DOI: 10.1002/chem.201303119 Inspiration from Old Dyes: TrisACHTUNGTRENNUNG(stilbene) Compounds as Potent Gram- Positive Antibacterial Agents Ramiz A. Boulos, [a, g] Nikki Y. T. Man, [a] Nigel A. Lengkeek, [a] Katherine A. Hammer, [d] Niki F. Foster, [d] Natalie A. Stemberger, [d, e] Brian W. Skelton, [f] Pan Yu Wong, [a] Boris Martinac, [b, c] Thomas V. Riley, [d, e] Allan J. McKinley,* [a] and Scott G. Stewart* [a] Introduction The growth in prevalence of antibacterial resistance is a major public health problem that our society is currently facing. [1] The search for original compounds and novel mo- lecular scaffolds with antimicrobial properties has attracted great interest in recent times due to the regular use of broad spectrum antibiotics leading to the increased occurrence of bacterial strains resistant to current antimicrobial formula- tions. [2] A decline in pharmaceutical endeavours and discov- eries in the area of antibacterial drug discovery has been also observed. [3] Alarmingly, there has also been an increase in the prevalence of infections caused by some Gram-posi- tive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile, resulting in serious or fatal diseases. Despite several new drugs in late-stage de- velopment, the current reduced commitment to antimicrobi- al research and lack of development pipelines has, inexora- bly, led to a steady decline in the treatment choices for more serious bacterial infections. [4] In the search for unexplored molecular scaffolds that pos- sess antibacterial properties and new cellular targets for such molecules, we had shown that mechanosensitive (MS) channels could be exploited in this way. [5, 6] In silico model- ling studies had shown that eriochrome cynanine a triphenyl methyl (TPM) dye bound to the MscL channel (Large-Con- ductance Mechanosensitive Channels) and this result was confirmed experimentally with patch-clamp and ESR ex- periments. [7] A range of commercial dyes with reported anti- bacterial properties were used as simple molecular tem- plates for novel analogues. In particular, we were interested Abstract: Herein we describe the prep- aration and structure-activity relation- ship studies on range of stilbene based compounds and their antibacterial ac- tivity. Two related compounds, each bearing carboxylic acid moieties, exhib- it good activity against several bacterial strains, including methicillin-resistant Staphylococcus aureus MRSA (ATCC 33592 and NCTC 10442). Compound 10 was most active against Moraxella catarrhalis with minimum inhibitory concentrations (MICs) of 0.12– 0.25 mg mL 1 and against Staphylococ- cus spp. with MICs ranging from 2– 4 mg mL 1 . The derivative 17 showed increased activity with MICs of 0.06– 0.25 mg mL 1 against M. catarrhalis and 0.12–1 against Staphylococcus spp. This level of activity is similar to that re- ported for S. aureus for antibiotics, such as vancomycin, with MICs of  2.0 mg mL 1 and clindamycin with MICs of  0.5 mg mL 1 . As an indicator of toxicity, 17 was tested for its ability to lyse sheep erythrocytes, and showed low haemolytic activity. Such results highlight the value of trisACHTUNGTRENNUNG(stilbene) compounds as antibacterial agents pro- viding suitable properties for further development. Keywords: antibacterial · biological activity · Heck cross-coupling · MRSA · stilbenes [a] Dr. R. A. Boulos, N. Y. T. Man, Dr. N. A. Lengkeek, P. Y. Wong, Prof. A. J. McKinley, Prof. S. G. Stewart School of Chemistry and Biochemistry The University of Western Australia, Crawley, WA 6009 (Australia) Fax: (+ 61) 8-6488-1005 E-mail : allan.mckinley@uwa.edu.au scott.stewart@uwa.edu.au [b] Prof. B. Martinac Victor Chang Cardiac Research Institute Lowy Packer Building, Darlinghurst, NSW, 2010 (Australia) [c] Prof. B. Martinac St Vincent)s Clinical School, The University of New South Wales Sydney, NSW 2052 (Australia) [d] Prof. K. A. Hammer, Dr. N. F. Foster, N. A. Stemberger, Prof. T. V. Riley School of Pathology and Laboratory Medicine The University of Western Australia, Crawley, WA 6009 (Australia) [e] N. A. Stemberger, Prof. T. V. Riley Path West Laboratory Medicine (WA) Queen Elizabeth II Medical Centre, Nedlands, WA, 6009 (Australia) [f] Prof. B. W. Skelton Centre for Microscopy, Characterisation and Analysis University of Western Australia, Crawley 6009 WA (Australia) [g] Dr. R. A. Boulos Present Addresses: School of Chemical and Physical Sciences Flinders University, Bedford Park, SA 5042 (Australia) Supporting information on for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303119. It contains 1 H and 13 C spectra. Chem. Eur. J. 2013, 00,0–0 # 2013 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim These are not the final page numbers! ÞÞ &1& FULL PAPER