title: 7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity.
abstract: Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N(2)-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N(2)-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10μg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice.
authors.affiliation: GLSynthesis Inc., One Innovation Drive, Worcester, MA 01605, USA.
authors.forename: Wei-Chu
authors.initials: WC
authors.lastname: Xu
authors.forename: George E
authors.initials: GE
authors.lastname: Wright
authors.forename: Neal C
authors.initials: NC
authors.lastname: Brown
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Long
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Zhi
authors.forename: Sofya
authors.initials: S
authors.lastname: Dvoskin
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Gambino
authors.forename: Marjorie H
authors.initials: MH
authors.lastname: Barnes
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Butler
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004926:Escherichia coli / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006147:Guanine; C010567:3-deazaguanine; D004258:DNA Polymerase III