Passage The β-Lactam Scaffold Is an Important Feature in a Class

Passage
The β-lactam scaffold is an important feature in a class of broad-spectrum antibiotics that includes the penicillins, cephalosporins, and monobactams.  These antibiotics are used to treat a variety of diseases caused by bacteria.  The penicillins work by inhibiting a step in the synthesis of peptidoglycan.  However, the development of antibiotic resistance in the form of enzymes such as β-lactamase is an ongoing problem.An aromatic ring linked to the β-lactam ring has been reported to participate in hydrophobic interactions with β-lactamase active sites, and an aromatic ring bonded to the nitrogen of the β-lactam has shown to be beneficial to biological activity.  With this in mind, researchers synthesized a group of penicillanic acid analogues with substituted aromatic rings bonded to the β-lactam ring in an effort to overcome the challenge of antibiotic resistance.  The substituents on the aromatic rings were varied, including -OCH₃ and -NO₂, to make several analogues.  A key step in the synthesis of these analogues was the coupling of Compounds 1 and 2 to form a compound with two β-lactam rings (Reaction 1) .
Reaction 1The researchers studied the analogues' structure-activity relationship and antimicrobial activity against the gram-negative bacteria Escherichia coli and the gram-positive bacteria Staphylococcus aureus.  Ampicillin, a penicillin derivative used to treat illnesses brought about by gram-positive and gram-negative bacteria, was used as a control.  The minimal inhibitory concentrations are shown in Table 1.Table 1  Minimal Inhibitory Concentration (MIC)
The penicillanic acid analogues were tested for their effect on mammalian cell viability because toxicity to cells is also an important factor to consider for potential drug candidates.  The general acceptable level of cell viability for a drug candidate is 70%.  These results are shown in Figure 1.
Figure 1  Cell viability assay results
Adapted from De rosa M, Vigliotta G, Palma G, Saturnino C, Soriente A. Novel Penicillin-Type Analogues Bearing a Variable Substituted 2-Azetidinone Ring at Position 6: Synthesis and Biological Evaluation. Molecules. 2015.
-The preparation of Compound 1 begins with a carboxylic acid (CA) derivative undergoing nucleophilic acyl substitution with methanol under reflux conditions to form butanoic acid with a methyl ester substituent on carbon 4.  Which structure was most likely the starting CA derivative?

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