Pleuromulin CAS 125-65-5

Pleuromulin is a class of potent antibacterial agents first isolated from the edible mushroom Clitophilus scyphoides in 1951, with a unique mechanism of inhibiting bacterial protein synthesis by binding to the 50S ribosomal subunit, thus avoiding cross-resistance with other major antibiotic classes. Its applications are mainly divided into veterinary medicine and human medicine, with semisynthetic derivatives playing a key role in both fields. In veterinary medicine, it is widely used to treat bacterial infections in food-producing animals, especially pigs and poultry.

Derivatives like tiamulin and valnemulin are effective against swine dysentery, porcine proliferative enteropathy, and enzootic pneumonia, as well as Mycoplasma infections in poultry and epizootic rabbit enteropathy, with specific doses adjusted for different animals and administration routes including feed, drinking water, and intramuscular injection. In human medicine, the development of derivatives has expanded its application: retapamulin is used topically for skin infections, while lefamulin, approved by the FDA in 2019, is the first systemic pleuromutilin for treating community-acquired bacterial pneumonia and acute bacterial skin infections. Notably, Pleuromulin has low spontaneous mutation frequency and slow resistance development, making it valuable in combating drug-resistant pathogens, though its use requires prudent monitoring to prevent resistance emergence.

Pleuromulin is a broad-spectrum diterpene antibiotic produced by Pleurotus ostreatus.

1. It can inhibit the synthesis of bacterial protein, so as to achieve the effect of inhibiting bacterial growth. Its mode of action is different from other types of antibiotics.

2. In terms of mechanism of action. Truncated Pleurotus antibiotics mainly act on the ribosome level of bacterial cells. It blocks the synthesis of bacterial proteins by inhibiting the activity of peptidyl transferase, so as to achieve a broad-spectrum antibacterial effect.

The truncated Pleurotus ostreatus drug is composed of three rings, forming the main skeleton, and its basic structure is an eight membered ring; The carbonyl group on the five membered ring and the hydroxyl group on C-11 are necessary groups for activity. Most of the studies abroad are chemical modification of C-14 to greatly improve its antibacterial activity and bioavailability. Because the C-14 of the truncated pleurotin drug contains free hydroxyl, it has no activity; By modifying the structure of C-14 into, derivatives with enhanced antibacterial activity against bacteria and mycoplasma can be obtained.

In addition, the antibacterial activity of compounds with neutral or acidic groups connected by C-14 side chains is very low, and the activity of connecting two basic side chains is also very low; However, the activity of thioether side chain derivatives connected to the basic center has been decisively improved. For example, tamoxin fumarate is a drug that contains thioether side chains. However, if the sulfur atom in the Thioether Group is replaced by the oxygen atom, the activity of the truncated pleurotin drug will be sharply reduced. If other basic substituents, such as guanidine or primary amine, are added to the side chain at the C-14 position, the activity level of thioether derivatives cannot be reached, and it is easy to hydrolyze and inactivate in vivo. Therefore, acylation modification of the C-14 position of the truncated pleurotin compound can significantly reduce the minimum inhibitory concentration and improve the antibacterial activity.

The molecular structure of Pleuromulin consists of four circular structures, as shown in the figure. Among them, the first ring is a benzo ring, the second ring is an oxygen heterocyclic ring, the third ring is a nitrile heterocyclic ring, and the fourth ring is a pyrrole ring. They are interconnected through C-C and C-N single bonds, forming complex molecular structures. This category of polycyclic compounds is commonly referred to as polycyclic ketones or polycyclic lactones.

(1) Spectroscopic analysis
Ultraviolet spectroscopy can provide information on the electronic structure of product. It exhibits two distinct absorption peaks in the ultraviolet region, located at 246 nm and 279 nm, respectively. These peaks can be attributed to their π - π * transitions and n - π * transitions. Near infrared spectroscopy can provide information about the molecular vibrational modes of product. The near-infrared spectroscopy shows the vibrational bands of various functional groups, such as carbonyl, hydroxyl, amino, and oxygen groups.

Nuclear magnetic resonance (NMR) technology can provide molecular structure information of product. Usually, ^ 1H NMR spectroscopy and ^ 13C NMR spectroscopy are used to determine its structure. In the ^ 1H NMR spectrum, it displays multiple chemical shift peaks, and the differences between these peaks can be used to determine the positions of different protons in the molecule. For example, it shows three peaks of methylene protons, with a single peak at 0.8 ppm caused by the first methylene proton, and a double peak at 1.2 ppm caused by the second and third methylene protons.

(2) Mass spectrometry analysis
Mass spectrometry is a very important tool that can provide molecular weight and structural information of molecules. In mass spectrometers, it is typically analyzed using high-resolution liquid chromatography-mass spectrometry (LC-MS). Electro spray ionization (ESI) or atmospheric pressure chemical ionization (APCI) are commonly used ionization technologies. In the mass spectrum, it shows the molecular ion peak [M+H] ^+at m/z 372, which conforms to its molecular formula.

(3) X-ray crystallographic analysis
X-ray crystallography is a technique used to determine crystal structure by projecting crystals into a beam of radiation, collecting scattering data, and using computational methods to analyze molecular structure. When using this technology, Pleuromulin needs to be crystallized and formed into a single crystal. Then, the crystal structure is determined by measuring the scattering mode of the crystal under an X-ray beam. Ultimately, X-ray crystallography technology can provide detailed information on molecular flow direction, atomic distance, and angle.