title: Convergent synthesis and cruzain inhibitory activity of novel 2-(N'-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines.
abstract: To search for new cruzain inhibitors, the synthesis of a series of novel 2-(N'-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines in a convergent manner is presented. The cruzain inhibitory activity of some of these compounds was evaluated and a binding model was proposed. All derivatives tested were active and the most significant inhibitory effect (80% at 100 microM) and IC(50) value (85 microM) were obtained from the 2-(N'-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine. Although further structural optimization to improve solubility is necessary, the molecular docking studies suggest that these inhibitors occupy the S2 pocket without irreversible enzyme inactivation, through hydrophobic interactions, thus, indicating a desirable mode of interaction for the design of novel inhibitors.
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil. zanatta@base.ufsm.br
authors.forename: Nilo
authors.initials: N
authors.lastname: Zanatta
authors.forename: Simone S
authors.initials: SS
authors.lastname: Amaral
authors.forename: Josiane M
authors.initials: JM
authors.lastname: Dos Santos
authors.forename: Débora L
authors.initials: DL
authors.lastname: de Mello
authors.forename: Liana da S
authors.initials: Lda S
authors.lastname: Fernandes
authors.forename: Helio G
authors.initials: HG
authors.lastname: Bonacorso
authors.forename: Marcos A P
authors.initials: MA
authors.lastname: Martins
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Deise M
authors.initials: DM
authors.lastname: Borchhardt
mesh_terms: D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C534172:2-(N'-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine; D004791:Enzyme Inhibitors; D006834:Hydrazines; D015800:Protozoan Proteins; D011743:Pyrimidines; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi