SAR studies on dihydropyrimidinone antibiotics Lianhong Xu ⇑ , Lijun Zhang, Robert Jones   , Clifford Bryant   , Nina Boddeker   , Eric Mabery, Gina Bahador, Julia Watson   , Jeffery Clough   , Murty Arimilli   , Wendy Gillette   , Dorothy Colagiovanni   , Keyu Wang, Craig Gibbs, Choung U. Kim Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA article info Article history: Received 5 January 2011 Revised 20 January 2011 Accepted 21 January 2011 Available online 31 January 2011 Keywords: TAN-1057A/B Antimicrobial agent Dipeptide antibiotic abstract There is an urgent need for the development of novel antimicrobial agents that offer effective treatment against MRSA. Using a new class of dipeptide antibiotic TAN-1057A/B as lead, we designed, synthesized and evaluated analogs of TAN-1057A/B. Several novel dihydropyrimidinone antibiotics demonstrating comparable antibiotic efficacy while possessing favorable selectivity were identified. Ó 2011 Elsevier Ltd. All rights reserved. Many antibacterial products are available on the world market, but successful treatment of bacterial infections is becoming increasingly problematic as resistance to current agents becomes more widespread. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of severe infections in both the hospital and community environments. 1,2 Although, several new classes of antimicrobial agents have reached the market in re- cent years with world wide efforts, there is still an urgent need for the development of novel agents that offer effective treatment against MRSA. TAN-1057A/B (1)(Fig. 1), isolated from bacteria Flexibacter by scientist at Takeda Chemical Co. in 1993, is a dipeptide antibiotic consisting a mixture of two equilibrate epimeric isomer 1a and 1b. It represents a novel antibacterial class, containing a unique 2,5-diamino-5,6-1H-dihydropyrimidin-4-one scaffold and a b- homoarginine side chain. TAN-1057A/B inhibits the bacterial translation, and displays potent minimal inhibitory concentration (MIC) against staphylococci including MRSA. 3 However, TAN- 1057A/B has low selectivity, inhibiting both prokaryotic and eukaryotic translation, it also has significant toxicity in vivo (LD 50 in the mouse: 50 mg/kg ip and 100 mg/kg iv). In addition, TAN- 1057A/B has reduced antibiotic activity against other pathogens, such as enterococci and pneumococci. Previously, limited structure–activity relationship (SAR) results on TAN-1057A/B have been published. 4 In this Letter, we report systematic SAR studies of TAN-1057A/B series analogs. Inhibitory activity against both prokaryotic and eukaryotic translation using biochemical translation assays 5 and MIC 6 were obtained respec- tively to evaluate selectivity and potency of the designed analogs. Chemistry was developed to enable the detailed studies of each portion of the lead TAN-1057. In general, analogs were assembled according to route depicted in Scheme 1, utilizing the strategy used in the total synthesis of TAN-1057A/B. 7 Dihydropyrimidinone 4 was constructed by treatment of appropriately substituted amine 6 with isothiuronium salt 7. Coupling of diazoketone 3, prepared from the corresponding amino acid 5, with dihydropyrimidinone amine in the presence of AgClO 4 followed by necessary deprotec- tion afforded compound 2. We initiated our efforts by examining the SAR around the dihy- dropyrimidinone core, the results are displayed in Table 1. Replace- ment of methyl (R 2 ) with ethyl (compound 8) significantly improved the selectivity but led to a reduction of both MIC and the inhibitory activity against translation. While acetyl amide replacing the urea moiety at the 2-position attaching to the hetero- cyclic ring (compound 9) provided mild improvement in both activity against bacterial translation and selectivity, other modifi- cations 8 at R 3 only yielded analogs with reduced potency 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.01.099 ⇑ Corresponding author. Tel.: +1 650 522 5828. E-mail address: lianhong.xu@gilead.com (L. Xu).   These authors are no longer with Gilead Sciences. N NH O N N H NH 2 O O N H CH 3 NH 2 H 2 N NH 1a TAN-1057A *S 1b TAN-1057B *R * 1 3 5 Figure 1. Dipeptide antibiotics TAN-1057A/B. Bioorganic & Medicinal Chemistry Letters 21 (2011) 1670–1674 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl