Synthesis and biological activity of novel mono-indole and mono-benzofuran inhibitors of bacterial transcription initiation complex formation

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 sigma(70)/sigma(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-sigma(70)/sigma(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. (C) 2015 Elsevier Ltd. All rights reserved.National Health and Medical Research Council (NHMRC) AustraliaNational Health and Medical Research Council of Australia [APP1008014]; UNSW AustraliaThis work was supported by a Project Grant from the National Health and Medical Research Council (NHMRC) Australia to N.K., P.L. and R.G. [NHMRC Grant APP1008014].; M.M. is thankful to UNSW Australia for a Tuition Fee Scholarship (TFS) and to N.K. for a Living Allowance Scholarship