Synthesis and Biological Evaluation of Macrocyclic Ligands

Macrocyclic ligands are ring-shaped molecules, typically containing twelve or more atoms, that offer unique structural preorganisation and high binding affinities for metal ions and biological targets. Their synthesis exploits a variety of strategies, including template-directed cyclisation, ring-closing metathesis and modern “click” chemistries, each designed to overcome entropic barriers to macrocycle formation. Functionalisation of the macrocyclic core with heterocyclic building blocks such as pyrazoles, tetrazoles or pyridines further tunes binding selectivity and biological activity. In metal complexation, macrocycles organize donor atoms in well defined geometries, yielding complexes with tailored redox, catalytic or imaging properties. In medicinal contexts, incorporation of hydrophobic and polar residues within the ring delivers candidates for antimicrobial, antifungal and enzyme-inhibitory applications. Rigorous structure–activity relationships (SAR) underpin optimisation of these scaffolds, guiding modifications that improve potency, solubility and metabolic stability. Advances in spectroscopic and crystallographic characterisation have clarified how ring size, donor set and conformational rigidity correlate with binding thermodynamics. Overall, the field is moving towards rational design of macrocycles that integrate multiple binding modalities, with growing emphasis on green-chemistry synthesis and in vitro biological evaluation against both microbial pathogens and therapeutic enzyme targets.

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Synthesis and Biological Evaluation of Macrocyclic Ligands publication trend

The graph below shows the total number of articles in synthesis and biological evaluation of macrocyclic ligands across all publications each year (not limited to Nature Index journals).

Technical terms

Macrocyclic ligand: A ring-shaped molecule, typically with more than twelve atoms, that can encircle and bind metal ions or biomolecular targets with high affinity.

Template-directed synthesis: A cyclisation approach in which a metal ion or molecular scaffold organises reactive precursors into a ring before bond formation.

Ring-closing metathesis: A catalytic reaction using metal carbenes to join the termini of a linear precursor, forming a carbon–carbon double bond within a macrocycle.

Metal chelation: The process by which a multidentate ligand binds a metal centre through several donor atoms, forming a stable complex.

Structure–activity relationship (SAR): A systematic analysis of how molecular modifications affect biological activity, guiding optimisation of lead compounds.

IC₅₀: The concentration of a compound required to inhibit a specific biological function or enzyme activity by 50%, used as a measure of potency.

References

1. Insights on the Synthesis of N-Heterocycles Containing Macrocycles and Their Complexion and Biological Properties. Molecules (2022).
2. Alkali Metal Complexes of an Octamethyl Isomeric Macrocycle: Synthesis, Characterization and Antimicrobial Studies. Asian Journal of Chemistry (2023).
3. New Generation of Hybrid Pyrazole–Tetrazole Tetrapodal Compounds: Synthesis and Biological Activities. Organics (2024).