{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T03:27:16Z","timestamp":1779334036350,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-20102"],"award-info":[{"award-number":["21-74-20102"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Objectives: In 2022, the World Health Organization highlighted the necessity for the development of new antifungal agents. Polyene antibiotics are characterized by a low risk of drug resistance; however, their use is limited by low solubility and severe side effects. Methods: A series of N-alkylated derivatives of amphotericin B and nystatin A1 as well as their N-(2-hydroxyethyl)amides were synthesized. Their antifungal activity was evaluated against various Candida strains and Aspergillus fumigatus using the broth microdilution method. Cytotoxicity was assessed using an MTT assay on human embryonic kidney cells HEK293 and human skin fibroblast cells hFB-hTERT6, as well as a hemolysis assay on erythrocytes. Membrane activity was analyzed by fluorimetric measurement of calcein leakage from model liposomes. Results: Derivatives containing the N-(hydroxyethyl)amino)ethyl fragment (compounds 3 and 4) exhibited relatively high antifungal activity, as did N-(2-hydroxyethyl)amides 5 and 9. Bis-modified compounds 6 and 10 did not outperform their mono-modified analogues in terms of activity or cytotoxicity. The mono-N-alkylated compound 3 showed the highest activity\/toxicity ratio, which correlated well with its selectivity for ergosterol-containing model membranes. Discussion: Combining two successful modifications does not necessarily improve the activity\/toxicity ratio of polyenes. Further studies can be performed for the optimization of carboxyl group of 3.<\/jats:p>","DOI":"10.3390\/antibiotics13121177","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T10:07:10Z","timestamp":1733306830000},"page":"1177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mono-N-alkylation of Amphotericin B and Nystatin A1 and Its Amides: Effect on the In Vitro Activity, Cytotoxicity and Permeabilization of Model Membranes"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2433-5713","authenticated-orcid":false,"given":"Olga","family":"Omelchuk","sequence":"first","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7014-7540","authenticated-orcid":false,"given":"Elena","family":"Bychkova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-2007","authenticated-orcid":false,"given":"Svetlana","family":"Efimova","sequence":"additional","affiliation":[{"name":"Institute of Cytology of Russian Academy of Sciences, 4 Tikhoretsky Ave., St. Petersburg 194064, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3508-231X","authenticated-orcid":false,"given":"Natalia","family":"Grammatikova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6010-7596","authenticated-orcid":false,"given":"George","family":"Zatonsky","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-1093","authenticated-orcid":false,"given":"Lyubov","family":"Dezhenkova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5803-0523","authenticated-orcid":false,"given":"Svetlana","family":"Solovieva","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7312-4579","authenticated-orcid":false,"given":"Olga","family":"Ostroumova","sequence":"additional","affiliation":[{"name":"Institute of Cytology of Russian Academy of Sciences, 4 Tikhoretsky Ave., St. Petersburg 194064, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1091-1011","authenticated-orcid":false,"given":"Anna","family":"Tevyashova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"},{"name":"School of Science, Constructor University, Campus Ring 1, 28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6595-0811","authenticated-orcid":false,"given":"Andrey","family":"Shchekotikhin","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Douglas, A.P., Stewart, A.G., Halliday, C.L., and Chen, S.C.-A. (2023). Outbreaks of Fungal Infections in Hospitals: Epidemiology, Detection, and Management. J. Fungi, 9.","DOI":"10.3390\/jof9111059"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1016\/S1473-3099(23)00692-8","article-title":"Global Incidence and Mortality of Severe Fungal Disease","volume":"24","author":"Denning","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","unstructured":"WHO (2022). Fungal Priority Pathogens List to Guide Research, Development and Public Health Action, Licence: CC BY-NC-SA 3.0 IGO."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2023-7-1","DOI":"10.7573\/dic.2023-7-1","article-title":"Antifungal Resistance, Combinations and Pipeline: Oh My!","volume":"12","author":"Stover","year":"2023","journal-title":"Drugs Context"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8897","DOI":"10.1021\/acs.jmedchem.1c02227","article-title":"Design, Synthesis, and Structure\u2013Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity","volume":"65","author":"Ma","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1021\/acs.biomac.1c01451","article-title":"Covalent Conjugation of Amphotericin B to Hyaluronic Acid: An Injectable Water-Soluble Conjugate with Reduced Toxicity and Anti-Leishmanial Potential","volume":"23","author":"Gama","year":"2022","journal-title":"Biomacromolecules"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113104","DOI":"10.1016\/j.ejmech.2020.113104","article-title":"Design, Synthesis and Biological Evaluation of a Novel N-Aminoacyl Derivative of Amphotericin B Methyl Ester as an Antifungal Agent","volume":"211","author":"Zhang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"114969","DOI":"10.1016\/j.addr.2023.114969","article-title":"Reviving the Interest in the Versatile Drug Nystatin: A Multitude of Strategies to Increase Its Potential as an Effective and Safe Antifungal Agent","volume":"199","author":"Sousa","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Omelchuk, O., Tevyashova, A., Efimova, S., Grammatikova, N., Bychkova, E., Zatonsky, G., Dezhenkova, L., Savin, N., Solovieva, S., and Ostroumova, O. (2024). A Study on the Effect of Quaternization of Polyene Antibiotics\u2019 Structures on Their Activity, Toxicity, and Impact on Membrane Models. Antibiotics, 13.","DOI":"10.3390\/antibiotics13070608"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1021\/acs.bioconjchem.8b00136","article-title":"Molecular Umbrellas Modulate the Selective Toxicity of Polyene Macrolide Antifungals","volume":"29","author":"Skwarecki","year":"2018","journal-title":"Bioconjug. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Haro-Reyes, T., D\u00edaz-Peralta, L., Galv\u00e1n-Hern\u00e1ndez, A., Rodr\u00edguez-L\u00f3pez, A., Rodr\u00edguez-Fragoso, L., and Ortega-Blake, I. (2022). Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications. Membranes, 12.","DOI":"10.3390\/membranes12070681"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Carolus, H., Pierson, S., Lagrou, K., and Van Dijck, P. (2020). Amphotericin B and Other Polyenes\u2014Discovery, Clinical Use, Mode of Action and Drug Resistance. J. Fungi, 6.","DOI":"10.3390\/jof6040321"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eabo2658","DOI":"10.1126\/sciadv.abo2658","article-title":"Amphotericin B Assembles into Seven-Molecule Ion Channels: An NMR and Molecular Dynamics Study","volume":"8","author":"Umegawa","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/262698a0","article-title":"Single Ionic Channels Induced in Lipid Bilayers by Polyene Antibiotics Amphotericin B and Nystatine","volume":"262","author":"Ermishkin","year":"1976","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nchembio.1496","article-title":"Amphotericin Forms an Extramembranous and Fungicidal Sterol Sponge","volume":"10","author":"Anderson","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1021\/acscentsci.1c00148","article-title":"Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides","volume":"7","author":"Guo","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Delhom, R., Nelson, A., Laux, V., Haertlein, M., Knecht, W., Fragneto, G., and Wacklin-Knecht, H.P. (2020). The Antifungal Mechanism of Amphotericin B Elucidated in Ergosterol and Cholesterol-Containing Membranes Using Neutron Reflectometry. Nanomaterials, 10.","DOI":"10.3390\/nano10122439"},{"key":"ref_18","first-page":"337","article-title":"Our Path to Less Toxic Amphotericins","volume":"27","author":"Endo","year":"2016","journal-title":"Synlett"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00430-014-0343-4","article-title":"Novel Nystatin A1 Derivatives Exhibiting Low Host Cell Toxicity and Antifungal Activity in an in Vitro Model of Oral Candidosis","volume":"203","author":"Salewska","year":"2014","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1021\/acsinfecdis.0c00068","article-title":"Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics","volume":"6","author":"Tevyashova","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1021\/acsmedchemlett.1c00538","article-title":"Water-Soluble Nystatin and Derivative","volume":"13","author":"Amir","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1021\/acs.oprd.6b00211","article-title":"Multigram Scale Synthesis of A21, A New Antibiotic Equally Effective and Less Toxic than Amphotericin B","volume":"20","author":"Regla","year":"2016","journal-title":"Org. Process Res. Dev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Antill\u00f3n, A., de Vries, A.H., Espinosa-Caballero, M., Falc\u00f3n-Gonz\u00e1lez, J.M., Flores Romero, D., Gonz\u00e1lez\u2013Dami\u00e1n, J., Jim\u00e9nez-Montejo, F.E., Le\u00f3n-Buitimea, A., L\u00f3pez-Ortiz, M., and Maga\u00f1a, R. (2016). An Amphotericin B Derivative Equally Potent to Amphotericin B and with Increased Safety. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162171"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nchembio.1821","article-title":"Nontoxic Antimicrobials That Evade Drug Resistance","volume":"11","author":"Davis","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1002\/chem.200701237","article-title":"Synthesis and In Vitro Biological Properties of Novel Cationic Derivatives of Amphotericin B","volume":"14","author":"Paquet","year":"2008","journal-title":"Chem.\u2014Eur. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1021\/ol060353o","article-title":"Significant Improvement of Antifungal Activity of Polyene Macrolides by Bisalkylation of the Mycosamine","volume":"8","author":"Paquet","year":"2006","journal-title":"Org. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"ii11","DOI":"10.1093\/jac\/dkac352","article-title":"Liposomal Amphotericin B-the Present","volume":"77","author":"Maertens","year":"2022","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e405","DOI":"10.1016\/S1473-3099(19)30312-3","article-title":"Global Guideline for the Diagnosis and Management of Mucormycosis: An Initiative of the European Confederation of Medical Mycology in Cooperation with the Mycoses Study Group Education and Research Consortium","volume":"19","author":"Cornely","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1021\/acsinfecdis.2c00237","article-title":"Semisynthetic Amides of Polyene Antibiotic Natamycin","volume":"9","author":"Tevyashova","year":"2023","journal-title":"ACS Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Efimova, S.S., Tevyashova, A.N., Olsufyeva, E.N., Bykov, E.E., and Ostroumova, O.S. (2017). Pore-Forming Activity of New Conjugate Antibiotics Based on Amphotericin B. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188573"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tevyashova, A., Efimova, S., Alexandrov, A., Omelchuk, O., Ghazy, E., Bychkova, E., Zatonsky, G., Grammatikova, N., Dezhenkova, L., and Solovieva, S. (2023). Semisynthetic Amides of Amphotericin B and Nystatin A1: A Comparative Study of In Vitro Activity\/Toxicity Ratio in Relation to Selectivity to Ergosterol Membranes. Antibiotics, 12.","DOI":"10.3390\/antibiotics12010151"},{"key":"ref_32","unstructured":"Zhang, J., Yan, S., Burke, M.D., Maji, A., and Nian, Y. (2021). Hybrid Amide Derivatives of Amphotericin B. (Patent WO2021026520A1)."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1021\/acs.jmedchem.7b01345","article-title":"Extra Sugar on Vancomycin: New Analogues for Combating Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci","volume":"61","author":"Guan","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gong, J., Xiao, M., Wang, H., Kudinha, T., Wang, Y., Zhao, F., Wu, W., He, L., Xu, Y.-C., and Zhang, J. (2018). Genetic Differentiation, Diversity, and Drug Susceptibility of Candida Krusei. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.02717"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"281","DOI":"10.35754\/0234-5730-2020-65-3-281-290","article-title":"Biofilm production among Candida spp. causing invasive candidiasis in patients with hematological malignancies and without hematological malignancies","volume":"65","author":"Malchikova","year":"2020","journal-title":"Russ. J. Hematol. Transfusiology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"559","DOI":"10.7883\/yoken.JJID.2016.574","article-title":"Time-Lapse Tracking of Candida Tropicalis Biofilm Formation and the Antifungal Efficacy of Liposomal Amphotericin B","volume":"70","author":"Kawai","year":"2017","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1021\/acsinfecdis.1c00245","article-title":"Well-Tolerated Amphotericin B Derivatives That Effectively Treat Visceral Leishmaniasis","volume":"7","author":"Morelle","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/bcpt.13592","article-title":"Preclinical Safety Evaluation of Amphotericin A21: A Novel Antifungal","volume":"129","author":"Regla","year":"2021","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.chembiol.2008.08.009","article-title":"Improved Antifungal Polyene Macrolides via Engineering of the Nystatin Biosynthetic Genes in Streptomyces Noursei","volume":"15","author":"Brautaset","year":"2008","journal-title":"Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"S\u00e6b\u00f8, I.P., Bj\u00f8r\u00e5s, M., Franzyk, H., Helgesen, E., and Booth, J.A. (2023). Optimization of the Hemolysis Assay for the Assessment of Cytotoxicity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032914"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/12\/1177\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:46:51Z","timestamp":1760114811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/12\/1177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,4]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["antibiotics13121177"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics13121177","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,4]]}}}