Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Linciano, P (Author) Other; Cullia, G (Author) Other; Borsari, C (Author) Other; Santucci, M (Author) Other; Ferrari, S (Author) Other; Witt, G (Author) Other; Gul, S (Author) Other; Kuzikov, M (Author) Other; Ellinger, B (Author) Other; Santarem, N (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Conti, P (Author) Other; Bolognesi, ML (Author) Other; Roberti, M (Author) Other; Prati, F (Author) Other; Bartoccini, F (Author) Other; Retini, M (Author) Other; Piersanti, G (Author) Other; Cavalli, A (Author) Other; Goldoni, L (Author) Other; Bertozzi, SM (Author) Other; Bertozzi, F (Author) Other; Brambilla, E (Author) Other; Rizzo, V (Author) Other; Piomelli, D (Author) Other; Pinto, A (Author) Other; Bandiera, T (Author) Other; Costi, MP (Author) Other

Journal

Title: European Journal of Medicinal Chemistry

Vol. 189

ISSN: 0223-5234

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 1 Citation

Other information

Authenticus ID: P-00R-NBP

DOI: 10.1016/j.ejmech.2020.112047

Abstract (EN): The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTRI. Nine compounds were active against parasitic PTRI and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16