Ruslin Hadanu

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

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.

QSAR Studies of Nitrobenzothiazole Derivatives as Antimalarial Agents

Quantitative Structure and Activity Relationship (QSAR) analyses were carried out for a series of 13 nitrobenzothiazole derivatives as antimalarial compounds to find out the structural relationship of their antimalarial activities against the W2 Plasmodium falciparum strain. The electronic descriptors have been determined using the atomic net charges (q), dipole moment (μ), E LUMO , E HOMO, polarizability (α) and Log P. In addition , the descriptors were calculated through HyperChem for Windows 8.0 using the PM3 semi-empirical method. The antimalarial activities (IC 50 ) were taken from literature [1]. Furthermore, the QSAR model was determined by multiple linear regression (MLR) approach, giving equation model of QSAR: Log IC 50 = 41.483 + 54.812 (qC2) – 50.058 (qS3) + 416.766 (qC4) + 440.734 ( qC5) – 754.213 (qC7) – 73.721 (qC8) + 246.715 (qC9) + 0.551 ( μ ) – 13.269 (E HOMO ) – 3.404 (E LUMO ) + 0.042 ( α ) + 0.107 (Log P). The most statistically significant QSAR model with correlation coefficients n = 13, (r) = 1.00 , (r 2 ) = 1.00 , SE = 0 , and PRESS = 3.40 were developed by MLR. Based on the model of the above QSAR equation 43 new nitrobenzothiazole derivatives were modeled and 24 of these compounds showed high antimalarial activity. It is recommended that these are synthesized for further investigation 4 new compounds (45, 49, 52 and 55) show equivalent activity to that achieved with chloroquine antimalarial drugs .