Inhibition of bovine and rat liver dihydrofolate reductase by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(4-substituted-phenyl)-s-triazines

Hansch, Corwin; Dietrich, Stephen W.; Fukunaga, James Y.

doi:10.1021/jm00137a013

Cited by 15 publications

(11 citation statements)

References 9 publications

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“…The equations defining the relationship between the partition coefficients of the small-molecules and the respective inhibition constants are shown in the figure along with the regression measure. This result is in broad agreement with already reported QSAR analysis for DHFRs from eukaryotic sources which had indicated that hydrophobic triazines are particularly effective against P. carinii DHFR 34 and mammalian DHFRs 31 . This similarity in QSAR behavior is in spite of the low sequence similarity shared by the prokaryotic and eukaryotic DHFRs.…”

Section: Resultssupporting

confidence: 93%

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: Resultssupporting

confidence: 93%

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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“…Most of the tested dihydrotriazines were already described and re-prepared according to cited references: syntheses of compounds 1e3, 15, 16, 18, 20, 23 and 28 [28], 4 [29], 5 [30], 14 [31], 19 [32] were achieved by a one-step acid-catalyzed cyclocondensation among an aromatic amine, dicyandiamide and a carbonyl compound (3component syntheses); for 26 and 27 was used the twocomponent syntheses which progresses in two steps by condensation of a preformed arylbiguanide and a carbonyl derivative [33]. The progress of the reaction was monitored by means of the negative result of colored copper complex formed characteristically by biguanide with a freshly cuprammonium sulphate solution.…”

Section: Chemistrymentioning

confidence: 99%

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Tonelli

Naesens

Gazzarrini

et al. 2017

European Journal of Medicinal Chemistry

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We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC = 5.8 μM, SI > 43).

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“…The dihydrotriazines 1–5 were synthesized according to cited references: compounds 1 and 2 were obtained by means of the two-component syntheses involving the preformed 1-(4-chlorophenyl)biguanide and an aldehyde derivative [ 43 ], while for 3 [ 44 ], 4 [ 45 ], and 5 [ 46 ], the three-component synthetic method of Modest was applied by reacting the appropriate para -substituted aniline hydrochloride salt, dicyandiamide, and acetone. The treatment of 4,6-diamino-1-(4-methoxyphenyl)-2,2-dimethyl-1,2-dihydrotriazine ( 5 ) with an excess of acetic anhydride at room temperature for 2 h yielded the corresponding N-acetyl derivative ( 6 ) ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Results of elemental analyses indicated that the purity of all compounds was ≥95%. The dihydrotriazines 1–5 were synthesized according to cited references [ 43 , 44 , 45 , 46 ], whereas 6 was synthesized as follows.…”

Section: Methodsmentioning

confidence: 99%

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

et al. 2021

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Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.

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Inhibition of bovine and rat liver dihydrofolate reductase by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(4-substituted-phenyl)-s-triazines

Cited by 15 publications

References 9 publications

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

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

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

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