methods","volume":"10","author":"Hathiwala","year":"2017","journal-title":"J. Infect. Public Health"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/1475-2875-10-194","article-title":"Assessment of LED fluorescence microscopy for the diagnosis of Plasmodium falciparum infections in Gabon","volume":"10","author":"Lenz","year":"2011","journal-title":"Malar. J."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2635\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:25:30Z","timestamp":1760196330000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,14]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["molecules23102635"],"URL":"https:\/\/doi.org\/10.3390\/molecules23102635","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201809.0589.v1","asserted-by":"object"}]},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,14]]}}}