Pöhner, I.I.PöhnerQuotadamo, A.A.QuotadamoPanecka-Hofman, J.J.Panecka-HofmanLuciani, R.R.LucianiSantucci, M.M.SantucciLinciano, P.P.LincianoLandi, G.G.LandiPisa, F. diF. diPisaDello Iacono, L.L.Dello IaconoPozzi, C.C.PozziMangani, S.S.ManganiGul, SherazSherazGulWitt, GesaGesaWittEllinger, BernhardBernhardEllingerKuzikov, MariaMariaKuzikovSantarem, N.N.SantaremCordeiro-Da-Silva, A.A.Cordeiro-Da-SilvaCosti, M.P.M.P.CostiVenturelli, A.A.VenturelliWade, R.C.R.C.Wade2022-12-082022-12-082022https://publica.fraunhofer.de/handle/publica/42974610.1021/acs.jmedchem.2c002322-s2.0-8513282694835675511The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.enjournal article