Selective Pneumocystis carinii dihydrofolate reductase inhibitors: design, synthesis, and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines

Journal of Medicinal Chemistry
A GangjeeW Pangborn

Abstract

Nonclassical antifolates, 2,4-diamino-5-substituted-furo[2, 3-d]pyrimidines 3-12 with bridge region variations of C8-S9, C8-N9, and C8-O9 and 1-naphthyl, 2-naphthyl, 2-phenoxyphenyl, 4-phenoxyphenyl, and 2-biphenyl side chains were synthesized as phenyl ring appended analogues of previously reported 2, 4-diamino-5-(anilinomethyl)furo[2,3-d]pyrimidines. The phenyl ring appended analogues were designed to specifically interact with Phe69 of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) to afford selective inhibitors of pcDHFR. Additional substituted phenyl side chains which include 2,5-dichloro, 3,4-dichloro, 3,4,5-trichloro, 3-methoxy, and 2,5-dimethoxy analogues 13-17 were also synthesized. The compounds were prepared by nucleophilic displacement of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine(2) with the appropriate thiol, amine, or naphthol. Compound 2 was obtained from 2,4-diamino-6-hydroxypyrimidine and 1, 3-dichloroacetone. The compounds were evaluated as inhibitors against DHFR from P. carinii, Toxoplasma gondii, and rat liver. Two analogues, 2,4-diamino-5-[(2'-naphthylthio)methyl]furo[2, 3-d]pyrimidine (5) and 2,4-diamino-5-[(2'-phenylanilino)methyl]furo[2,3-d]pyrimidine (11) showed significant selec...Continue Reading

References

Jul 1, 1991·Antimicrobial Agents and Chemotherapy·M C Broughton, S F Queener

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Citations

Jul 14, 2001·European Journal of Medicinal Chemistry·F ZuccottoI H Gilbert
Jul 2, 2003·European Journal of Medicinal Chemistry·Isaac O DonkorSherry F Queener
Aug 5, 2009·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Vivian CodyAleem Gangjee
Feb 1, 2008·Expert Opinion on Therapeutic Patents·David B BolstadAmy C Anderson
Apr 16, 2014·Antimicrobial Agents and Chemotherapy·Jayme L DahlinAndrew H Limper
Apr 25, 2012·Journal of Molecular Modeling·Osvaldo A Santos-FilhoNubia Boechat
Feb 11, 2005·Chemical Reviews·Ivan M KompisRudolf L Then

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