Novel non-classical C9-methyl-5-substituted-2,4-diaminopyrrolo[2,3-d]pyrimidines as potential inhibitors of dihydrofolate reductase and as anti-opportunistic agents

Abstract

Six novel C9-methyl-5-substituted-2,4-diaminopyrrolo [2,3-d]pyrimidines 18-23 were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and as anti-opportunistic agents. These compounds represent the only examples of 9-methyl substitution in the carbon-carbon bridge of 2,4-diaminopyrrolo[2,3-d]pyrimidines. The analogs 18-23 were synthesized in a concise eightstep procedure starting from the appropriate commercially available aromatic methyl ketones. The key step involved a Michael addition reaction of 2,4,6-triaminopyrimidine to the appropriate 1-nitroalkene, followed by ring closure of the nitro adducts via a Nef reaction. The compounds were evaluated as inhibitors of DHFR from Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma) and rat liver (rl). The biological result indicated that some of these analogs are potent inhibitors of DHFR and some have selectivity for pathogen DHFR. Compound 23 was a two digit nanomolar inhibitor of tgDHFR with 9.6-fold selectivity for tgDHFR.

The Nitro to Carbonyl Conversion (Nef Reaction): New Perspectives for a Classical Transformation

“…[157] Thee nhanced nucleophilicity of triaminopyrimidine 243 hasb een suitably exploited in the conjugate addition with nitroalkenes 244 which did not require any addedc atalyst or promoter. [158] A classicalh ydrolytic Nefr eactiono fa dduct 245 was then pursued with concomitant ring closure to the pyrroline ring that by 1,3-hydrogen shift led to the final pyrrole unit in compounds 246.…”

Novel 2‐hydrazino‐pyrimidin‐4(3H)‐one derivatives as potential dihydrofolate reductase inhibitors

“…The results of this assay are given in Table 2, along with previously reported data for reference compounds [12].…”

“…For e.g., 138.102 (32) indicates 32% inhibition at 138.102 lM concentration. a Data taken from reference [12].…”

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

“…Recombinant P. carinii DHFR has supplanted the use of cell free extracts for evaluation of DHFR inhibitors [22,49,50,51]. The enzyme is routinely expressed in DHFRdeficient strains of E. coli using the pET8C or other expression systems and released from the bacteria by sonication with subsequent centrifugation.…”