2,4-Diaminothieno[2,3-d]pyrimidine Analogues of Trimetrexate and Piritrexim as Potential Inhibitors of Pneumocystis carinii and Toxoplasma gondii Dihydrofolate Reductase

Andre Rosowsky, Clara E. Mota, Joel E. Wright, James H. Freisheim, James J. Heusner, John J. McCormack, Sherry F. Queener

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68 Scopus citations

Abstract

A series of eight previously undescribed 2,4-diaminothieno[2,3-d]pyrimidine analogues of the potent dihydrofolate reductase (DHFR) inhibitors trimetrexate (TMQ) and piritrexim (PTX) were synthesized as potential drugs against Pneumocystis carinii and Toxoplasma gondii, which are major causes of severe opportunistic infections in AIDS patients. 2,4-Diamino-5-methyl-6-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 3,4,5-trimethoxy or 2,5-dimethoxy substitution in the aryl/aralkyl moiety and 2,4-diamino-5-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 2,5-dimethoxy substitution in the aryl/aralkyl moiety were obtained by reaction of the corresponding 2-amino-3-cyanothiophenes with chloroformamidine hydrochloride. The aryl group in the 5,6-disubstituted analogues was either attached directly to the hetero ring or was separated from it by one or two carbons, whereas the aryl group in the 5-monosubstituted analogues was separated from the hetero ring by two or three carbons. 2-Amino-3-cyano-5-methyl-6-(aryl/alkyl)thiophene intermediates for the preparation of the 5,6-disubstituted analogues were prepared from ω-aryl-2-alkylidenemalononitriles and sulfur in the presence of a secondary amine, and 2-amino-3-cyano-4-(aryl/ aralkyl)thiophene intermediates for the preparation of the 5-monosubstituted analogues were obtained from ω-aryl-1-chloro-2-alkylidenemalononitriles and sodium hydrosulfide. Synthetic routes to the heretofore unknown ylidenemalononitriles, and the ketone precursors thereof, were developed. The final products were tested in vitro as inhibitors of DHFR from Pneumocystis carinii, Toxoplasma gondii, rat liver, beef liver, and Lactobacillus casei. A selected number of previously known 2,4-diaminothieno[2,3-d]pyrimidines lacking the 3,4,5-trimethoxyphenyl and 2,5-dimethoxyphenyl substitution pattern of TMQ and PTX, respectively, were also tested for comparison. None of the compounds was as potent as TMQ or PTX, and while some of them showed some selectivity in their binding to Pneumocystis cariniii and Toxoplasma gondii versus rat liver DHFR, this effect was not deemed large enough to warrant further preclinical evaluation.

Original languageEnglish (US)
Pages (from-to)3103-3112
Number of pages10
JournalJournal of Medicinal Chemistry
Volume36
Issue number21
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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