Synthesis and Biological Activity of Heterocyclic Derivatives

The synthesis of nitrogen‐containing heterocycles has undergone remarkable evolution, driven by the need for novel therapeutics and sustainable processes. Core scaffolds such as quinazolines, quinazolinones, quinoxalines and related bridged or fused systems have been accessed via multi‐component reactions, metal‐free domino sequences, photocatalytic methods and microwave‐assisted protocols. Green and atom‐efficient approaches now predominate, reducing reliance on harsh reagents and enabling one‐pot assemblies of complex motifs. Structure–activity relationship studies have revealed that subtle substitution at key ring positions can modulate lipophilicity, target binding and cell permeability. Biologically, heterocyclic derivatives exhibit a spectrum of activities including antiviral, antibacterial, anticancer, anti‐inflammatory and enzyme‐inhibitory effects. Halogenation, hybridisation with natural product scaffolds and incorporation of fluorescent reporters have further enhanced potency, selectivity and imaging capabilities. Together, these advances illustrate how rational design, sustainable synthesis and detailed bioactivity profiling are converging to deliver multifunctional small molecules with applications spanning drug discovery, chemical biology and agriscience.

Research from Nature Portfolio

Recent studies have established a fully metal‐free, one‐pot domino protocol to assemble 4,5,7,8‐substituted quinazolines endowed with intrinsic fluorescence. This strategy merges multiple bond‐forming steps under mild conditions, affording high yields while avoiding transition‐metal residues. The newly synthesised heterocycles display potent antiviral activity against human cytomegalovirus with half‐maximal effective concentrations in the submicromolar range. In addition, hybridisation of artesunic acid with the quinazoline core yielded conjugates that retained antiviral potency and fluorescence, paving the way for simultaneous mechanistic studies and cellular uptake visualisation without external labelling.

Synthesis and Biological Activity of Heterocyclic Derivatives publication trend

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

Technical terms

Heterocycle: A cyclic compound featuring one or more atoms other than carbon within the ring.

Quinazoline: A bicyclic system consisting of a benzene ring fused to a pyrimidine moiety.

Domino reaction: A sequence of bond‐forming events that occur under a single set of conditions without isolating intermediates.

Photocatalyst: A substance that accelerates a chemical reaction upon absorption of light, enabling milder reaction conditions.

Structure–activity relationship (SAR): The correlation between chemical structure modifications and changes in biological activity.

Enzyme inhibition: The reduction of enzyme activity by a small molecule binding at or near the active site.

References

1. Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions. Nature Communications (2017).
2. TBA(FeCl3Br) Complex as a Photocatalyst in the Csp3–H Bond Activation in Alcohols for the Synthesis of N‑Based Heterocycles. ACS Sustainable Chemistry & Engineering (2024).
3. In Vitro α-Glucosidase and α-Amylase Inhibition, Cytotoxicity and Free Radical Scavenging Profiling of the 6-Halogeno and Mixed 6,8-Dihalogenated 2-Aryl-4-methyl-1,2-dihydroquinazoline 3-Oxides. Antioxidants (2023).