EnglishFolate analogue inhibitors of Leishmania major pteridine reductase (PTR1) are potential anti-parasitic drug candidates for combined therapy with dihydrofolate reductase (DHFR) inhibitors. To identify new molecules with specificity for PTR1, we carried out a virtual screening of the Available Chemicals Directory (ACD) database to select compounds that could interact with L. major PTR1 but not with human DHFR. Through two rounds of drug discovery, we successfully identified eighteen drug-like molecules with low micromolar affinities and high in vitro specificity profiles. Their efficacy against Leishmania species was studied in cultured cells of the promastigote stage, using the compounds both alone and in combination with 1 (pyrimethamine; 5-(4-Chlorophenyl)-6-ethylpyrimidine-2,4-diamine). Six compounds showed efficacy only in combination. In toxicity tests against human fibroblasts, several compounds showed low toxicity. One compound, 5c (riluzole; 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine), a known drug approved for CNS pathologies was active in combination and is suitable for early pre-clinical evaluation of its potential for label extension as a PTR1 inhibitor and anti-parasitic drug candidate.
| Data di pubblicazione: | 2011 |
| Titolo: | Virtual screening identification of nonfolate compounds, including a CNS drug, as antiparasitic agents inhibiting pteridine reductase |
| Autore/i: | Ferrari, S.; Morandi, F.; Motiejunas, D.; Nerini, E.; Henrich, S.; Luciani, R.; Venturelli, A.; Lazzari, S.; Calò, S.; Gupta, S.; Hannaert, V.; Michels, P.A.M.; Wade, R.C.; Costi, M.P. |
| Autore/i UNIMORE: | |
| Digital Object Identifier (DOI): | 10.1021/jm1010572 |
| Rivista: | |
| Volume: | 54 |
| Fascicolo: | 1 |
| Pagina iniziale: | 211 |
| Pagina finale: | 221 |
| Codice identificativo ISI: | WOS:000285818000016 |
| Codice identificativo Scopus: | 2-s2.0-78651093844 |
| Codice identificativo Pubmed: | 21126022 |
| Citazione: | Virtual screening identification of nonfolate compounds, including a CNS drug, as antiparasitic agents inhibiting pteridine reductase / Ferrari, S.; Morandi, F.; Motiejunas, D.; Nerini, E.; Henrich, S.; Luciani, R.; Venturelli, A.; Lazzari, S.; Calò, S.; Gupta, S.; Hannaert, V.; Michels, P.A.M.; Wade, R.C.; Costi, M.P.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 54:1(2011), pp. 211-221. |
| Tipologia | Articolo su rivista |
File in questo prodotto:
| File | Descrizione | Tipologia | |
|---|---|---|---|
| jm1010572_2011.pdf | file pdf | Versione editoriale | Administrator Richiedi una copia |
I documenti presenti in Iris Unimore sono rilasciati con licenza Creative Commons Attribuzione - Non commerciale - Non opere derivate 3.0 Italia, salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris
Copyright © 2019