Design and synthesis of quinolinones as methionyl-tRNA synthetase inhibitors Farhanullah, a Su Yeon Kim, a Eun-Jeong Yoon, b Eung-Chil Choi, b Sunghoon Kim, c Taehee Kang, d Farhana Samrin, a,e Sadhna Puri e and Jeewoo Lee a, * a Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea b Laboratory of Microbiology, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea c Center for ARS Network, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea d Imagene Co. Ltd., Biotechnology Incubating Center, Seoul National University, Seoul 151-742, Republic of Korea e Department of Chemistry, Dayanand Girls Post Graduate College, Kanpur 208024, India Received 5 May 2006; revised 26 June 2006; accepted 28 June 2006 Available online 18 July 2006 Abstract—Five new structural analogues of substituted-1H-quinolinones (19, 20, 23, 24, and 26) have been synthesized and evalu- ated for Staphylococcus aureus methionyl-tRNA synthetase enzyme inhibitory activity. These compounds were also tested against pathogens of six S. aureus, two Enterococcus faecalis, and one Enterococcus faecium. Among all the synthesized quinolinones, compound 20 displayed significant inhibitory activities in the strains of E. faecalis and E. faecium. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Aminoacyl-tRNA synthetases (aaRSs) are a group of enzymes that precisely transfer amino acids from cellu- lar pool to their corresponding tRNA cognates to form aminoacyl-tRNAs which serve as substrates for protein synthesis. 1 The transfer of a particular amino acid to tRNA under influence of aaRS occurs through forma- tion of an active intermediate aminoacyladenylate (aa-AMP) by the reaction of the amino acid and ATP. The aa-AMP thus formed is attacked by either 2 0 -OH or 3 0 -OH of adenosine of tRNA to form ester with ami- noacyl moiety. The catalytic activity of aaRSs is organ- ism specific and it is different in pathogens and human beings. This difference in catalytic activity of aaRSs provides an opportunity to inhibit pathogens’ aaRSs selectively without perturbing host aaRSs. Thus, amino- acyl-tRNA synthetases make an alternative drug target to develop antibacterial agents for the treatment of anti- biotic-resistant bacterial strains such as methicillin, resistant Staphylococcus aureus (MRSA) and Vancomy- cin resistant enterococci (VRE). 2–4 Aminoacyladenylate (aa-AMP) being highly active and susceptible to hydrolysis makes the possibility of synthe- sizing its stabilized analogues having potential inhibito- ry properties. In this respect various isosteres of linear chain attached to aa-AMP, such as alkylphosphate, ester, amide, hydroxamate, sulfamate, 5 sulfamide, N-alkoxysulfamide, and N-hydroxysulfamide have been prepared as replacement of the hydrolytically labile acylphosphate of the aminoacyladenylate. Inhibitors of aminoacyladenylate have been also synthesized by modifying hydroxyl groups of ribose present in aminoacyladenylate. 6 Recently, a quinoline derivative 7 has been identified by high throughput screening of a library of compounds as a competitive inhibitor of methionyl-tRNA synthe- tase (MRS). Structure–activity relationship 7–10 study of the derivative led to the synthesis of 2 with IC 50 value 16 nM against MRSA. Bioorganic & Medicinal Chemistry 14 (2006) 7154–7159 0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2006.06.062 Keywords: Methionyl-tRNA synthetase inhibitor; Antibacterial agent; Quinolone. * Corresponding author. Tel.: +82 2 880 7846; fax: +82 2 888 0649; e-mail: jeewoo@snu.ac.kr