%0 Generic
%A Wang, Yulin
%D 2009
%F heidok:10018
%K Malaria , drug development
%R 10.11588/heidok.00010018
%T Parasitological Evaluation of SC81458 and SC83288, a Novel Class of Drugs against Plasmodium Falciparum
%U https://archiv.ub.uni-heidelberg.de/volltextserver/10018/
%X Drug resistance is one of the most important reasons for the increase in rates of malarial morbidity and mortality. However, even now, there is no effective anti-malarial vaccine available. Presently, development of anti-malarials acting by novel pathways is the best option to control this disease. The biphenyl urea compound, the lead compound in this study, is a new structural class of potent anti-malarial agents. We obtained two subclasses of active compounds, termed “sulfnamidomethylen” and “diarylsulfone” during the optimisation to the lead compound with computer assistance. The dose-response curves of the two subclasses of compounds indicated that they exert their anti-malarial action by different mechanisms. The curve of the diarylsulfone showed a biphasic property, while the curve of the sulfnamidomethylen is single phasic and very steep.  Then we optimized the sulfnamidomethylen compound based on SAR analysis for more potential anti-malarial activity. SC81458 was the first candidate compound we obtained, which showed an IC50-value of 5.5 nM, and IC99-value of 15.0 nM against Dd2. Then parasitological evaluation showed that SC81458 exhibits potent in vitro activity against a wide range of Plasmodium falciparum strains, with the IC50-values at the magnitude of nano molar. The study of the property of SC81458 against drug resistance selection indicated that there were no Dd2 parasites recovered within eight weeks when 108 parasites are exposed to SC81458 at the concentration of 100 nM continuously. The stage-specific susceptibility and growth inhibition time course study of SC81458 showed that the trophozoites and schizonts are more sensitive to SC81458, showing a 6 hrs IC50-value of 36.9 nM and 53.7 nM, respectively, while the rings exhibited a 6 hrs IC50-value of 5124.3 nM. SC81458 can totally kill the trophozoites within 30 minutes at a concentration of less than 1 µM, a non-toxic concentration to mammalian cells. Furthermore, the in vivo test in the humanized mouse model showed that SC81458 exhibits an excellent in vivo activity against both drug sensitive (3D7) and resistant (W2) P. falciparum strains. However, SC81458 showed poor bioavailability. Then SC81458 was further optimized for better bioavailability. The backup compound SC83288 was obtained, which showed better bioavailability (10%) and excellent anti-P. falciparum activity (slightly better than SC81458). The parasitological evaluation of SC83288 indicated that SC83288 exhibits the same anti-Plasmodium property as SC81458 does, which suggested that the two compounds should exert their action by the same mechanism.