Design, synthesis, and biological evaluation of 2,4-diamino-5-methyl-6-substituted-pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors.
2,4-diamino-5-methyl-6-(substituted-phenyl)thiopyrrolo[2,3-d]pyrimidines 4-11 were synthesized as dihydrofolate reductase (DHFR) inhibitors against opportunistic pathogens that afflict patients with AIDS. Synthesis was achieved from 2,4-diamino-5-methypyrrolo[2,3-d]pyrimidine and substituted phenylthiols under modified conditions reported by Gangjee et al. Some of these compounds were potent and selective against DHFR from both Toxoplasma gondii and Mycobacterium avium compared to mammalian DHFR. Compound 11 with a 1-naphthyl substituent is 16-fold more potent and equally selective against Toxoplasma gondii DHFR as the clinically used trimethoprim.
Gangjee
Aleem
A
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, 600 Forbes Avenue, Duquesne University, Pittsburgh, PA 15282, USA. gangjee@duq.edu
Lin
Xin
X
Queener
Sherry F
SF
D000818:Animals; D018360:Crystallography, X-Ray; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009162:Mycobacterium avium / Q000737:chemistry; D045363:Pneumocystis carinii / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D014122:Toxoplasma / Q000737:chemistry
C488119:2,4-diamino-5-methyl-6-(2',5'-dimethoxyphenylthio)pyrrolo(2,3-d)pyrimidine; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013440:Sulfides; D013762:Tetrahydrofolate Dehydrogenase