Yongyuth YuthavongTirayut VilaivanNetnapa ChareonsethakulSumalee KamchonwongpaisanWorachart SirawarapornRachel QuarrellGordon LoweThailand National Center for Genetic Engineering and BiotechnologyChulalongkorn UniversityMahidol UniversityUniversity of Oxford2018-09-072018-09-072000-07-13Journal of Medicinal Chemistry. Vol.43, No.14 (2000), 2738-2744002226232-s2.0-0034644146https://repository.li.mahidol.ac.th/handle/20.500.14594/25862The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dihydrofolate reductase (DHFR) is a key mutant responsible for cycloguanil-resistant 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 prepared, 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 decrease cycloguanil binding further through the effect on the orientation of the p-chlorophenyl group. By moving the p-chloro-substituent to the m-position in the chlorophenyl group, the activity against the A16V+S108T mutant enzyme 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 inhibitory activity similar to that of cycloguanil against the wild-type DHFR and about 120-fold more effective than cycloguanil against the A16V+S108T mutant 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 cycloguanil.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyPharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1021/jm0009181