Triazines, Quinazolines and Related Dihydrofolate Reductase Inhibitors

Mamalis, P.; Werbel, Leslie M.

doi:10.1007/978-3-642-69254-3_13

Cited by 4 publications

(1 citation statement)

References 102 publications

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“…Furthermore, the linker oxygen next to phenyl may be changed to sulfur ( 8x , 8y , and 8aa ) without appreciable loss of activity. When the comparative in vivo data reported in the literature for the WR-99210 related triazines were corroborated, it was found that shortening the linker between the phenyl ring and the biguanide group ( 8bb , 8 cc , and 8dd ) degrades activity.…”

Section: In Vitro Activitymentioning

confidence: 91%

Phenoxypropoxybiguanides, Prodrugs of DHFR−Inhibiting Diaminotriazine Antimalarials

et al. 2001

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A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diaminotriazine WR-99210 (8s), have been prepared. Several of them, such as 5b (PS-33) and 5m (PS-26), maintain or exceed the in vivo activity of PS-15 while not requiring the use of highly regulated starting materials. The putative diaminotriazine metabolites of these new analogues (compounds 8) have also been prepared and shown to maintain the activity against resistant P. falciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.

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Section: In Vitro Activitymentioning

confidence: 91%

Phenoxypropoxybiguanides, Prodrugs of DHFR−Inhibiting Diaminotriazine Antimalarials

et al. 2001

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Drug Resistance in Protozoa

Geary

Edgar

Jensen

1986

Chemotherapy of Parasitic Diseases

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Pyrimethamin-resistantPlasmodium falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines

et al. 1991

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Methotrexate resistance induced in cultured Plasmodium falciparum depends on an altered dihydrofolate reductase with decreased affinity for methotrexate as well as for pyrimethamine. In contrast, pyrimethamine-resistant field isolates of P. falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines. The structure of the latter class was optimized by the use of trimethoprim as a lead and the substitution of methoxy groups at the benzyl ring by 3-(4'-aminophenyl-4-sulfonylphenylamino)propoxy or by (4'-aminophenyl-4-sulfonylphenyl)methoxy, which resulted in antimalarials of high potency. The efficiency of these newly designed 2,4-diamino-5-(substituted benzyl) pyrimidines was confirmed by their strong inhibitory effect on plasmodial dihydrofolate reductase as well as by in vitro screening against drug-sensitive and -resistant strains of P. falciparum.

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Triazines, Quinazolines and Related Dihydrofolate Reductase Inhibitors

Cited by 4 publications

References 102 publications

Phenoxypropoxybiguanides, Prodrugs of DHFR−Inhibiting Diaminotriazine Antimalarials

Phenoxypropoxybiguanides, Prodrugs of DHFR−Inhibiting Diaminotriazine Antimalarials

Drug Resistance in Protozoa

Pyrimethamin-resistantPlasmodium falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines

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