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

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


European journal of medicinal chemistry 189 (2020), Art. 112047
ISSN: 0009-4374
ISSN: 0223-5234
ISSN: 1768-3254
Fraunhofer IME ()

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 LmPTR1. Nine compounds were active against parasitic PTR1 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.