title: Synthesis and structure-activity relationships of novel substituted 8-amino, 8-thio, and 1,8-pyrazole congeners of antitubercular rifamycin S and rifampin.
abstract: A series of rifamycin S and rifampin analogues incorporating substituted 8-amino, 8-thio, and 1,8-pyrazole substituents has been synthesized. The compounds were made by activation of the C-8 phenol as a sulfonate ester, followed by displacement with selected nitrogen and sulfur nucleophiles. The analogues were screened in assays to quantify their antitubercular activity under both aerobic and anaerobic conditions, and for inhibition of wild-type Mycobacterium tuberculosis (MTB) RNAP and rifamycin-resistant MTB RNAP (S450L) via an in vitro rolling circle transcription assay. Additionally, the MIC(90) values were determined for these analogues against Escherichia coli strains. Although none of the analogues displayed superior enzymatic or microbiological activity to their parent scaffolds, the results are consistent with the Rif C-8 hydroxyl acting as a hydrogen bond acceptor with S450 and that Rif resistance in the S450L mutant is due to loss of this hydrogen bond. Representative analogues were also evaluated in the human pregnane X receptor (PXR) activation assay.
authors: Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109-1065, USA.
authors: Yafei
authors: Y
authors: Jin
authors: Sumandeep K
authors: SK
authors: Gill
authors: Paul D
authors: PD
authors: Kirchhoff
authors: Baojie
authors: B
authors: Wan
authors: Scott G
authors: SG
authors: Franzblau
authors: George A
authors: GA
authors: Garcia
authors: H D Hollis
authors: HD
authors: Showalter
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012293:Rifampin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012294:Rifamycins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D011720:Pyrazoles; D012294:Rifamycins; C032779:rifamycin S; D012293:Rifampin