Convergent synthesis and cruzain inhibitory activity of novel 2-(N'-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines.
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.
Zanatta
Nilo
N
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
Amaral
Simone S
SS
Dos Santos
Josiane M
JM
de Mello
Débora L
DL
Fernandes
Liana da S
Lda S
Bonacorso
Helio G
HG
Martins
Marcos A P
MA
Andricopulo
Adriano D
AD
Borchhardt
Deise M
DM
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
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