Additive In Vitro Antiplasmodial Effect of N-Alkyl and N-Benzyl-1,10-Phenanthroline Derivatives and Cysteine Protease Inhibitor E64

Abstract

Potential new targets for antimalarial chemotherapy include parasite proteases, which are required for several cellular functions during the Plasmodium falciparum life cycle. Four new derivatives of N-alkyl and N-benzyl-1,10-phenanthroline have been synthesized. Those are (1)-N-methyl-1,10-phenanthrolinium sulfate, (1)-N-ethyl-1,10-phenanthrolinium sulfate, (1)-N-benzyl-1,10-phenanthrolinium chloride, and (1)-N-benzyl-1,10-phenanthrolinium iodide. Those compounds had potential antiplasmodial activity with IC50 values from 260.42 to 465.38 nM. Cysteine proteinase inhibitor E64 was used to investigate the mechanism of action of N-alkyl and N-benzyl-1,10-phenanthroline derivatives. A modified fixed-ratio isobologram method was used to study the in vitro interactions between the new compounds with either E64 or chloroquine. The interaction between N-alkyl and N-benzyl-1,10-phenanthroline derivatives and E64 was additive as well as their interactions with chloroquine were also additive. Antimalarial mechanism of chloroquine is mainly on the inhibition of hemozoin formation. As the interaction of chloroquine and E64 was additive, the results indicated that these new compounds had a mechanism of action by inhibiting Plasmodium proteases.

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (2): Plasmodium spp.

“…Meanwhile, it showed high selectivity on P. falciparum proteases with very high IC 50 value on Vero cells [103] . In addition, in vivo investigation showed clearance of parasitemia 4 days after treatment of P. berghei-infected mice [104] . To identify the mechanism of action, a third study was conducted by comparing the in vitro and in vivo results with those obtained using chloroquine and E-64.…”

N-{4-[(5-Methylisoxazol-3-yl)sulfamoyl]phenyl}benzamide

“…The N-alkylated moiety is present in many natural products as well as in drugs, see: Wijayanti et al (2010). For the synthesis and the biological properties of amide derivatives of sulfonamide-type drugs, see: Hussain (2009).…”

SYNERGY OF A NOVEL ANTIBIOTIC ADJUVANT ENTITY AGAINST MULTI DRUG RESISTANT <I>ENTEROBACTERIACEAE</I>

“…Effect of NAA on ∑ FIC of double combinations, ceftriaxone plus sulbactam was also conduced using checkerboard method (Wijayanti et al, 2010) in the absence and presence of increasing concentration of disodium edetate in all positive controls as well as clinical isolates.…”

“…In vitro drug interaction was determined by the checkerboard method as described by Wijayanti et al (2010) and results were analyzed with the FIC indices. For each ratio, a two-dimensional checkerboard with twofold dilutions was used for the study.…”