title: Discovery of new uncompetitive inhibitors of glucose-6-phosphate dehydrogenase.
abstract: The enzyme glucose-6-phosphate dehydrogenase (G6PDH) catalyzes the first step of the oxidative branch of the pentose phosphate pathway, which provides cells with NADPH, an essential cofactor for many biosynthetic pathways and antioxidizing enzymes. In Trypanosoma cruzi, the G6PDH has being pursued as a relevant target for the development of new drugs against Chagas disease. At present, the best characterized inhibitors of T. cruzi G6PDH are steroidal halogenated compounds derivatives from the mammalian hormone precursor dehydroepiandrosterone, which indeed are also good inhibitors of the human homologue enzyme. The lack of target selectivity might result in hemolytic side effects due to partial inhibition of human G6PDH in red blood cells. Moreover, the treatment of Chagas patients with steroidal drugs might also cause undesired androgenic side effects. Aiming to identify of new chemical classes of T. cruzi G6PDH inhibitors, we performed a target-based high-throughput screen campaign against a commercial library of diverse compounds. Novel TcG6PDH inhibitors were identified among thienopyrimidine and quinazolinone derivatives. Preliminary structure activity relationships for the identified hits are presented, including structural features that contribute for selectivity toward the parasite enzyme. Our results indicate that quinazolinones are promising hits that should be considered for further optimization.
authors.affiliation: Institute of Biology, University of Campinas, Campinas, SP, Brazil Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, SP, Brazil.
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Mercaldi
authors.affiliation: Institute of Biology, University of Campinas, Campinas, SP, Brazil Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, SP, Brazil.
authors.forename: Americo T
authors.initials: AT
authors.lastname: Ranzani
authors.affiliation: Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, SP, Brazil artur.cordeiro@lnbio.cnpem.br.
authors.forename: Artur T
authors.initials: AT
authors.lastname: Cordeiro
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D052999:Quinazolinones; D014344:Trypanocidal Agents; C476003:thienopyrimidine; D005954:Glucosephosphate Dehydrogenase
keywords: Chagas disease; high-throughput screening; pentose phosphate pathway; quinazolinones; thienopyrimidines