Development of a lead inhibitor for the A16V+S108T mutant of dihydrofolatereductase from the cycloguanil-resistant strain (T9/94) of Plasmodium falciparum
Y. Yuthavong et al., Development of a lead inhibitor for the A16V+S108T mutant of dihydrofolatereductase from the cycloguanil-resistant strain (T9/94) of Plasmodium falciparum, J MED CHEM, 43(14), 2000, pp. 2738-2744
The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dih
ydrofolate reductase (DHFR) is a key mutant responsible for cycloguanil-res
istant malaria due to steric interaction between Val-16 and one of the C-2
methyl groups of cycloguanil. 4,6-Diamino-1,2-dihydrotriazines have been pr
epared, in which both methyl groups of cycloguanil are replaced by H or by
H and an alkyl or phenyl group, and their inhibition constants against wild
-type and mutant DHFR determined. The S108T mutation is considered to decre
ase cycloguanil binding further through the effect on the orientation of th
e p-chlorophenyl group. By moving the p-chloro-substituent to the m-positio
n in the chlorophenyl group, the activity against the A16V+S108T mutant enz
yme is improved, and this effect is reinforced by the p-chloro substituent
in the 3,4-dichlorophenyl group. A lead compound has been found with inhibi
tory activity similar to that of cycloguanil against the wild-type DHFR and
about 120-fold more effective than cycloguanil against the A16V+S108T muta
nt enzyme. The activity of this compound against P. falciparum clone (T9/94
RC17) which harbors the A16V+S108T DHFR is about 85-fold greater than cycl
oguanil.