Triazine–benzimidazole hybrids: Anticancer activity, DNA interaction and dihydrofolate reductase inhibitors

Singla, Prinka; Luxami, Vijay; Paul, Kamaldeep

doi:10.1016/j.bmc.2015.03.012

Cited by 80 publications

(30 citation statements)

References 27 publications

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“…Detailed QSAR analysis of diaminotriazine derivatives has been carried out on DHFRs from several different organisms 29–39 . Recently, hybrids of triazines have also been demonstrated to show inhibitory activity on DHFRs 40, 41 .…”

Section: Introductionmentioning

confidence: 99%

Ligand binding studies, preliminary structure–activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase

Srinivasan

Tonddast-Navaei

Skolnick

2015

European Journal of Medicinal Chemistry

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Gram-negative bacteria are implicated in the causation of life-threatening hospital-acquired infections. They acquire rapid resistance to multiple drugs and available antibiotics. Hence, there is the need to discover new antibacterial agents with novel scaffolds. For the first time, this study explores the 1,3,5-triazine-2,4-diamine and 1,2,4-triazine-2,4-diamine group of compounds as potential inhibitors of E. coli DHFR, a pivotal enzyme in the thymidine and purine synthesis pathway. Using differential scanning fluorimetry, DSF, fifteen compounds with various substitutions on either the 3rd or 4th positions on the benzene group of 6,6-dimethyl-1-(benzene)-1,3,5-triazine-2,4-diamine were shown to bind to the enzyme with varying affinities. Then, the dose dependence of inhibition by these compounds was determined. Preliminary quantitative structure-activity relationship analysis and docking studies implicate the alkyl linker group and the sulfonyl fluoride group in increasing the potency of inhibition. 4-[4-[3-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1-yl)phenyl]butyl]benzenesulfonyl fluoride (NSC120927), the best hit from the study and a molecule with no reported inhibition of E. coli DHFR, potently inhibits the enzyme with a Ki value of 42.50 ± 5.34 nM, followed by 4-[6-[4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1-yl)phenyl]hexyl]benzenesulfonyl fluoride(NSC132279), with a Ki value of 100.9 ± 12.7 nM. Detailed kinetic characterization of the inhibition brought about by five small-molecule hits shows that these inhibitors bind to the dihydrofolate binding site with preferential binding to the NADPH-bound binary form of the enzyme. Furthermore, in search of novel diaminotriazine scaffolds, it is shown that lamotrigine, a 1,2,4-triazine-3,5-diamine and a sodium-ion channel blocker class of antiepileptic drug, also inhibits E. coli DHFR. This is the first comprehensive study on the binding and inhibition brought about by diaminotriazines of a gram-negative prokaryotic enzyme and provides valuable insights into the SAR as an aid to the discovery of novel antibiotics.

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Section: Introductionmentioning

confidence: 99%

Ligand binding studies, preliminary structure–activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase

Srinivasan

Tonddast-Navaei

Skolnick

2015

European Journal of Medicinal Chemistry

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“…Also of key importance is knowledge about the potential drug binding site or pocket(s) on the surface of the target [65,66]. In most cases, the target site for docking is the functionally most responsive orthosteric site, which, for example, can be the active site of an enzyme [67] or the agonist/ antagonist-binding site of a G-protein-coupled receptor (GPCR). In some cases, active site inhibition is either ineffective or leads to toxicity if the site is highly conserved among related proteins.…”

Section: Overview Of Structure-based Computer-aided Drug Discoverymentioning

confidence: 99%

Computational allosteric ligand binding site identification on Ras proteins

McCarthy

Prakash

Gorfe

2016

ABBS

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A number of computational techniques have been proposed to expedite the process of allosteric ligand binding site identification in inherently flexible and hence challenging drug targets. Some of these techniques have been instrumental in the discovery of allosteric ligand binding sites on Ras proteins, a group of elusive anticancer drug targets. This review provides an overview of these techniques and their application to Ras proteins. A summary of molecular docking and binding site identification is provided first, followed by a more detailed discussion of two specific techniques for binding site identification in ensembles of Ras conformations generated by molecular simulations.

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“…al [59]. synthesized a new series of triazine-benzimidazole hybrids with different substitution of primary and secondary amines at one of the position of triazine in moderate to good yields and evaluated for their inhibitory activities over 60 human tumor cell lines at one dose and five dose concentrations.…”

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confidence: 99%