1. CONCLUSIONS AND FUTURE DIRECTIONS
Strategies for synthesis of various aza-β-lactam derivatives as potential β-lactamase inhibitors Jonathan Fifer, Marc A. Boudreau* Department of Chemistry, University of New Hampshire, Durham, NH 03824, Unites States.
INTRODUCTION
SYNTHETIC APPROACH
With the growing global problem of antibiotic resistance, the search for new potential treatment options has been the focus of many research groups. One strategy to overcome this problem is to develop compounds that will inhibit the β-lactamase enzymes, which hydrolyze β-lactam antibiotics.1 By targeting these enzymes, the activity of traditional β-lactam antibiotics may be restored. From many years of research, some compounds have shown promising inhibition towards β-lactamases and have even become commercially available.2 The β-lactamase inhibitor is paired with the traditional β-lactam antibiotic. This prevents hydrolysis of the β-lactam and allows it to attack the bacteria. Unfortunately, there are only a handful of clinically-used inhibitors of β-lactamases, and resistance to them has developed. Compounds containing an aza-β-lactam ring are hypothesized to be potential inhibitors of β-lactamases.3 In contrast to the β-lactam, an aza-β-lactam contains a second nitrogen atom in the lactam ring. As depicted in Figure 1, upon nucleophilic attack by the β-lactamase, the resulting acyl-enzyme intermediate (a carbamate) is expected to be more hydrolytically stable than the corresponding acyl-enzyme intermediate of a β-lactam (an ester) due to the increased resonance stabilization afforded by the nitrogen. Several strategies have been explored to synthesize a library of compounds that contain the aza-β-lactam ring, to then be tested for β-lactamase inhibitory activity (Fig. 2). These approaches include both traditional batch chemistry and flow chemistry.
Table 1: Optimization of 4π
electrocyclization using flow chemistry
Concentration
(M) t
(min)
Flow rate
(mL/min)
Temperature
( οC)
% Conversion from 1 to 2
0.016 30
0.322 21 60
0.161 44
0.032 23 36
0.048 15 32 rt 33
120
0.080 92
150
0.060 95
Scheme 1: Synthesis of aza-carbacephem and
aza-carbacepham3
RESEARCH GOAL
Synthesize a library of derivatives varying R1 and R2.
Scheme 2: Proposed synthesis of aza-carbapenem and aza-carbapenam
R1= H, F, OMe
R2= H, F
CONCLUSIONS AND FUTURE DIRECTIONS
Figure 2. Modification of the substituents at position R1 and R2 is thought to alter the electronics of the aza-β-lactam ring to provide resonance stabilization upon nucleophilic attack.
Synthesis of the aza-carbacephem and aza-carbacepham are currently being optimized. Synthetic strategies are currently being explored for the aza-carbapenem and aza-carbapenam derivatives.
Utilizing flow chemistry, the conversion of 1 to 2 via a 4p electrocyclization reaction was drastically increased.
With the fully optimized procedure, the phenyl ring can be functionalized to create a library of aza-β-lactam derivatives, which will be investigated as potential β-lactamase inhibitors.
Figure 1. Inactivation mechanism of b-lactamase enzyme by β-lactam and aza-β-lactam
References: 1) Leonard, D. A.; Bonomo, R. A.; Powers, R. A. Acc. Chem. Res., 2013, 46 (11), ) Worthington, R. J.; Melander, C. J. Org. Chem., 2013, 78 (9), 4207– ) Chandrakala, P. S.; Katz, A. K.; Carrell, H. L.; Sailaja, P. R.; Podile, A. R.; Nangia, A.; Desiraju, G. R. J. Chem. Soc., Perkin Trans , No. 16, 2597–2608.
Acknowledgments: University of New Hampshire