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Harnessing the Power of Macrocycles: Advancing Drug Discovery and Combating Tuberculosis

May 25, 2023

Figuring Out Macrocycles

Macrocycles are molecules and ions containing a ring of twelve or more atoms, representing attractive candidates in organic synthesis and drug discovery. They stand in the “middle space” between the two molecular weight extremes, small molecules, and biologics, and combine the best characteristics of both.

Macrocyclic compounds have several features that make them “up to the taskto tackle “difficult” genomic targets with extended binding sites, i.e., class B G-protein-coupled receptors (GPCRs), protein−protein interactions, and some enzymes. Until recently, the most common approach to moderate these targets was “biologics” drugs, with limitations of high cost, reduced patient compliance, lack of cellular penetration, and low oral bioavailability.

Compounds in this space are bigger and more complex than small molecules, engaging
targets through numerous and spatially distributed binding interactions, thereby increasing both binding affinity and selectivity [1]. In addition, macrocyclization may improve plasma stability, cell permeability, and oral absorption [2].

Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by the FDA for treating bacterial and viral infections, cancer, obesity, immunosuppression, etc. [3].

As the role of macrocycles in pharmaceuticals increases, there is an urgent need for new synthetic methodologies and approaches to access various macrocycle entities.

Enhancing the pharmaceutical toolbox to fight tuberculosis

Pyridine-based macrocycles have been found to have strong antibacterial activity against Mycobacterium tuberculosis and other bacteria.

Although Mycobacterium tuberculosis (Mtb), which causes Tuberculosis (TB) disease, was identified more than 130 years ago, there is still an urgent demand for new anti-TB entities, since classical toxic drugs are losing their effectiveness [4].

Macrocycles, with their diverse chemical structures and the potential to bind to challenging targets, offer a new avenue to improve treatment outcomes. They can target essential proteins and enzymes within the bacteria, disrupting critical cellular processes and inhibiting bacterial growth. Additionally, macrocycles can be designed to have improved pharmacokinetic properties, enhancing their efficacy and reducing the likelihood of resistance development.

Pyridine and imidazole scaffolds compounds stand out as promising molecules against drug resistance and can contribute considerable improvements in drug discovery of new antitubercular agents.

The pharmacophore combination of well-defined scaffolds is proven to be one of the most useful strategies in drug discovery. Studies showed that the combination of pyridine, imidazole/benzimidazole and p-chlorobenzoyl moieties (evaluated for their in vitro antimycobacterial activity against Mtb H37Rv (grown under aerobic conditions), could be an excellent solubility microbiological medium for a future drug candidate [5].

VIO Chemicals biocatalytic route

We have developed a biocatalytic route that offers a simplified and cost-effective manufacturing process for 2,6-Bis(hydroxymethyl)pyridine, a valuable precursor in manufacturing macrocycles.

The enzymatic transformation simplifies the multi-step classical chemical route to a one-pot reaction, offering a sustainable alternative with high productivity and excellent space-time yields.

Learn more about it.


  1. Giordanetto F., Kihlberg J., (2013). Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties? Journal of Medicinal Chemistry, 57(2), 278–295. DOI:10.1021/jm400887j 
  2. Begnini F., Poongavanam V., Over B., Castaldo M., Geschwindner S., Johansson P., Tyagi M., Tyrchan C., Wissler L., Sjö P., Schiesser S., Kihlberg J., (2021). Mining Natural Products for Macrocycles to Drug Difficult Targets. Journal of Medicinal Chemistry, 64 (2), 1054-1072 DOI: 10.1021/acs.jmedchem.0c01569
  3. Sun D., (2022). Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles. Molecules, 2;27(3):1012. DOI: 10.3390/molecules27031012. PMID: 35164274; PMCID: PMC8839925.
  4. Villamizar-Mogotocoro AF., Vargas-Méndez LY., Kouznetsov VV., (2020) Pyridine and quinoline molecules as crucial protagonists in the never-stopping discovery of new agents against tuberculosis. Eur J Pharm Sci. DOI: 10.1016/j.ejps.2020.105374.
  5. https://www.future-science.com/doi/10.4155/fmc-2019-0063