{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:24:03Z","timestamp":1777861443730,"version":"3.51.4"},"reference-count":72,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and A\u03b242 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the A\u03b242 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids 16 and 17, with similar or even higher A\u03b242 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies.<\/jats:p>","DOI":"10.3390\/biom16040593","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T14:05:36Z","timestamp":1776348336000},"page":"593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Biological Profiling of New 1,2,3,4-Tetrahydrobenzo[h]naphthyridine-Based Hybrids as Dual Inhibitors of \u03b2-Amyloid and Tau Aggregation with Anticholinesterase Activity"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0958-8421","authenticated-orcid":false,"given":"Aldrick B.","family":"Verano","sequence":"first","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain"},{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), Av. Diagonal 643, E-08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1837-2051","authenticated-orcid":false,"given":"Anna","family":"Sampietro","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain"},{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), Av. Diagonal 643, E-08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5092-3538","authenticated-orcid":false,"given":"Ana","family":"Mallo-Abreu","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain"},{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), Av. Diagonal 643, E-08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0289-6763","authenticated-orcid":false,"given":"Rosaria","family":"Spagnuolo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5801-1704","authenticated-orcid":false,"given":"Bel\u00e9n","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2890-3856","authenticated-orcid":false,"given":"Manuela","family":"Bartolini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Isabel","family":"Loza","sequence":"additional","affiliation":[{"name":"BioFarma Research Group, Centro Singular de Investigaci\u00f3n en Medicina Molecular y Enfermedades Cr\u00f3nicas (CIMUS), Departamento de Farmacolog\u00eda, Farmacia y Tecnolog\u00eda Farmac\u00e9utica, Universidade de Santiago de Compostela, Av. de Barcelona s\/n, E-15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5523-1979","authenticated-orcid":false,"given":"Jos\u00e9","family":"Brea","sequence":"additional","affiliation":[{"name":"BioFarma Research Group, Centro Singular de Investigaci\u00f3n en Medicina Molecular y Enfermedades Cr\u00f3nicas (CIMUS), Departamento de Farmacolog\u00eda, Farmacia y Tecnolog\u00eda Farmac\u00e9utica, Universidade de Santiago de Compostela, Av. de Barcelona s\/n, E-15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Ju\u00e1rez-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain"},{"name":"Institut de Qu\u00edmica Te\u00f2rica i Computacional (IQTC), Facultat de Qu\u00edmica i F\u00edsica, Universitat de Barcelona, C. Mart\u00ed i Franqu\u00e9s 1, E-08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3894-2362","authenticated-orcid":false,"given":"Raimon","family":"Sabate","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), Av. Diagonal 643, E-08028 Barcelona, Spain"},{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1702-0369","authenticated-orcid":false,"given":"Carles","family":"Galdeano","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), Av. Diagonal 643, E-08028 Barcelona, Spain"},{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8140-8555","authenticated-orcid":false,"given":"Diego","family":"Mu\u00f1oz-Torrero","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. 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