Synthesis and biological activity of novel mono-indole and mono-benzofuran inhibitors of bacterial transcription initiation complex formation. Issue 8 (15th April 2015)

• Record Type: Journal Article
• Authors: Mielczarek, Marcin; Thomas, Ruth V.; Ma, Cong; Kandemir, Hakan; Yang, Xiao; Bhadbhade, Mohan; Black, David StC.; Griffith, Renate; Lewis, Peter J.; Kumar, Naresh
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 8(2015)
• Page Start: 1763
• Page End: 1775
• Publication Date: 2015-04-15
• Subjects: PLVOWXROZRTXMF-UHFFFAOYSA-N -- GKAWVLDDCYBEKF-UHFFFAOYSA-N -- UQMSDBZZWKSNCU-UHFFFAOYSA-N -- NOWMEQYXODYIEE-UHFFFAOYSA-N -- HAXUSKBOXWTQEJ-UHFFFAOYSA-N -- VCAIVLGVJWFIOA-UHFFFAOYSA-N -- DGEFMJGCYMACHO-UHFFFAOYSA-N -- JMHRNWULPJIZRV-UHFFFAOYSA-N -- RZQPAQOFGPUUOC-UHFFFAOYSA-N -- VUWXXHSEERXSKQ-UHFFFAOYSA-N -- CLNDCNPVCYIXOC-UHFFFAOYSA-N; Mono-indoles -- Mono-benzofurans -- RNA polymerase -- σ70/σA factors -- Antibacterial activity -- Structure–activity relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.037
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Our ongoing research focused on targeting transcription initiation in bacteria has resulted in synthesis of several classes of mono-indole and mono-benzofuran inhibitors that targeted the essential protein–protein interaction between RNA polymerase core and σ 70 / σ A factors in bacteria. In this study, the reaction of indole-2-, indole-3-, indole-7- and benzofuran-2-glyoxyloyl chlorides with amines and hydrazines afforded a variety of glyoxyloylamides and glyoxyloylhydrazides. Similarly, condensation of 2- and 7-trichloroacetylindoles with amines and hydrazines delivered amides and hydrazides. The novel molecules were found to inhibit the RNA polymerase– σ 70 / σ A interaction as measured by ELISA, and also inhibited the growth of both Gram-positive and Gram-negative bacteria in culture. Structure–activity relationship (SAR) studies of the mono-indole and mono-benzofuran inhibitors suggested that the hydrophilic–hydrophobic balance is an important determinant of biological activity.