{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:04:34Z","timestamp":1792037074467,"version":"4.4.0"},"reference-count":65,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["22-24384S"],"award-info":[{"award-number":["22-24384S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["LX22NPO510"],"award-info":[{"award-number":["LX22NPO510"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["DZRO-FVZ22-ZHN II"],"award-info":[{"award-number":["DZRO-FVZ22-ZHN II"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Next Generation EU","award":["22-24384S"],"award-info":[{"award-number":["22-24384S"]}]},{"name":"Next Generation EU","award":["LX22NPO510"],"award-info":[{"award-number":["LX22NPO510"]}]},{"name":"Next Generation EU","award":["DZRO-FVZ22-ZHN II"],"award-info":[{"award-number":["DZRO-FVZ22-ZHN II"]}]},{"name":"Ministry of Defence of the Czech Republic\u2014DRO of the University of Defence, Faculty of Military Health Sciences Hradec Kralove, Czech Republic\u2014Medical issues of WMD II","award":["22-24384S"],"award-info":[{"award-number":["22-24384S"]}]},{"name":"Ministry of Defence of the Czech Republic\u2014DRO of the University of Defence, Faculty of Military Health Sciences Hradec Kralove, Czech Republic\u2014Medical issues of WMD II","award":["LX22NPO510"],"award-info":[{"award-number":["LX22NPO510"]}]},{"name":"Ministry of Defence of the Czech Republic\u2014DRO of the University of Defence, Faculty of Military Health Sciences Hradec Kralove, Czech Republic\u2014Medical issues of WMD II","award":["DZRO-FVZ22-ZHN II"],"award-info":[{"award-number":["DZRO-FVZ22-ZHN II"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds\u2019 effects on cholinesterases and monoamine oxidase A\/B (MAO-A\/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.<\/jats:p>","DOI":"10.3390\/ijms24119124","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T08:14:28Z","timestamp":1684829668000},"page":"9124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Structure-Guided Design of N-Methylpropargylamino-Quinazoline Derivatives as Multipotent Agents for the Treatment of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"Barbora","family":"Svobodova","sequence":"first","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenka","family":"Pulkrabkova","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawid","family":"Panek","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Misiachna","sequence":"additional","affiliation":[{"name":"Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"},{"name":"Department of Physiology, Faculty of Science, Charles University in Prague, Albertov 6, 128 43 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marharyta","family":"Kolcheva","sequence":"additional","affiliation":[{"name":"Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Andrys","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Handl","sequence":"additional","affiliation":[{"name":"Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3713-2467","authenticated-orcid":false,"given":"Jan","family":"Capek","sequence":"additional","affiliation":[{"name":"Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlina","family":"Nyvltova","sequence":"additional","affiliation":[{"name":"Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Rousar","sequence":"additional","affiliation":[{"name":"Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Prchal","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vendula","family":"Hepnarova","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Hrabinova","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6693-6061","authenticated-orcid":false,"given":"Lubica","family":"Muckova","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Tosnerova","sequence":"additional","affiliation":[{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Karabanovich","sequence":"additional","affiliation":[{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5146-6850","authenticated-orcid":false,"given":"Vladimir","family":"Finger","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ondrej","family":"Soukup","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Horak","sequence":"additional","affiliation":[{"name":"Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6977-7596","authenticated-orcid":false,"given":"Jan","family":"Korabecny","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1056\/NEJMra0909142","article-title":"Alzheimer\u2019s Disease","volume":"362","author":"Querfurth","year":"2010","journal-title":"N. 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