Review articleA closer look at N2,6-substituted 1,3,5-triazine-2,4-diamines: Advances in synthesis and biological activities
Graphical abstract
Introduction
The 1,3,5-triazine ring has been attracting the attention of researchers around the world as a skeleton for diverse bioactive molecules. The explored chemical space around the 1,3,5-triazine scaffold is shaped by the availability of cyanuric chloride (1) as an inexpensive and convenient starting material [1]. The selective sequential replacement of chlorine atoms by nucleophiles (typically N-, O-, S-, or P-nucleophiles) under controlled conditions allowed the preparation of a great variety of 2,4,6-substituted 1,3,5-triazines (Scheme 1). This approach can be applied to synthesise N2,6-substituted 1,3,5-triazine-2,4-diamines (N2-substituted guanamines) (Fig. 1), but the utility of the method is limited by availability and compatibility issues of C-nucleophiles. Therefore, the diversity of synthetic approaches to N2,6-substituted 1,3,5-triazine-2,4-diamines has been expanding with increasing interest over the past decade. The second section of this review discusses advances in the synthesis of N2,6-substituted 1,3,5-triazine-2,4-diamines with the R1 substituent connected to the triazine ring via the C–C bond.
Historically, the 1,3,5-triazine chemistry focused on pesticide development. That resulted in the introduction of several effective agents for crop protection, including cellulose biosynthesis inhibitors indaziflam [2,3] and triaziflam [4], which share the N2,6-substituted 1,3,5-triazine-2,4-diamine scaffold (Fig. 1). However, recent research directions on the biological activities of N2,6-substituted 1,3,5-triazine-2,4-diamines shifted more towards their pharmacological effects and potential therapeutic applications. The most interesting findings are discussed in the third section of this review.
Section snippets
Synthesis of N2,6-substituted 1,3,5-triazine-2,4-diamines
Depending on the starting materials for constructing the scaffold of our interest, methods for the synthesis of N2,6-substituted 1,3,5-triazine-2,4-diamines can be formally classified to:
- 1.
Reactions of biguanides with one-carbon inserting synthons
- 2.
Reactions of amidines with dielectrophilic reagents
- 3.
Rearrangements involving 1,3,5-ring formation
- 4.
Multicomponent reactions
- 5.
Functionalisation of 1,3,5-triazines
The discussion of synthetic approaches to N2,6-substituted 1,3,5-triazine-2,4-diamines in the
Biological activity of N2,6-substituted 1,3,5-triazine-2,4-diamines
The pharmacology of N2,6-substituted 1,3,5-triazine-2,4-diamines is rather diverse. The combination of substituents in position 6 and at one of the amino groups of 1,3,5-triazine-2,4-diamines determines the affinity and selectivity of these compounds to different biological targets. The advancements in this area are exemplified below according to the targeted biomolecules.
Conclusion
N2,6-Substituted 1,3,5-triazine-2,4-diamines have demonstrated potential for developing new bioactive compounds. This skeleton serves well for constructing molecules targeting various enzymes, receptors, transporters, and nucleic acids with an array of therapeutic applications, particularly in cancer, inflammation, and CNS disorders. Many bioactive N2,6-substituted 1,3,5-triazine-2,4-diamines have been developed in the last two decades, mainly targeting several cancer-related enzymes such as
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
This work is supported by the Ministry of Higher Education, Malaysia under Fundamental Research Grant Scheme (Grant no. FRGS/1/2020/STG04/MUSM/02/2).
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