Imidazopyrimidine: from a relatively exotic scaffold to an evolving structural motif in drug discovery

Abstract

Nitrogen-fused heterocycles are of immense importance in modern drug discovery and development. Among them, imidazopyrimidine is a highly versatile scaffold with vast pharmacological utility. These compounds demonstrate a broad spectrum of pharmacological actions, including antiviral, antifungal, anti-inflammatory, and anticancer. Their adaptable structure allows for extensive structural modifications, which can be utilized for optimizing pharmacological effects via structure-activity relationship (SAR) studies. Additionally, imidazopyrimidine derivatives are particularly noteworthy for their ability to target specific molecular entities, such as protein kinases, which are crucial components of various cellular signaling pathways associated with multiple diseases. Despite the evident importance of imidazopyrimidines in drug discovery, there is a notable lack of a comprehensive review that outlines their role in this field. This review highlights the ongoing interest and investment in exploring the therapeutic potential of imidazopyrimidine compounds, underscoring their pivotal role in shaping the future of drug discovery and clinical medicine.

Fig. 1. Structures of pyrimidine (1) and imidazo[1,2-a]pyrimidine (2).

Fig. 2. Structural representation of (3) lapatinib, (4) gefitinib, (5) vandetanib, and (6) erlotinib.

Fig. 3. Chronology of the evolution of imidazopyrimidines based on their biological activity.

Fig. 4. Graphical representation of the emerging trend of imidazopyrimidines garnering research attention.

Fig. 5. Binding interactions of imidazopyrimidine-conjugated benzimidazole tubulin inhibitors. Red dashed lines showing H-bond interactions.

Fig. 6. Binding interactions of imidazo[1,2-a]pyrimidine-conjugated indole in Raf kinase inhibitors.

Fig. 7. (A) Ribbon structure showing binding of 10 to Raf kinase inhibitors and further magnified allosteric site of Raf kinase inhibitors with the bound ligand in red. (B) Ribbon structure showing binding of 11e to Raf kinase inhibitors and further magnified allosteric site of Raf kinase inhibitors with 11e. PDB ID: 3IDP.

Fig. 8. (A) Ribbon structure showing binding of imatinib to PKM2 inhibitors and further magnified allosteric site of PKM2 kinase inhibitors with the bound ligand in blue. (B) Ribbon structure showing binding of 16a to PKM2 kinase inhibitors and further magnified allosteric site of PKM2 kinase inhibitors with 16a. PDB ID: 4B2D. (C) Key interactions of 16a with the allosteric site of PKM2 kinase inhibitors. The dark pink colour represents the pi–pi interaction, light pink represents the pi–alkyl type of interaction, the red colour represents the pi–sigma type of interaction, the green colour represents the H-bonding and the orange colour represents the other miscellaneous interactions.

Fig. 9. Modification of imidazopyrimidine as a critical scaffold after several modifications on the hit scaffold.

Fig. 10. MIC values of selenium linked imidazopyrimidine derivatives against different fungus species (all concentrations are expressed in μg ml⁻¹).

Fig. 11. Screening of different compounds against C. albicans in comparison with griseofulvin.

Fig. 12. Improvement of antiviral activity by lead optimization from the hit core.

Fig. 13. (A) Ribbon structure showing binding of 34 to the pseudomonas virus bound ligand in yellow. (B) Magnified ribbon structure showing binding of 34 to the pseudomonas species. PDB ID: 5T6S and key interactions of 34 with F303, L347, Y433 and L37.

Fig. 14. Heteroarylamide derivatives of imidazopyrimidine play an essential role in phosphodiesterase 10A (PDE10A).

Moumita Ghosh Chowdhury

Vaishnavi Kalmegh

Saumya Kapoor

Vaishnavi Kamble

Amit Shard