Synthesis of 2,4-diaminopteridines with bulky lipophilic groups at the 6-position as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and mammalian dihydrofolate reductase Journal Article

  


Authors: Rosowsky, A.; Forsch, R. A.; Queener, S. F.; Bertino, J. R.
Article Title: Synthesis of 2,4-diaminopteridines with bulky lipophilic groups at the 6-position as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and mammalian dihydrofolate reductase
Abstract: Ten previously undescribed 2,4-diamino-6-(2- naphthylamino)methylpteridines with lipophilic chlorine or long-chain alkyl groups on the naphthyl moiety and either hydrogen or a methyl group on N10 were synthesized from the appropriate 2-naphthylamine or N-methyl-2- naphthylamine by reaction with 2-amino-5-chloromethylpyrazine-3-carbonitrile and ring closure with guanidine. One analogue with a methyl group at the 7- position was also prepared. The N10-unsubstituted analogues were consistently less active than the N10-methyl analogues as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase. However the potency of the series as a whole was relatively low against all three enzymes, with the best inhibitors giving IC50 values only in the 0.1-1.0 μM range and several giving IC50 values in the 10-100 μM range. Moreover, while several compounds with IC50 values of <10 μM showed some selectivity for the Pneumocystis carinii and/or Toxoplasma gondii enzyme relative to the rat liver enzyme, the magnitude of this effect was marginal (<4-fold). Assays were also performed against purified human dihydrofolate reductase and against wild-type and methotrexate-resistant human leukemic lymphoblasts in culture. Activity against the enzyme was very low, the best inhibitors giving only 50-70% inhibition at 10 μM. Although none of the compounds inhibited the growth of wild-type CEM cells by more than 20% at 1 μM, several were more active (60-75% inhibition at 1 μM) against the methotrexare-resistant subline CEM/MTX, which is defective in metho-trexate and reduced folate transport, than they were against the methotrexate- sensitive parental CEM cells. Overall the results suggest that 2,4-diamino- 6-substituted pteridines with chlorine or long-chain alkyl substituents in the 2-naphthyl moiety and hydrogen or a methyl group on N10 are not likely to be therapeutically useful agents.
Keywords: controlled study; human cell; nonhuman; methotrexate; enzyme inhibition; antiprotozoal agent; drug synthesis; structure activity relation; rat; dihydrofolate reductase inhibitor; dihydrofolate reductase; infrared spectroscopy; concentration response; proton nuclear magnetic resonance; pteridine derivative; toxoplasma gondii; pneumocystis carinii; human; priority journal; article; 2,4-diaminoptefidines; bulky lipophilic group; antiprotozoal activity
Journal Title: Pteridines
Volume: 8
Issue: 3
ISSN: 0933-4807
Publisher: Walter de Gruyter GmbH  
Date Published: 1997-01-01
Start Page: 173
End Page: 187
Language: English
PROVIDER: scopus
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0030666275&partnerID=40&md5=9552763c3414144846ec0f60573153c6
Notes: Article -- Export Date: 17 March 2017 -- Source: Scopus