RESUMEN
Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC50 values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Anisoles/farmacología , Antimaláricos/farmacología , Cicloheptanos/farmacología , Inhibidores Enzimáticos/farmacología , Plasmodium falciparum/efectos de los fármacos , Aminopeptidasas/metabolismo , Anisoles/síntesis química , Anisoles/química , Antimaláricos/síntesis química , Antimaláricos/química , Cicloheptanos/síntesis química , Cicloheptanos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/enzimología , Relación Estructura-ActividadRESUMEN
The synthesis of racemic substituted 7-amino-5,7,8,9-tetrahydrobenzocyclohepten-6-one hydrochlorides was optimized to enhance reproducibility and increase the overall yield. In order to investigate their specificity, series of enzyme inhibition assays were carried out against a diversity of proteases, covering representative members of aspartic, cysteine, metallo and serine endopeptidases and including eight members of the monometallic M1 family of aminopeptidases as well as two members of the bimetallic M17 and M28 aminopeptidase families. This aminobenzosuberone scaffold indeed demonstrated selective inhibition of M1 aminopeptidases to the exclusion of other tested protease families; it was particularly potent against mammalian APN and its bacterial/parasitic orthologues EcPepN and PfAM1.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Aminopeptidasas/química , Cumarinas/química , Cumarinas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
In order to probe the S1 and S1' mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with Ki values in the nanomolar range.
