Virtual Screening Identification of Nonfolate Compounds, Including a CNS Drug, as Antiparasitic Agents Inhibiting Pteridine Reductase

• Published in: Journal of medicinal chemistry 2011-01, Vol.54 (1), p.211-221
• Main Authors: Ferrari, Stefania, Morandi, Federica, Motiejunas, Domantas, Nerini, Erika, Henrich, Stefan, Luciani, Rosaria, Venturelli, Alberto, Lazzari, Sandra, Calò, Samuele, Gupta, Shreedhara, Hannaert, Veronique, Michels, Paul A. M, Wade, Rebecca C, Costi, M. Paola
• Format: Article
• Language: English
• Subjects: Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Central Nervous System Agents - chemical synthesis; Central Nervous System Agents - chemistry; Central Nervous System Agents - pharmacology; Drug Design; Drug Synergism; Fibroblasts - cytology; Fibroblasts - drug effects; Humans; Leishmania - drug effects; Leishmania - enzymology; Models, Molecular; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - chemistry; Parasitic Sensitivity Tests; Pyrimethamine - analogs & derivatives; Pyrimethamine - chemical synthesis; Pyrimethamine - chemistry; Pyrimethamine - pharmacology; Quantitative Structure-Activity Relationship; Riluzole - analogs & derivatives; Riluzole - chemical synthesis; Riluzole - chemistry; Riluzole - pharmacology; Small Molecule Libraries; Tetrahydrofolate Dehydrogenase - chemistry; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1010572

Folate analogue inhibitors of Leishmania major pteridine reductase (PTR1) are potential antiparasitic 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 preclinical evaluation of its potential for label extension as a PTR1 inhibitor and antiparasitic drug candidate.