Pyridine Compounds with Antimicrobial Activities

Pyridine antibiotics are compounds containing a pyridine ring and are used as anti-infective agents. The chemical was initially synthesized by Ramsey in 1877, then further developed by Hanch's synthetic approach. Pyridine is a six-membered nitrogen-containing heteroaromatic. It's chemically resembling benzene, but with special weak alkali and aromatic stability as it has nitrogen atoms. Such features make it a basic concept for the design of multi-biological drugs (antibacterial, antiviral, antifungal). The effect of therapy can be enhanced by adding more rings or functional groups and drug-resistant strains can be targeted in specific ways. Improved pharmacokinetic and bioavailability make pyridine derivatives an interesting route for combating the antimicrobial resistance challenge.

Chemistry of pyridine compounds

Chemical structure of pyridine

Pyridine is a six-membered aromatic ring structure, wherein a carbon atom has been swapped out for a nitrogen atom, giving it radically different electron distribution from benzene. Pyridine's nitrogen atom has a single pair of electrons that are absent from aromatic electron delocalisation, so it's a weak base and a potential tertiary amine for protonation and coordination reactions. It also enhances the hydrogen bonding of pyridine with biological molecules like enzymes and proteins, critical to the therapeutic efficacy of drugs. Furthermore, pyridine is able to form stable salts by protonating with acids, which makes its salts more soluble in water and hence more bioavailable.

Structure, numbering, and active sites of pyridine. (Islam, M. B., 2023)

The electron-withdrawing effect of the nitrogen atom causes the pyridine ring to appear electron-deficient, especially at the C-2 and C-4 positions, which is conducive to the occurrence of nucleophilic substitution reactions. Electrophilic substitution reactions are rare and usually need to be carried out under extreme conditions due to the passivation of nitrogen atoms.

Various functional groups introduced by the nucleophilic substitution reaction, such as amino (-NH2), hydroxyl (-OH), methoxy (-OCH3), and sulfanilide (-SO2NH2), significantly enhanced the antibacterial activity of pyridine. These functional groups increase the binding affinity of pyridine derivatives to bacterial or viral targets by strengthening hydrogen bonds or increasing lipophilicity, helping them penetrate cell membranes. For example, amino and hydroxyl groups enhance biological activity by interacting with the active site of the enzyme, while electron-withdrawing groups such as nitro groups (-NO ˇ) enhance activity by stabilizing the conformation of key molecules.

Biological relevance of pyridine

Pyridine is a structural component of a variety of natural products, including alkaloids (such as nicotine), vitamins (such as nicotinic acid and pyridoxine), and coenzymes (such as NAD and NADP). These natural products play an important role in the nervous system, metabolic pathways and redox reactions of cellular metabolism. The naturally occurring pyridine molecule not only highlights its importance in evolution, but also provides inspiration for the design of synthetic analogues with similar or enhanced biological functions. For example, synthetic derivatives of niacin have shown great potential in the treatment of cardiovascular and metabolic diseases due to their ability to regulate lipid profiles and inflammatory responses.

Synthesis of pyridine compounds

In order to cope with the increasingly serious problem of antibiotic resistance, the synthesis technology of pyridine derivatives has undergone significant progress. Pyridine, as a multifunctional scaffold, can be functionalized in multiple locations, thereby developing derivatives with enhanced biological activity and therapeutic potential. Improvements in synthetic technology provide an effective way to introduce different substituents or achieve the fusion of pyridine with other heterocycles, broadening the application range of pyridine in drug design.

Synthesis of substituted pyridine

A common method to increase the activity of pyridine antibiotics is to introduce functional groups that improve pharmacological properties. Substituents such as nitro, amino, hydroxyl and methoxy can significantly affect the molecular stability, solubility and target binding affinity of pyridine derivatives.

Functional groups are often introduced at the C-2 and C-4 positions of the pyridine ring to improve the antibacterial activity of pyridine compounds. Modern methods such as metal-catalyzed cross-coupling reactions (such as Suzuki or Heck couplings) further enhance the ability to introduce complex functional groups into pyridine scaffolds. These methods have high selectivity and high yields and are suitable for the synthesis of derivatives with specific biological activities. The multi-step synthesis of nicotinic acid derivatives is a typical example. These compounds have broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria, and their effectiveness has been verified in particular against drug-resistant strains such as Staphylococcus aureus and Escherichia coli.

Synthesis of ring-fused pyridine

The fusion of pyridine with other heterocycles is an effective strategy to improve its therapeutic performance. This approach not only adds molecular complexity, but also provides additional functional groups to interact with bacterial or viral targets.

Ring fusion strategies often involve cyclization reactions that integrate pyridine into a larger heterocyclic framework. These methods include multi-component reactions (MCR), ring condensation processes, and catalyst-mediated conversions. By combining pyridine with other biologically active ingredients such as imidazole, thiazole, or oxazolidinone, molecules with dual or enhanced modes of action can be created.

Catalyst-assisted synthesis

The use of catalysts significantly improves the synthesis of pyridine antibiotics and achieves environmentally friendly and efficient reactions. The catalyst-assisted method improves reaction efficiency, reduces synthesis steps, and facilitates the formation of a variety of pyridine derivatives.

Multi-component reaction (MCR): MCR involves the simultaneous reaction of three or more precursors and is particularly suitable for the synthesis of complex pyridine derivatives. Lewis acids (such as SnCl ˇ or FeCl) and transition metal complexes (such as Pd or Ni catalysts) promote these reactions, providing a high degree of structural diversity. For example, a recent study used zeolite catalysts to synthesize substituted pyridines in a three-component reaction of formaldehyde, ammonia and ethanol. The resulting derivatives have high purity and significant antibacterial activity.

Zeolite and green catalysis: Zeolite catalysts have high specific surface area and adjustable acidity, and perform well in pyridine synthesis. They react under mild conditions, reducing energy consumption and minimizing the use of harmful solvents. Integrating green chemistry principles into pyridine synthesis is not only in line with the Sustainable Development Goals, but also provides a scalable method for industrial production.

Antibacterial mechanism of pyridine

Pyridine antibiotics disrupt the survival and proliferation of microorganisms by targeting the basic structure and processes of bacteria. Its unique chemical properties allow it to interact with specific molecular targets and exert effective antibacterial activity.

Pyridine derivatives bind to the active sites of bacterial DNA rotation-cutting enzymes and topoisomerase, preventing unwinding and supercoiling of bacterial DNA, thereby inhibiting cell division and inducing bacterial apoptosis. For example, fluorinated pyridine compounds have shown significant effects in inhibiting DNA spin-cutting enzymes in Gram-positive pathogens.

Certain pyridine derivatives act by destabilizing bacterial cell walls. These compounds interfere with the synthesis of peptidoglycans, key components of bacterial cell walls, weakening the structural integrity of the cell wall and causing cell lysis. The cell wall is the main protective barrier for Gram-positive bacteria, and these pyridine antibiotics can effectively inhibit Gram-positive bacteria.

Antibacterial pyridine derivatives at BOC Sciences

Pharmaceutical fermentation services at BOC Sciences

Application of pyridine antibiotics

Sulfapyridine, one of the earliest pyridine-based antibiotics, works by inhibiting folate synthesis of bacteria and has antibacterial activity against a variety of gram-positive and gram-negative bacteria.

Isoniazid contains a pyridine ring and is an antibiotic used to treat tuberculosis. Its antibacterial mechanism is mainly by inhibiting the synthesis of mucopeptides in the cell wall of Mycobacterium tuberculosis. Ethiamide is a prodrug that is activated by ethanase, a monooxygenase in Mycobacterium tuberculosis, and then binds with NAD+ to form an adduct that inhibits InhA like isoniazid.

Quinolones antibiotics are synthetic antibacterial drugs. The fluoroquinolone derivative delafacin showed strong activity against Gram-positive bacteria, including MRSA, and some Gram-negative bacteria. Its broad-spectrum coverage and enhanced pharmacokinetic properties (such as improving tissue penetration and reducing the development of drug resistance) make it a valuable option for the treatment of severe infections. Similarly, cefotalin is a cephalosporin derivative with a pyridine core that is effective against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae.

Pyridine derivatives have shown significant effects on pathogens that are resistant to traditional antibiotics. For example, pyridine-imidazole mixtures have shown excellent efficacy against MRSA by targeting DNA replication and bacterial protein synthesis pathways. In addition, oxazolidinone pyridine derivatives are effective against vancomycin-resistant enterococci (VRE), expanding their therapeutic potential in hospital-acquired infections.

Studies have shown that pyridine derivatives are superior to standard treatment in some cases. For example, the antibacterial activity of niacin derivatives against fungal pathogens such as Candida albicans and Aspergillus niger is comparable to, or even better than, fluconazole. Similarly, Mannich bases and quaternary ammonium pyridinium salts have shown strong inhibitory effects on Gram-positive and Gram-negative bacteria, comparable to existing antibiotics such as norfloxacin.

References

1. Islam, M. B., et al. Recent advances in pyridine scaffold: Focus on chemistry, synthesis, and antibacterial activities. BioMed Research International. 2023, 2023(1): 9967591.
2. Marinescu, M., Popa, C. V. Pyridine compounds with antimicrobial and antiviral activities. International Journal of Molecular Sciences. 2022, 23(10): 5659.