RESUMEN
A series of novel 8-aminoquinolines (8-AQs) with an aminoxyalkyl side chain were synthesized and evaluated for in vitro antiplasmodial properties against asexual blood stages, liver stages, and sexual stages of Plasmodium falciparum. 8-AQs bearing 2-alkoxy and 5-phenoxy substituents on the quinoline ring system were found to be the most promising compounds under study, exhibiting potent blood schizontocidal and moderate tissue schizontocidal in vitro activity.
Asunto(s)
Aminoquinolinas/química , Antimaláricos/química , Plasmodium falciparum/crecimiento & desarrollo , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Antimaláricos/síntesis química , Antimaláricos/farmacología , Supervivencia Celular/efectos de los fármacos , Células Hep G2 , Humanos , Estadios del Ciclo de Vida/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Structural optimization of 3-hydroxy-N'-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of Plasmodium falciparum, excellent parasite selectivity, and nanomolar activity against the earliest forms of gametocyte development. Particularly, derivatives with a 1,3-dihalo-6-trifluoromethylphenanthrene moiety showed outstanding in vivo properties and demonstrated in part curative activity in the Plasmodium berghei mouse model when administered perorally.
Asunto(s)
Amidas/química , Antimaláricos/química , Hidrazonas/química , Malaria/tratamiento farmacológico , Fenantrenos/química , Plasmodium berghei/efectos de los fármacos , Amidas/síntesis química , Amidas/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacología , Células Hep G2 , Humanos , Hidrazonas/síntesis química , Hidrazonas/farmacología , Malaria/parasitología , Ratones , Fenantrenos/síntesis química , Fenantrenos/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
3-Hydroxy-N'-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum with nanomolar IC50 values in the range of 8-28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a P. berghei malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a >1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound 29 displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of P. falciparum in vitro.
