Medicinal Chemistry

Topic:
Beta-Lactam Antibacterials

In this article, we discover the fundamental medicinal chemistry facts about beta-lactam antibacterial drugs – examining the chemistry that you need to know that explain how and why these commonly used medicines work the way they do.

Medicinal Chemistry of Beta-Lactam Antibiotics

This section focuses on the medicinal chemistry of beta-lactam antibiotics; the second part of our series on the medicinal chemistry of antibacterial compounds.

Penicillin derivatives, cephalosporins, monobactams and carbapenems all belong to this popular class of drugs. A four-membered lactam ring, known as a β-lactam ring, is a common structural feature of this class (see below). To this day, the pharmacology of beta-lactam antibiotics has clearly bore out an excellent safety and efficacy profile. Most of these medicines work by interfering with bacterial cell wall synthesis; the cell wall being an optimum drug target because it is something that bacterial cells possess, but not human cells.

Penicillin and its Derivatives

Penicillin consists of a fused a β-lactam ring and a thiazolidine ring; part of the heterocyclic bicyclic system is the β-lactam ring. The bicyclic system confers greater ring strain on the β-lactam ring, an aspect important for activity. An amide and a carboxylic acid group are also present. The carboxylic acid group is a possible site of modification to make prodrugs. Also – note the stereochemistry of the acylamino side chain with respect to the 4-membered ring and the cis stereochemistry for the hydrogen atoms highlighted in green. The key structural features of penicillins can be summarised as follows:

  • Fused β-lactam and thiazolidine ring forming a bicyclic system (Penam)
  • Free carboxylic acid
  • Acylamino side chain
  • Cis stereochemistry for the hydrogen

Texts describing penicillins may appear to have conflicting numbering systems; as there are two different, widely used numbering systems. The USP assigns the nitrogen atom at number 1 and the sulfur atom at number 4. In contrast, the Chemical Abstracts system assigns sulfur as number 1 and the nitrogen as number 4. Keep these differing numbering systems in mind when reviewing texts on beta-lactam medicinal chemistry.

Chemical Properties & Reactions

Penicillin’s overall shape is similar to a half-open book. As we talked about earlier, the bicyclic ring system has large, torsional strain and angle strain. Unlike typical tertiary amides, the carbonyl group of the strained four-membered ring is very reactive and susceptible to nucleophilic attack. Think about amide resonance from introductory organic chemistry and its effect on amide reactivity. In the case of the β-lactam ring, amide resonance is diminished. For steric reasons the bonds to the nitrogen cannot be planar; the opening of the four-membered ring relieves strain.

Penicillins can react with amines to form inactive amides. This has implications on co-administration and formulation.

Activity – Can you draw a reaction mechanism for the scheme shown below?

Penicillins are also generally susceptible to hydrolysis under alkaline conditions. Alkaline hydrolysis can be catalysed by the presence of metal ions such as Cu2+.The resulting hydrolysis products do not possess antibacterial activity; this is valuable knowledge for the storage, analysis, and processing of these medicinal chemistry compounds.

Penicillins are also generally susceptible to hydrolysis under alkaline conditions. Alkaline hydrolysis can be catalysed by the presence of metal ions such as Cu2+.The resulting hydrolysis products do not possess antibacterial activity; this is valuable knowledge for the storage, analysis, and processing of these medicinal chemistry compounds.

Like many other drugs, penicillins face enzyme-catalysed degradation in vivo. Amidases catalyse the conversion of the C6 amide to an amine. Amidases are useful in industry for the production of 6-Aminopenicillanic acid (6-APA). This compound is used a precursor for many semisynthetic penicillins.

Drug resistance is also a growing problem.β-lactamases (beta lactamases) are mainly responsible for this.

β-lactamases are serine protease enzymes that act against the β-lactam drugs through a similar mechanism as the transpeptidase enzyme; the bacterial enzyme targeted by penicillin. The mechanism of action will be shown later.

β-lactamases are serine protease enzymes that act against the β-lactam drugs through a similar mechanism as the transpeptidase enzyme; the bacterial enzyme targeted by penicillin. The mechanism of action will be shown later.

  • Augmentin®: Amoxicillin + clavulanic acid
  • Timentin®: Ticarcillin + clavulanic acid

Drug resistance is also a growing problem.β-lactamases (beta lactamases) are mainly responsible for this.

Synthesis of Semisynthetic Derivatives

We briefly mentioned 6-APA earlier. 6-APA is acquired through enzymatic hydrolysis of Penicillin G or Penicillin V, or through traditional organic chemistry. Reaction with an acid chloride at the C6 primary amine allows the synthesis of many semisynthetic penicillin derivatives (try to draw the reaction mechanism as practice!). The free carboxylic acid is, though, a possible site of modification. Ester prodrugs such as pivampicillin were developed to improve the pharmacokinetic properties of their parent drug. Pivampicillin is a pivaloyloxymethyl ester prodrug of ampicillin.

Spectroscopy

We emphasized the cis stereochemistry of the H5-H6 protons at the start of this beta-lactam review. Generally speaking, the H5-H6 coupling constant (1H NMR) is in the range of 4-5 Hz. 13C NMR studies and DEPT experiments would help distinguish between CH, CH2 and CH3. When studying the IR spectra of penicillins, one must be on the lookout for the carbonyl stretches – particularly for the characteristic β-lactam carbonyl stretch at around 1770-1790 cm-1.

Depending on which penicillin is being studied, the side chain would give characteristic NMR and IR signals.The predicted 1H NMR spectrum of ampicillin is shown below. Note that the spectrum below is merely an estimate. Can you explain why the benzylic protons appear shifted downfield than expected?