title: Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring.
abstract: Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H(37)Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7-deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 μM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 μM, MIC isoniazid 0.28 μM and MIC PA-824 0.44 μM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low-oxygen-recovery assay (LORA) ≥ 60 μM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli.
authors.affiliation: Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway.
authors.forename: Abhijit Datta
authors.initials: AD
authors.lastname: Khoje
authors.forename: Aisvareya
authors.initials: A
authors.lastname: Kulendrn
authors.forename: Colin
authors.initials: C
authors.lastname: Charnock
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Scott
authors.initials: S
authors.lastname: Franzblau
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Gundersen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002522:Chlorocebus aethiops; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014709:Vero Cells
chemical_list: C512929:7-deazapurine; D000900:Anti-Bacterial Agents; D007093:Imidazoles; D011687:Purines; C015008:triazolopyrimidinone; C029899:imidazole