Review article
A closer look at N2,6-substituted 1,3,5-triazine-2,4-diamines: Advances in synthesis and biological activities

https://doi.org/10.1016/j.ejmech.2022.114645Get rights and content

Highlights

  • Synthetic approaches to N2,6-substituted 1,3,5-triazine-2,4-diamines.

  • Diverse biotargets for N2,6-substituted 1,3,5-triazine-2,4-diamines.

  • N2,6-substituted 1,3,5-triazine-2,4-diamines as enzyme inhibitors.

  • N2,6-substituted 1,3,5-triazine-2,4-diamines as receptor ligands.

  • Anticancer N2,6-substituted 1,3,5-triazine-2,4-diamines.

Abstract

N2,6-Substituted 1,3,5-triazine-2,4-diamines (N2-substituted guanamines) attracted significant interest due to their potential in the development of bioactive molecules. With just two points of diversity, this scaffold is proved to be suitable for constructing compounds targeting various enzymes, receptors, transporters, and nucleic acids with an array of therapeutic applications, particularly in cancer, inflammation, and CNS disorders. This review discusses progress in the synthesis of N2,6-substituted 1,3,5-triazine-2,4-diamines and their biological activities ranging from the inhibition of cancer-related enzymes (e.g. DNA topoisomerase IIα, carbonic anhydrases, ubiquitin-conjugating enzyme 2B, lysophosphatidic acid acyltransferase β and various kinases) to the binding to CNS-relevant receptors (e.g. histamine H4, serotonin 5-HT6, adenosine A2a, and α7 nicotinic acetylcholine receptors).

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).

References (109)

  • C. Liu et al.

    A novel one-pot synthesis of N,6-disubstituted 1,3,5-triazine-4,6-diamines from isothiocyanates and amidines

    Tetrahedron Lett.

    (2007)
  • D.W. Ludovici et al.

    Evolution of anti-HIV drug candidates part 2: diaryltriazine (DATA) analogues

    Bioorg. Med. Chem. Lett.

    (2001)
  • P. Zhao et al.

    Iodine-promoted multicomponent synthesis of 2,4-diamino-1,3,5-triazines

    Org. Lett.

    (2020)
  • B. Pogorelčnik et al.

    Monocyclic 4-amino-6-(phenylamino)-1,3,5-triazines as inhibitors of human DNA topoisomerase IIα

    Bioorg. Med. Chem. Lett

    (2014)
  • F. Sączewski et al.

    Carbonic anhydrase inhibitors: inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides

    Bioorg. Med. Chem.

    (2008)
  • Z. Brzozowski et al.

    Carbonic anhydrase inhibitors. Regioselective synthesis of novel series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII

    Eur. J. Med. Chem.

    (2012)
  • M.A. Sanders et al.

    Pharmacological targeting of RAD6 enzyme-mediated translesion synthesis overcomes resistance to platinum-based drugs

    J. Biol. Chem.

    (2017)
  • B. Haynes et al.

    Gold nanoparticle conjugated Rad6 inhibitor induces cell death in triple negative breast cancer cells by inducing mitochondrial dysfunction and PARP-1 hyperactivation: synthesis and characterisation

    Nanomed. Nanotechnol. Biol. Med.

    (2016)
  • H. Kothayer et al.

    Synthesis and in vitro anticancer evaluation of some 4,6-diamino-1,3,5-triazine-2-carbohydrazides as Rad6 ubiquitin conjugating enzyme inhibitors

    Bioorg. Med. Chem. Lett.

    (2016)
  • M.G. Douvas et al.

    Effect of lysophosphatidic acid acyltransferase-β inhibition in acute leukemia

    Leuk. Res.

    (2006)
  • F. Hong et al.

    N-diarylpyridine positional isomers as inhibitors of lysophosphatidic acid acyltransferase-β

    Bioorg. Med. Chem. Lett.

    (2005)
  • J.M. Atkinson et al.

    An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma

    Cancer Cell

    (2011)
  • W.J. Pitts et al.

    Rapid synthesis of triazine inhibitors of inosine monophosphate dehydrogenase

    Bioorg. Med. Chem. Lett.

    (2002)
  • M. Bader

    Inhibition of serotonin synthesis: a novel therapeutic paradigm

    Pharmacol. Ther.

    (2020)
  • H. Jin et al.

    Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors

    Bioorg. Med. Chem. Lett.

    (2009)
  • D. Łażewska et al.

    Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands

    Eur. J. Med. Chem.

    (2014)
  • K. Kamińska et al.

    (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands

    Eur. J. Med. Chem.

    (2015)
  • D. Łażewska et al.

    Alkyl derivatives of 1,3,5-triazine as histamine H4 receptor ligands

    Bioorg. Med. Chem.

    (2019)
  • D. Łażewska et al.

    The computer-aided discovery of novel family of the 5-HT6 serotonin receptor ligands among derivatives of 4-benzyl-1,3,5-triazine

    Eur. J. Med. Chem.

    (2017)
  • D. Łażewska et al.

    Synthesis and computer-aided analysis of the role of linker for novel ligands of the 5-HT6 serotonin receptor among substituted 1,3,5-triazinylpiperazines

    Bioorg. Chem.

    (2019)
  • W. Ali et al.

    Synthesis and computer-aided SAR studies for derivatives of phenoxyalkyl-1,3,5-triazine as the new potent ligands for serotonin receptors 5-HT6

    Eur. J. Med. Chem.

    (2019)
  • K.G. Ma et al.

    Alpha 7 nicotinic acetylcholine receptor and its effects on Alzheimer's disease

    Neuropeptides

    (2019)
  • U. Švajger et al.

    Novel toll-like receptor 4 (TLR4) antagonists identified by structure- and ligand-based virtual screening

    Eur. J. Med. Chem.

    (2013)
  • P.C.T. Tang et al.

    Inhibition of human equilibrative nucleoside transporters by 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine

    Eur. J. Pharmacol.

    (2016)
  • H. Ahrens

    Indaziflam: an innovative broad spectrum herbicide. In Discovery and Synthesis of Crop Protection Products

    Am. Chem. Soc.

    (2015)
  • C. Brabham et al.

    Indaziflam herbicidal action: a potent cellulose biosynthesis inhibitor

    Plant Physiol.

    (2014)
  • K. Grossmann et al.

    Triaziflam and diaminotriazine derivatives affect enantioselectively multiple herbicide target sites

    Z. Naturforsch. C Biosci.

    (2001)
  • E.M. Smolin et al.

    s-Triazines and Derivatives

    (1959)
  • S.A. Gamage et al.

    Synthesis and evaluation of imidazo[1,2-a]pyridine analogues of the ZSTK474 class of phosphatidylinositol 3-kinase inhibitors

    Chem. Asian J.

    (2019)
  • G.-H. Kuo et al.

    Synthesis and identification of [1,3,5]triazine-pyridine biheteroaryl as a novel series of potent cyclin-dependent kinase inhibitors

    J. Med. Chem.

    (2005)
  • J. Li et al.

    Highly efficient and recyclable porous organic polymer supported iridium catalysts for dehydrogenation and borrowing hydrogen reactions in water

    ChemCatChem

    (2021)
  • M. Zeng et al.

    Ruthenium-catalysed synthesis of tri-substituted 1,3,5-triazines from alcohols and biguanides

    New J. Chem.

    (2016)
  • S.R. Chaurasia et al.

    Graphene oxide as a carbo-catalyst for the synthesis of tri-substituted 1,3,5-triazines using biguanides and alcohols

    Catal. Commun.

    (2020)
  • R. Bardovskyi et al.

    Synthesis and characterisation of new heterocycles related to aryl[e][1,3]diazepinediones rearrangement to 2,4-diamino-1,3,5-triazine derivatives

    New J. Chem.

    (2020)
  • E.J. Modest

    Chemical and biological studies on 1,2-dihydro-s-triazines. II. Three-component synthesis

    J. Org. Chem.

    (1956)
  • E.J. Modest et al.

    Chemical and biological studies of 1,2-dihydro-s-triazines. III. Two-component synthesis

    J. Org. Chem.

    (1956)
  • A. Junaid et al.

    A one-pot synthesis of N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines and systematic evaluation of their ability to host ethanol in crystals

    RSC Adv.

    (2019)
  • A. Junaid et al.

    A new one-pot synthesis of 1,3,5-triazines: three-component condensation, Dimroth rearrangement and dehydrogenative aromatisation

    ACS Comb. Sci.

    (2019)
  • A. Junaid et al.

    Design, synthesis, and biological evaluation of new 6,N2-diaryl-1,3,5-triazine-2,4-diamines as anticancer agents selectively targeting triple negative breast cancer cells

    RSC Adv.

    (2020)
  • A. Junaid et al.

    6,N2-Diaryl-1,3,5-triazine-2,4-diamines: synthesis, antiproliferative activity and 3D-QSAR modeling

    RSC Adv.

    (2020)
  • Cited by (7)

    View all citing articles on Scopus
    View full text