title: Synthesis, in vitro evaluation, and SAR studies of a potential antichagasic 1H-pyrazolo[3,4-b]pyridine series.
abstract: The development of new drugs against Trypanosoma cruzi is still required since the only two drugs currently used cause severe side effects. In this work we described the synthesis, the in vitro biological evaluation, and the SAR results of 1H-pyrazolo[3,4-b]pyridine derivatives, a new antichagasic agent series. The presence of fluorine, hydroxyl or nitro group at Y position resulted in at least one or two promising compounds in each set of derivatives (6f, 6g, 6i, 6l, and 6m). The SAR study showed that trypanocidal activity observed depends on both geometric and stereoelectronic parameters (MEP and frontier molecular orbitals HOMO and LUMO). We also used the Osiris program for calculating and comparing the fragment based druglikeness of the most active derivative (6g) (IC(50)=1.9microg/mL), the inactive compound (6o), and the current toxic antichagasic drugs (nifurtimox and benznidazole). Interestingly 6g presented a potential druglikeness higher than nifurtimox and benznidazole while 6o presented the lowest value among them.
authors.affiliation: Universidade Federal Fluminense (UFF), Laboratório de Química Medicinal (LQMed), Faculdade de Farmácia, Rua Mário Viana, 523, Santa Rosa, 24241-000, Niterói, RJ, Brazil. ldias@vm.uff.br
authors.forename: Luiza R S
authors.initials: LR
authors.lastname: Dias
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Santos
authors.forename: Sérgio de
authors.initials: Sd
authors.lastname: Albuquerque
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Alessandra M T
authors.initials: AM
authors.lastname: de Souza
authors.forename: Antônio C C
authors.initials: AC
authors.lastname: Freitas
authors.forename: Maria A V
authors.initials: MA
authors.lastname: DiVaio
authors.forename: Lucio M
authors.initials: LM
authors.lastname: Cabral
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: C478081:1H-pyrazolo(3,4-b)pyridine; D011720:Pyrazoles; D011725:Pyridines; D014344:Trypanocidal Agents