Conjugation of N-acylhydrazone and 1,2,4-oxadiazole leads to the identification of active antimalarial agents.

Malaria, caused by several Plasmodium species, is the major life-threatening parasitic infection worldwide. Due to the parasite resistance to quinoline based drugs, the search for antimalarial agents is necessary. Here, we report the structural design, synthesis and antiparasitic evaluation of two novel series of 1,2,4-oxadiazoles in conjugation to N-acylhydrazones, both groups recognized as privileged structures, as well as the studies on the antimalarial activity of 16 previous described analogues. By varying substituents attached to the phenyl ring, it was possible to retain, enhance or increase the antiparasitic activity in comparison to the nonsubstituted derivatives. Replacement of substituted aryl rings by ferrocenyl and cinnamyl moieties attached in the N-acylhydrazone ablated the antiparasitic response, evidencing the structural features associated with the activity. Active compounds exhibited in vitro potency similar to mefloquine, but not all inhibited ß-hematin formation. Additionally, the active compounds displayed low cytotoxicity in HepG2 cells and did not cause hemolysis in uninfected erythrocytes. In Plasmodium berghei-infected mice, the compounds reduced parasitemia but exhibited limited efficacy in increasing mice survival when compared to chloroquine, suggesting that pharmacological improvement is still necessary.

Atividade antimalárica, espectro e mecanismo de ação de compostos de rutênio e platina com a cloroquina / Antimalarial activity, spectrum and mechanism of action of ruthenium and platinum compounds with chloroquine

INTRODUÇÃO: A malária é uma das doenças infecciosas de maior incidência e que mais leva a óbito no mundo. Os medicamentos disponíveis são capazes de combater o parasita no ciclo intraeritrocítico, no entanto há cepas resistentes ao tratamento com quinolinas e temisininas. Além disso, os medicamentos em uso clínico não eliminam as formas sexuadas do parasita, responsáveis pela transmissão, nem os hipnozoítos, fase hepática latente causadora das recidivas da doença. Em virtude disso, é necessário identificar novos fármacos antimaláricos. Dentre as classes de moléculas com potencial terapêutico antimalárico, os complexos com metais de transição se destacam como possíveis candidatos...

Synthesis of 4'-(2-ferrocenyl)-2,2':6'2''-terpyridine: characterization and antiprotozoal activity of Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes.

A terpyridine ligand Fctpy was reacted with divalent metals (Cu, Co, Mn, Ni and Zn), yielding five complexes of general formula [Metal(Fctpy)2][PF6]2. The structure of Fctpy was determined by single crystal X-ray diffraction studies. The complexes characterized using various spectroscopic techniques suggested an octahedral geometry around the central metal ion. These complexes were screened for their antiamoebic, trypanocidal and antimalarial activities. It was found that, complexes 2 and 3 showed better IC50 values than metronidazole against HM1:IMSS strain of Entamoeba histolytica. A substantial parasitic inhibition was not observed for the trypanocidal activity. However, for the erythrocytic stage of W2 strain of Plasmodium falciparum, the complexes inhibited ß-hematin formation. At the concentration of 10 µg/mL, these complexes did not display toxicity.

Design, synthesis and biological evaluation of 3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propionic acid hydrazones as antiprotozoal agents.

N-Acylhydrazones derived from 7-chloro-4-piperazin-1-yl-quinoline were synthesized and biologically evaluated for blood-stage of Plasmodium falciparum and Entamoeba histolytica trophozoites. N-Acylhydrazone F12 was found to inhibit the P. falciparum growth as well as its life cycle with good selectivity, which was achieved by inhibiting hematin formation. Compound F24 showed better IC50 value than the amoebicidal drug metronidazole.