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Novel nonclassical inhibitors of glycinamide ribonucleotide formyltransferase: 10‐Formyl and 10‐hydroxymethyl derivatives of 5,8,10‐trideazapteroic acid
Author(s) -
Liu Li,
Nair M. G.,
Kisliuk R. L.
Publication year - 1996
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/(sici)1099-1352(199603)9:2<169::aid-jmr261>3.0.co;2-#
Subject(s) - ic50 , hydroxymethyl , chemistry , stereochemistry , recombinant dna , enzyme , biochemistry , ribonucleotide , in vitro , nucleotide , gene
Several new 10‐formyl and 10‐hydroxymethyl derivatives of 5,8,10‐trideazapteroic acid have been synthesized by a novel and convenient enamine alkylation procedure. Two of these compounds (10a and 10b) were shown to be very powerful inhibitors of L. casei (10a, IC 50 = 8 × 10 −6 M ; 10b, IC 50 = 7 × 10 −6 M ) and recombinant mouse (10a, IC 50 = 3.4 × 10 −5 M ; 10b, IC 50 = 2.8 × 10 −5 M ) glycinamide ribonucleotide formyltransferase (GARFT). These IC 50 values are comparable to the classical GARFT inhibitor (6R)‐DDATHF (IC 50 , L. casei 2.3 × 10 −6 M ; recombinant mouse 2.3 × 10 −5 M ) under identical assay conditions. For both compounds, the inhibition of L. casei GARFT increased with time of incubation, but not markedly with the recombinant mouse enzyme. Due to their potential ability to interfere with purine biosynthesis and to penetrate microbial cells the new nonclassical GARFT inhibitors reported here may be useful for the treatment of infections caused by microorganisms that are sensitive and resistant to conventional antimicrobial agents.