ChemInform Abstract: Synthesis of New 2,4‐Diamino‐7H‐pyrrolo[2,3‐d]pyrimidines via the Taylor Ring Transformation/Ring Annulation Strategy.

Abstract

Synthesis of New 2,4-Diamino-7H-pyrrolo[2,3-d]pyrimidines via the Taylor Ring Transformation/Ring Annulation Strategy. -Synthesis of the title compounds (VII) and results on their inhibition of dihydrofolate reductase are reported.

The Effect of 5-Alkyl Modification on the Biological Activity of Pyrrolo[2,3-d]pyrimidine Containing Classical and Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents

“…Several compounds displayed 10-fold or higher selectivity ratios for M. aVium DHFR. Against P. carinii DHFR, in general, the 5-propyl nonclassical analogues (11)(12)(13)(14)(15)(16)(17)(18) were more potent and selective than the corresponding 5-isopropyl analogues (19)(20)(21)(22)(23)(24)(25)(26)(27). Against M. aVium DHFR, the nature of the phenyl substitution along with the 5-alkyl group determined the potency and selectivity of the compound.…”

“…E. coli DHFR (Table 1): In general the 5-isopropyl compounds (19)(20)(21)(22)(23)(24)(25)(26)(27) with the exceptions of 19 and 20 were more potent and selective against E. coli DHFR than the corresponding 5-propyl compounds (11)(12)(13)(14)(15)(16)(17)(18). In the 5-propyl series, analogue 16 with a 3,4-dimethoxyphenyl side chain was the most potent and selective compound against E. coli DHFR.…”

“…T. gondii DHFR (Table 1): In general the 5-propyl compounds (13)(14)(15)(16)(17)(18) with the exception of 13 were more potent and selective against T. gondii DHFR than the corresponding 5-isopropyl compounds (21)(22)(23)(24)(25)(26). In the 5-propyl series, analogue 17 with a 1-naphthyl side chain was the most potent compound against T. gondii DHFR and was 50-fold more potent than TMP, 5-fold less potent than MTX and equipotent with pyrimethamine.…”

“…The 1-naphthyl substitution in 17 was found to display moderate DHFR inhibitory activity, while a 2-naphthyl substitution in 18 was found to be slightly detrimental for activity compared to 13. In the 5-isopropyl (19)(20)(21)(22)(23)(24)(25)(26)(27) series, the most potent analogue contained a 1-naphthyl side chain 25 and displayed submicromolar inhibitory potency. All other substitutions in the side chains as in 19-27, with the exception of 25, displayed micromolar or higher inhibitory potency.…”

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Novel classical antifolates (3 and 4) and 17 nonclassical antifolates (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of 3, 4, and 11-27 were 2,4diamino-5-alkylsubstituted-7H-pyrrolo [2,3-d]pyrimidines, 31 and 38, prepared by a ring transformation/ ring annulation sequence of 2-amino-3-cyano-4-alkyl furans to which various aryl thiols were attached at the 6-position via an oxidative addition reaction using I 2 .

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