title: Novel nonclassical inhibitors of glycinamide ribonucleotide formyltransferase: 10-formyl and 10-hydroxymethyl derivatives of 5,8,10-trideazapteroic acid.
abstract: 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, IC50 = 8 x 10(-6) M; 10b, IC50 = 7 x 10(-6) M) and recombinant mouse (10a, IC50 = 3.4 x 10(-5) M; 10b, IC50 = 2.8 x 10(-5) M) glycinamide ribonucleotide formyltransferase (GARFT). These IC50 values are comparable to the classical GARFT inhibitor (6R)-DDATHF (IC50, L. casei 2.3 x 10(-6)M; recombinant mouse 2.3 x 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile 36688, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: M G
authors.initials: MG
authors.lastname: Nair
authors.forename: R L
authors.initials: RL
authors.lastname: Kisliuk
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000478:Alkylation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D019877:Hydroxymethyl and Formyl Transferases; D007780:Lacticaseibacillus casei / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D051026:Phosphoribosylglycinamide Formyltransferase; D011622:Pterins / Q000737:chemistry; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D013763:Tetrahydrofolates / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011622:Pterins; D011994:Recombinant Proteins; D013763:Tetrahydrofolates; C045894:lometrexol; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D000217:Acyltransferases