{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T09:35:35Z","timestamp":1782293735331,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008725","name":"Agencia Nacional de Investigaci\u00f3n e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["Fondo Mar\u00eda Vin\u0303as FMV_1_2014_1_103488)"],"award-info":[{"award-number":["Fondo Mar\u00eda Vin\u0303as FMV_1_2014_1_103488)"]}],"id":[{"id":"10.13039\/100008725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Comisio\u0301n Sectorial de Investigaci\u00f3n Cient\u00edfica (Universidad de la Republica)","award":["CSIC-Grupos I+D 1063"],"award-info":[{"award-number":["CSIC-Grupos I+D 1063"]}]},{"name":"Programa de Desarrollo de las Ciencias B\u00e1sicas","award":["PEDECIBA"],"award-info":[{"award-number":["PEDECIBA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N-indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels\u2013Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC50 1\u20138 \u03bcM) and two of them (compounds 6 and 14) showed a good selectivity index.<\/jats:p>","DOI":"10.3390\/molecules27030829","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T04:49:51Z","timestamp":1643258991000},"page":"829","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Iboga Inspired N-Indolylethyl-Substituted Isoquinuclidines as a Bioactive Scaffold: Chemoenzymatic Synthesis and Characterization as GDNF Releasers and Antitrypanosoma Agents"],"prefix":"10.3390","volume":"27","author":[{"given":"Mariana","family":"Pazos","sequence":"first","affiliation":[{"name":"Laboratorio de S\u00edntesis Org\u00e1nica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, General Flores 2124, Montevideo 11800, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Dibello","sequence":"additional","affiliation":[{"name":"Laboratorio de S\u00edntesis Org\u00e1nica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, General Flores 2124, Montevideo 11800, Uruguay"},{"name":"Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Manuel","family":"Mesa","sequence":"additional","affiliation":[{"name":"Laboratorio de S\u00edntesis Org\u00e1nica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, General Flores 2124, Montevideo 11800, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalibor","family":"Sames","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Columbia University, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5000-1333","authenticated-orcid":false,"given":"Marcelo Alberto","family":"Comini","sequence":"additional","affiliation":[{"name":"Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Seoane","sequence":"additional","affiliation":[{"name":"Laboratorio de S\u00edntesis Org\u00e1nica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, General Flores 2124, Montevideo 11800, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6053-3162","authenticated-orcid":false,"given":"Ignacio","family":"Carrera","sequence":"additional","affiliation":[{"name":"Laboratorio de S\u00edntesis Org\u00e1nica, Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de la Rep\u00fablica, General Flores 2124, Montevideo 11800, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1039\/D0NP00033G","article-title":"The iboga enigma: The chemistry and neuropharmacology of iboga alkaloids and related analogs","volume":"38","author":"Iyer","year":"2021","journal-title":"Nat. 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