{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:53:35Z","timestamp":1760057615794,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Fungal pathogens are increasingly developing concerning resistance against the currently available antifungal drugs, which creates a constant demand for new antifungal agents. Methods: Here, we report the synthesis of C3,N4-substituted triazole derivatives containing a N4-(2-((4-methoxybenzyl)thio)phenyl) group. By selectively removing the 4-methoxybenzyl group, we were able to access the free thiol analogs which, under oxidative conditions, undergo a cyclization reaction yielding a C5-substituted benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. We were able to show a broad functional group tolerance for the preparation of the triazole derivatives, as well as the tricyclic heteroarenes prepared thereof. Mechanistic investigations suggest that the oxidative cyclization reaction proceeds via an ionic pathway involving a disulfide intermediate. Isolation of the disulfide intermediate and resubjecting it to the reaction conditions shows that the presence of acid significantly increases its rate of conversion to the corresponding benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. Antifungal testing of both the novel triazoles and the benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles was carried out with Candida albicans (SC5314) and a clinical strain of Trichosporon asahii (OK01). Results: Most of the novel sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles showed activity against Candida albicans (SC5314) and the emerging pathogen Trichosporon asahii (OK01). Conclusions: A series of new sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles were synthesized. Antifungal testing revealed modest activity against Candida albicans (SC5314) and Trichosporon asahii (OK01).<\/jats:p>","DOI":"10.3390\/ph18020249","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T06:06:06Z","timestamp":1739340366000},"page":"249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Access to Substituted Tricyclic Heteroarenes by an Oxidative Cyclization Reaction and Their Antifungal Performance"],"prefix":"10.3390","volume":"18","author":[{"given":"Rehema","family":"Nakiwala","sequence":"first","affiliation":[{"name":"Department of Chemistry, 107 Physical Sciences, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6000-9159","authenticated-orcid":false,"given":"Noopur","family":"Dasgupta","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, 307 Life Sciences East, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, 307 Life Sciences East, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika I.","family":"Lutter","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, 307 Life Sciences East, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6152-5220","authenticated-orcid":false,"given":"Jeanne L.","family":"Bolliger","sequence":"additional","affiliation":[{"name":"Department of Chemistry, 107 Physical Sciences, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5352","DOI":"10.1038\/s41467-022-32249-5","article-title":"The Importance of Antimicrobial Resistance in Medical Mycology","volume":"13","author":"Gow","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_2","first-page":"100137","article-title":"Fungal Infections: Pathogenesis, Antifungals and Alternate Treatment Approaches","volume":"3","author":"Reddy","year":"2022","journal-title":"Curr. Res. Microb. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden Killers: Human Fungal Infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.cnc.2021.07.002","article-title":"Invasive Fungal Infections Among Immunocompromised Patients in Critical Care Settings: Infection Prevention Risk Mitigation","volume":"33","year":"2021","journal-title":"Crit. Care Nurs. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sahu, S.R., Bose, S., Singh, M., Kumari, P., Dutta, A., Utkalaja, B.G., Patel, S.K., and Acharya, N. (2022). Vaccines against Candidiasis: Status, Challenges and Emerging Opportunity. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.1002406"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wadhwa, K., and Kaur, H. (2022). Triazole resistance in aspergillus fumigatus-a comprehensive review. J. Microbiol. Biotechnol. Food Sci., 11.","DOI":"10.55251\/jmbfs.4159"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s11908-022-00782-5","article-title":"Antifungal Resistance and the Role of New Therapeutic Agents","volume":"24","author":"Logan","year":"2022","journal-title":"Curr. Infect. Dis. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"106673","DOI":"10.1016\/j.ijantimicag.2022.106673","article-title":"Albicans Biofilms: Antifungal Resistance, Immune Evasion, and Emerging Therapeutic Strategies","volume":"60","author":"Fan","year":"2022","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1021\/acs.chemrev.0c00199","article-title":"Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond","volume":"121","author":"Lee","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S1369-5274(02)00344-2","article-title":"Resistance of Human Fungal Pathogens to Antifungal Drugs","volume":"5","author":"Sanglard","year":"2002","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.39.1.1","article-title":"Resistance of Candida Species to Fluconazole","volume":"39","author":"Rex","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yamin, D., Akanmu, M.H., Al Mutair, A., Alhumaid, S., Rabaan, A.A., and Hajissa, K. (2022). Global Prevalence of Antifungal-Resistant Candida parapsilosis: A Systematic Review and Meta-Analysis. Trop. Med. Infect. Dis., 7.","DOI":"10.3390\/tropicalmed7080188"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.2147\/IDR.S267219","article-title":"Managing Fungal Infections in Cystic Fibrosis Patients: Challenges in Clinical Practice","volume":"14","author":"Magee","year":"2021","journal-title":"IDR"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1128\/JCM.00460-09","article-title":"Trichosporon Mycotoxinivorans, a Novel Respiratory Pathogen in Patients with Cystic Fibrosis","volume":"47","author":"Hickey","year":"2009","journal-title":"J. Clin. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e169","DOI":"10.1017\/S0950268820001624","article-title":"Epidemiological Study of Trichosporon Asahii Infections over the Past 23 Years","volume":"148","author":"Li","year":"2020","journal-title":"Epidemiol. Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1164\/rccm.2008-740ST","article-title":"An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients","volume":"183","author":"Limper","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Padovan, A.C.B., Rocha, W.P.d.S., Toti, A.C.d.M., Freitas de Jesus, D.F., Chaves, G.M., and Colombo, A.L. (2019). Exploring the Resistance Mechanisms in Trichosporon asahii: Triazoles as the Last Defense for Invasive Trichosporonosis. Fungal Genet. Biol., 133.","DOI":"10.1016\/j.fgb.2019.103267"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/cpdd.376","article-title":"Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of 14C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers","volume":"7","author":"Townsend","year":"2018","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.ejmech.2004.06.007","article-title":"Synthesis and Antimicrobial Activities of Some New 1-(5-Phenylamino-[1,3,4]thiadiazol-2-yl)methyl-5-oxo-[1,2,4]triazole and 1-(4-Phenyl-5-thioxo-[1,2,4]triazol-3-yl)methyl-5-oxo-[1,2,4]triazole Derivatives","volume":"39","author":"Demirbas","year":"2004","journal-title":"Eur. J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113961","DOI":"10.1016\/j.ejmech.2021.113961","article-title":"Heat Shock Protein 90 (Hsp90)\/Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Azoles-Resistant Candida albicans","volume":"227","author":"Li","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.ejmech.2005.01.007","article-title":"Synthesis and Antimicrobial Activity of 4-Phenyl\/Cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-thiazolyl)acetamido]thio-4H-1,2,4-triazole Derivatives","volume":"40","author":"Chevallet","year":"2005","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4369","DOI":"10.1021\/acsomega.2c07755","article-title":"Synthesis of Benzimidazole-1,2,4-Triazole Derivatives as Potential Antifungal Agents Targeting 14\u03b1-Demethylase","volume":"8","author":"Evren","year":"2023","journal-title":"ACS Omega"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00706-002-0546-z","article-title":"Synthesis, Characterization, and Evaluation of Antimicrobial Activity of Some 1,2,4-Triazole Derivatives Bearing an Antipyryl Moiety","volume":"134","author":"Ulusoy","year":"2003","journal-title":"Monatshefte Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5950","DOI":"10.1021\/acs.jmedchem.3c00165","article-title":"Discovery of BRD4\u2013HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant Candida albicans","volume":"66","author":"Li","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1094\/Phyto-66-1135","article-title":"Tricyclazole: A New Systemic Fungicide for Control of Piricularia Oryzae on Rice","volume":"66","author":"Froyd","year":"1976","journal-title":"Phytopathology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8329","DOI":"10.1007\/s11164-016-2599-3","article-title":"Synthesis of Novel 7-Fluoro-3-Substituted-1,2,4-Triazolo [3,4-b]benzothiazoles (FTBs) as Potent Antifungal Agents: Molecular Docking and in Silico Evaluation","volume":"42","author":"Kukreja","year":"2016","journal-title":"Res. Chem. Intermed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"957","DOI":"10.6023\/cjoc1111162","article-title":"Synthesis and Antifungal Activity of Novel Substituted-3-Aryl-1,2,4-triazolo[3,4-b]benzothiazoles","volume":"32","author":"Jianquan","year":"2012","journal-title":"Chin. J. Org. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/jhet.885","article-title":"Novel Synthesis and Antimicrobial Activity of 3-Substituted 5-Bromo-7-methyl-1,2,4-triazolo-[3,4-b]-benzothiazoles","volume":"49","author":"Bhagat","year":"2012","journal-title":"J. Heterocycl. Chem."},{"key":"ref_29","first-page":"118","article-title":"Synthesis of Some New Substituted Triazole Fused with Benzothiazoles and Their Antibacterial Activity","volume":"15","author":"Bhagat","year":"2017","journal-title":"Mater. Sci. Indian J."},{"key":"ref_30","first-page":"693","article-title":"Microwave prompted rapid reaction for the synthesis of some triazolo-benzothiazoles, naphthathiazoles and to study their antibacterial activity","volume":"3","author":"Swamy","year":"2010","journal-title":"Rasayan J. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9190","DOI":"10.1002\/slct.201901312","article-title":"Chloramine-T Mediated Facile One Pot Synthesis of Pyrazolyltriazolobenzothiazole Hybrids as Potent Anti-Infective Agents","volume":"4","author":"Kamal","year":"2019","journal-title":"ChemistrySelect"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1021\/acs.jmedchem.2c01460","article-title":"[1,2,4]Triazolo[3,4-b]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes","volume":"66","author":"Murthy","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/ps.2096","article-title":"Synthesis of New Compounds Related to the Commercial Fungicide Tricyclazole","volume":"67","author":"Balcer","year":"2011","journal-title":"Pest Manag. Sci."},{"key":"ref_34","first-page":"797","article-title":"Synthesis and Reactions of Both Tautomers of 2-Hydrazinobenzothiazole","volume":"40","author":"Gvozdjakova","year":"1986","journal-title":"Chem. Pap."},{"key":"ref_35","first-page":"163","article-title":"Synthesis of New Triazolo and Pyrazolo Derivatives of Benzothiazole","volume":"20","author":"Desmukh","year":"2010","journal-title":"Indian J. Heterocycl. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1021\/jo00938a012","article-title":"Synthesis of S-Triazole[3,4-b]benzothiazoles","volume":"39","author":"Wikel","year":"1974","journal-title":"J. Org. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5766","DOI":"10.1021\/jo962190v","article-title":"Photochemical Synthesis of S-Triazolo[3,4-b]benzothiazole and Mechanistic Studies on Benzothiazole Formation","volume":"62","author":"Jayanthi","year":"1997","journal-title":"J. Org. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1039\/C4GC02156H","article-title":"Convenient Synthesis of Benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles with 1 Mol% CuCl2\u00b72H2O as Catalyst in Water","volume":"17","author":"Wen","year":"2015","journal-title":"Green Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ard\u00f3n-Mu\u00f1oz, L.G., and Bolliger, J.L. (2022). Synthesis of Benzo[4,5]thiazolo[2,3-c][1,2,4]triazole Derivatives via C-H Bond Functionalization of Disulfide Intermediates. Molecules, 27.","DOI":"10.3390\/molecules27051464"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1080\/10426507.2023.2171040","article-title":"Synthesis of Sulfur Heterocycles by C\u2013H Bond Functionalization of Disulfide Intermediates","volume":"198","author":"Bolliger","year":"2023","journal-title":"Phosphorus Sulfur Silicon Relat. Elem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1021\/ol048863a","article-title":"Efficient and Regiospecific One-Pot Synthesis of Substituted 1,2,4-Triazoles","volume":"6","author":"Stocks","year":"2004","journal-title":"Org. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1007\/s10593-005-0240-2","article-title":"Recyclization of 1,3,4-Oxadiazoles and Bis-1,3,4-Oxadiazoles into 1,2,4-Triazole Derivatives. Synthesis of 5-Unsubstituted 1,2,4-Triazoles","volume":"41","author":"Korotkikh","year":"2005","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"30841","DOI":"10.1039\/D1RA04337D","article-title":"Halogen-Containing Heteroaromatic Carbenes of the 1,2,4-Triazole Series and Their Transformations","volume":"11","author":"Glinyanaya","year":"2021","journal-title":"RSC Adv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.1021\/acs.organomet.5b00198","article-title":"Highly Quantum Efficient Phosphorescent Sky Blue Emitters Based on Diastereomeric Iridium(III) Complexes of Atropisomeric 5-Aryl-4H-1,2,4-triazole Ligands","volume":"34","author":"Feldman","year":"2015","journal-title":"Organometallics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13686","DOI":"10.1039\/D1DT02161C","article-title":"Phenyl-pyta-tricarbonylrhenium(I) Complexes: Combining a Simplified Structure and Steric Hindrance to Modulate the Photoluminescence Properties","volume":"50","author":"Poirot","year":"2021","journal-title":"Dalton Trans."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jorganchem.2012.08.018","article-title":"Thiol-Functionalized 1,2,4-Triazolium Salt as Carbene Ligand Precursor","volume":"719","author":"Holm","year":"2012","journal-title":"J. Organomet. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17923","DOI":"10.1021\/acsomega.9b03109","article-title":"Catalytic Preparation of 1-Aryl-Substituted 1,2,4-Triazolium Salts","volume":"4","author":"Hutchinson","year":"2019","journal-title":"ACS Omega"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.1007\/s11095-017-2256-6","article-title":"Photodegradation Pathways of Protein Disulfides: Human Growth Hormone","volume":"34","author":"Steinmann","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1128\/AAC.02067-12","article-title":"Azole Affinity of Sterol 14\u03b1-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens","volume":"57","author":"Warrilow","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1021\/om400143u","article-title":"Stepwise Deprotonation of a Thiol-Functionalized Bis(1,2,4-Triazolium) Salt as a Selective Route to Heterometallic NHC Complexes","volume":"32","author":"Seitz","year":"2013","journal-title":"Organometallics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1021\/jo01092a023","article-title":"The Synthesis of Polyazaindenes and Related Compounds","volume":"24","author":"Reynolds","year":"1959","journal-title":"J. Org. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1007\/BF02135397","article-title":"A Novel Oxidative Cyclization of 4-Arylthiosemicarbazides and Related Compounds","volume":"20","author":"Rao","year":"1964","journal-title":"Experientia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1039\/p19720001519","article-title":"Reactions of Substituted 2-Benzothiazolyl Hydrazones with Bromine. Route to s-Triazolo[3,4-b][1,3]Benzothiazoles","volume":"12","author":"Butler","year":"1972","journal-title":"J. Chem. Soc. Perkin Trans. 1"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Berkow, E.L., Lockhart, S.R., and Ostrosky-Zeichner, L. (2020). Antifungal Susceptibility Testing: Current Approaches. Clin. Microbiol. Rev., 33.","DOI":"10.1128\/CMR.00069-19"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/249\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:32:05Z","timestamp":1760027525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/249"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,12]]},"references-count":54,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ph18020249"],"URL":"https:\/\/doi.org\/10.3390\/ph18020249","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2025,2,12]]}}}