F1_1514.pptx

Synthesis and Antibacterial Activities of Aza Tetracyclines:
A Novel Class of Tetracycline Analogs
Contact:
X. XIAO, R. CLARK, M. HE, D. LOFLAND, W. O’BRIEN, L. PLAMONDON
Leland Webster
Tetraphase Pharmaceuticals, Watertown, MA.
Leland.webster@tphase.com
Abstract/Introduction
Results Results
Background: A unique fully synthetic platform for tetracycline synthesis provides access to
Table 1. Antibacterial Activity of 7-R-8-Aza-9-H-Tetracyclines
Table 3. Antibacterial Activity of 7-F-8-Aza-9-R-Tetracyclines
a broad range of tetracyclines that would be inaccessible by semisynthesis. Novel aza MIC (μg/mL)
tetracycline analogs with a heterocyclic moiety were designed, synthesized and tested. The MIC (μg/mL)
SA101 SA100 SA161 SA158 EF103 EF159 SP106 SP160 EC107 EC155 AB110 PA111 EC108 KP109 KP153 structure-antibacterial activity relationship (SAR) of diverse aza tetracyclic analogs was SA101 SA100 SA161 SA158 EF103 EF159 SP106 SP160 EC107 EC155 AB110 PA111 EC108 KP109 KP153 tet(K) 29212 tet(M) 49619 tet(M) 25922 tet(A) 19606 27853 13047 13883 tet(A) 01 H 0.5 1 32 16 16
tet(K) 29212 tet(M) 49619 tet(M) 25922 tet(A) 19606 27853 13047 13883 tet(A) Method: Novel aza tetracyclic analogs were synthesized from a key bicyclic AB precursor
via a single-step tandem Michael-Dieckmann reaction. In vitro antibacterial activity was 4 32 0.016 8 0.25 >32 0.25 8 0.5 0.5 >32 evaluated by susceptibility testing according to CLSI guidelines. In vivo efficacy was 03 Ph 0.063
4 >32 0.031 4 0.5 >32 0.13 >32 2 determined in a mouse systemic infection model against Staphylococcus aureus ATCC 13709. 8 0.5 16 0.063 2 0.25 >32 0.5 4 0.5 1 >32 Conclusion: Aza tetracyclic analogs exhibit very good in vitro and in vivo activity against
05 N(CH3)2
bacterial pathogens including tetracycline-resistant strains with efflux- or ribosomal-mediated resistance. This demonstrates the potential of the total synthetic approach as a 06 F 0.031
4 32 0.016 8 0.25 >32 0.25 8 0.5 0.5 >32 platform to overcome known mechanisms of tetracycline resistance. 07 Cl 1 1 32 32 32 >32 1 32 2 >32 32 >32 8 4 >32
Conclusions
Table 2. Antibacterial Activity of 7-Cl-8-Aza-9-R-Tetracyclines
Chemistry: A typical synthesis of 7-Cl-8-aza-9-amino-tetracyclines is outlined below.
MIC (μg/mL)
Antibacterial Activity: See Introduction section above.
SA101 SA100 SA161 SA158 EF103 EF159 SP106 SP160 EC107 EC155 AB110 PA111 EC108 KP109 KP153 tet(K) 29212 tet(M) 49619 tet(M) 25922 tet(A) 19606 27853 13047 13883 tet(A) 07 H 1 1 32 32 32
SA: Staphylococcus aureus; EF: Enterococcus faecalis; SP: Streptococcus pneumoniae : EC: Esherichia coli; AB: Acinetobacter baumannii; PA: Pseudomonas aeruginosa; ECl, Enterobacter cloacae; KP: Klebsiella Conclusions
0.031 1 0.5 0.063 4 0.031 4 0.5 16 0.031 16 4 •
Novel 8-aza tetracycline analogs were prepared via a total synthetic approach and evaluated for antibacterial activity. 1 0.5 16 >32 >32 >32 16 >32 >32 >32 >32 •
A variety of substituents were installed at C7 and C9 leading to unique analogs with promising antibacterial activity in vitro and in vivo (see poster F1-1515 for additional data). •
Series will be further optimized for spectrum, potency, and physicochemical properties. Reference
2 2 32 32 8 >32 1 16 4 >32 8 >32 8 8 >32 M.G. Charest, C.D. Lerner, J.D. Brubaker, D.R. Siegel, A.G. Myers, Science, 308, 395 (2005).
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