Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents

DOI: 10.1016/j.bmcl.2012.09.066

Source and publish data:

Bioorganic and Medicinal Chemistry Letters p. 7174 - 7178 (2012)

Update date:2022-09-26

Topics:

Authors:

Venkatraj, Muthusamy

Ari?n, Kevin K.

Heeres, Jan

Joossens, Jurgen

Messagie, Jonas

Michiels, Johan

Van Der Veken, Pieter

Vanham, Guido

Lewi, Paul J.

Augustyns, Koen

Read Full Text PDF DownLoad Join now for total 90,000,000 free articles

Article abstract of DOI:10.1016/j.bmcl.2012.09.066

This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.

Full text of DOI:10.1016/j.bmcl.2012.09.066

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7174–7178

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: w ww.elsevier.com/locate/bmcl

Synthesis, evaluation and structure–activity relationships of triazine dimers

as novel antiviral agents

Muthusamy Venkatraj ^a, Kevin K. Ariën ^b, Jan Heeres ^a, Jurgen Joossens ^a, Jonas Messagie ^a,

Johan Michiels ^b, Pieter Van der Veken ^a, Guido Vanham ^b,c, Paul J. Lewi ^a, Koen Augustyns ^a,

⇑

^aLaboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

^bVirology Unit, Division of Microbiology, Department of Biomedical Sciences, Institute of Tropical Medicine, Nationalestraat 155, B-2000 Antwerp, Belgium

^cDepartment of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 19 June 2012

Revised 17 September 2012

Accepted 18 September 2012

Available online 27 September 2012

This letter reports the synthesis and structure–activity relationship (SAR) study of a series of triazine

dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach

in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed

submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.

Keywords:

HIV-1 reverse transcriptase

NNRTIs

Anti-HIV-1 activity

Triazines

Triazine dimers

HIV-1 reverse transcriptase (RT) plays a vital role in the HIV-1

life cycle and is therefore the most important target for viral inhi-

bition. There are two major classes of HIV RT inhibitors: nucleoside

reverse transcriptase inhibitors (NRTIs) that bind to the substrate

binding site, and non-nucleoside reverse transcriptase inhibitors

(NNRTIs) that bind to the allosteric site, distinct from the catalytic

binding site.^1–4The ﬁrst-generation NNRTIs such as nevirapine,

delavirdine and efavirenz exhibit very potent anti-HIV-1 activity

and low toxicity.⁵However, rapid drug resistance emergence due

to single point mutations in the NNRTI binding site, limited the

therapeutic effectiveness.⁶Efforts to develop the next-generation

NNRTIs have focused on the design of compounds with an im-

proved drug resistance proﬁle. Etravirine (Intelence^Ò, TMC125),⁷

a diarylpyrimidine (DAPY) was approved in 2008 for the treatment

of HIV-1 infection in treatment-experienced patients who show

evidence of HIV-1 resistant strains. Another DAPY compound rilp-

ivirine (Edurant^Ò, TMC278)⁸was approved in 2011. Dapivirine,

also known as TMC120 is currently under development for HIV-

microbicidal applications.⁹A closely related scaffold type, diaryltri-

azine (DATA),¹⁰also has been successfully investigated for the dis-

covery of highly potent NNRTIs against wild-type and single

mutant strains (Fig. 1). The excellent pharmacological proﬁles of

the DAPYs have encouraged several research groups to explore

next-generation NNRTI agents for the treatment of HIV infections

and also for use as microbicides.¹¹The discovery of dimeric inhib-

itors by extension into the entrance channel of HIV-1 reverse

transcriptase has also been reported.¹²

As part of our research program for the development of novel

antiviral agents as microbicides¹³we synthesized a library of tri-

azine dimers. These compounds were obtained through a bivalent

ligand approach in which two triazine moieties are covalently con-

nected by suitable linkers (Fig. 1). The rationale for the develop-

ment of high molecular weight triazine dimers as microbicides is

to limit systemic absorption and increase local effectiveness. We

report herein the synthesis, anti-HIV-1 activity evaluation and pre-

liminary SAR studies of these new compounds.

The synthesis of the triazine dimers was straightforward

(Table 1): 6-chloro-2,4-disubstituted triazines (‘monomers’) were

synthesized by a reported procedure.¹⁰The homodimers 1–38

were obtained by treating 2 mol equiv of one monomer type with

one molar equivalent of a diamine (the ‘linker’) in dry dioxane at

reﬂux, in the presence of DIPEA. The heterodimers 39–47 were ob-

tained from reacting a mixture of two different monomer types

(one molar equivalent of each) with one molar equivalent of linker

under the same conditions (Scheme 1).¹⁴

The newly synthesized triazine dimers were evaluated for anti-

HIV-1 activity and cytotoxicity in TZM-b1 cells.¹⁵A relevant DAPY

(TMC120) and DATA reverse transcriptase inhibitor were used as

the reference compounds. The results, expressed as EC₅₀(50%

effective concentration), CC₅₀(50% cytotoxic concentration) and

⇑

Corresponding author. Tel.: +32 3 265 27 17; fax +32 3 265 27 39.

E-mail address: Koen.Augustyns@ua.ac.be (K. Augustyns).

http://dx.doi.org/10.1016/j.bmcl.2012.09.066

M. Venkatraj et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7174–7178

7175

Figure 1. Chemical structures of DAPY, DATA and target compounds.

Table 1

Structural characteristics of triazine dimers 1–47

R¹

R⁴

R⁵

R⁷

R³

R²

R⁶

Linker

R¹²

R¹⁰

R⁸

R¹¹

R¹⁴

R⁹

R¹³

1-47

Compd

R¹

R²

R³

R⁴

R⁵

R⁶

R⁷

Linker

R⁸

R⁹

R¹⁰

R¹¹

R¹²

R¹³

R¹⁴

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₄NH

HN(CH₂)₅NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₄NH

HN(CH₂)₅NH

HN(CH₂)₆NH

HN(CH₂)₁₀NH

HN(CH₂)₃NH

HN(CH₂)₄NH

HN(CH₂)₅NH

HN(CH₂)₃NH

HN(CH₂)₅NH

HN(CH₂)₂NH

(continued on next page)

7176

M. Venkatraj et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7174–7178

Table 1 (continued)

Compd

R¹

R²

R³

R⁴

R⁵

R⁶

R⁷

Linker

R⁸

R⁹

R¹⁰

R¹¹

R¹²

R¹³

R¹⁴

OMe

NMe

HN(CH₂)₃NH

HN(CH₂)₅NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₅NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₅NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₂NH

OMe

NMe

Cyano vinyl

HN(CH₂)₂NH

HN(CH₂)₃NH

HN(CH₂)₂NH

Scheme 1. Synthesis of triazine dimers 1–47. Reagents and conditions: (a) diaminoalkanes/diaminobenzene/piperazine, DIPEA, dry dioxane, 110 °C.

SI (selectivity index given by the CC₅₀/EC₅₀ratio) values are sum-

marized in Table 2. The experimental results indicate that most

of the compounds exhibit submicromolar activity against HIV-1

and no cytotoxicity. Compounds 1–4 are inactive. These results

concur with structure–activity relationship (SAR)-data reported

earlier for the monomeric DATA compounds¹⁰that describe the

presence of a cyano group at para positions R⁷and R¹⁴as essential

for antiviral activity. Noteworthy, this ﬁnding is indicative of a

comparable binding mode for DATA monomers and monomeric

part of the dimeric analogues. Compounds 5–12 were obtained

from monomeric triazine, 4-((4-chloro-6-(mesitylamino)-1,3,5-

triazin-2-yl)amino)benzonitrile with different linkers (alkylidene-

diamino, arylenediamino and piperazindiyl). The EC₅₀values of

5–12 indicate that alkylidenediamino linkers [–NH(CH)_nNH–,

n = 2 and 3] and arylenediamino linker are more favourable.

Replacement of a methyl at R¹, R², R⁸and R⁹by bromo/hydrogen

groups (13–17) was tolerated. Replacement of a methyl group at

R³and R¹⁰by hydrogen (18–20) or a cyanovinyl group (24) was

allowed and by a bromo group (21–23) was well tolerated.

Replacement of NH by NMe at X and Y resulted in a fourfold loss

of activity (25 vs 5 and 26 vs 6) and NH by O led to decrease in

the activity by 1.5–10 fold (27 vs 5, 28 vs 6, 29 vs 8, 30 vs 18, 31

vs 19, 32 vs 21 and 33 vs 22). Removal of the para-cyano or its shift

to the meta position resulted in complete loss of activity (37and 38

vs 27). Heterodimers (39–47), obtained by combination of two dif-

ferent monomers did not improve the potency. Arylamino triazine

dimers 5, 6 and 21–23 with EC₅₀6 0.2 lM and CC₅₀P 100 lM

were selected for further evaluation. Compared to TMC120 these

compounds are 70–100 fold less active, but show no signs of

cytotoxicity.

Five compounds (5, 6 and 21–23) were further tested against

single and double mutant strains in comparison with TMC120

and DATA (Table 3). These ﬁve compounds exhibit moderate activ-

ity (EC₅₀= 1–10

lM) against the single mutant strains Ba-L V106A

and VI829 Y181C but lost potency against double mutant strain

VI829 L100I, K103N (EC₅₀P 10 lM).

Finally, a time-of-drug addition assay^16,17with compound 5 re-

vealed that this arylamino triazine dimer inhibits HIV-1 replication

M. Venkatraj et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7174–7178

7177

Table 2

Anti-HIV-1 activity of triazine dimers 1–47 in TZM-b1 cells

Compd

EC₅₀

CC₅₀

Compd

EC₅₀

CC₅₀

>10

nd^a

—

TMC120

0.57

0.74

1.28

0.82

0.97

4.23

5.15

1.13

0.42

0.92

0.66

0.76

>10

>100

>175

>135

>78

>122

>103

>88

>108

>132

—

nd^a

0.15

0.20

1.49

0.71

0.87

0.27

6.07

0.17

0.59

0.46

1.63

0.25

0.49

1.44

0.57

0.70

0.20

0.14

0.44

>100

>666

>500

>67

>141

>115

>370

>16

>588

>169

>217

>61

>400

>204

>70

>176

>143

>500

>714

>227

>100

nd^a

>10

nd^a

—

0.68

0.42

2.71

3.19

7.98

0.56

0.38

0.72

3.63

>100

2.88

>147

>238

>37

>31

>12

>178

>263

>139

>28

1439

0.002

nd—not determined.

Table 3

Activity of 5, 6 and 21–23 against single and double mutant strains of HIV-1

Compd

WT Ba-L

WT VI829

Ba-L V106A

VI829 Y181C

VI829 L100I, K103N

EC₅₀

(

lM)

EC₅₀

(

lM)

EC₅₀

(

lM)

6.3

6.5

12.5

14.4

13.4

7.2

EC₅₀

(

lM)

EC₅₀

(

lM)

DATA

TMC120

0.15

0.20

0.14

0.21

0.32

0.27

0.17

0.20

0.95

1.29

2.50

2.01

1.88

6.52

8.98

9.69

6.07

7.71

31.1

28.0

35.9

35.7

38.6

6.9

>10

>47

>32

>37

>59

>50

0.0012

0.002

0.0012

0.002

0.0086

0.0025

0.0083

0.0108

0.29

242

>500

1.3

5.4

Figure 2. (A) Schematic representation and chronology of the HIV replication cycle. (B) A time-of-drug addition assay (TOA) shows that compound 5 inhibits HIV replication

at the reverse transcription process with a proﬁle similar to that of a prototypic NNRTI, TMC120. The TOA principle relies on how long the addition of a compound can be

postponed before antiviral activity is lost in vitro.

with a similar proﬁle as TMC120 (Fig. 2), suggesting that these no-

vel triazine dimers function as non-nucleoside reverse transcrip-

tase inhibitors.

In summary, a novel series of triazine dimers 1–47 was synthe-

sized and evaluated against wild-type HIV-1 in TZM-bl cells.

Several compounds exhibited submicromolar activity. These

7178

M. Venkatraj et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7174–7178

Herrera, C.; Cranage, M.; McGowan, I.; Anton, P.; Shattock, R. J. Antimicrob.

Agents Chemother. 2009, 53, 1797.

10. Ludovici, D. W.; Kavash, R. W.; Kukla, M. J.; Ho, C. Y.; Ye, H.; De Corte, B. L.;

Andries, K.; de Bethune, M. P.; Azijn, H.; Pauwels, R.; Moereels, H. E.; Heeres, J.;

Koymans, L. M.; de Jonge, M. R.; Van Aken, K. J.; Daeyaert, F. F.; Lewi, P. J.; Das,

K.; Arnold, E.; Janssen, P. A. Bioorg. Med. Chem. Lett. 2001, 11, 2229.

compounds showed better toxicity proﬁles in comparison with

TMC120. The preliminary SAR of this series of compounds was

established. The selected triazine dimers 5, 6 and 21–23 showed

moderate activity against single mutant strains and no activity

against double mutant strains. Although these triazine dimers

did not provide the improved activity in comparison with DAPY

(TMC120) and DATA (monomer), they represent a novel class of

antiviral agents with no signs of cytotoxicity.

11. (a) Tian, X. T.; Qin, B.; Lu, H.; Lai, W.; Jiang, S.; Lee, K. H.; Chen, C. H.; Xie, L.

Bioorg. Med. Chem. Lett. 2009, 19, 5482; (b) Qin, B.; Jiang, X.; Lu, H.; Tian, X.;

Barbault, F.; Huang, L.; Qian, K.; Chen, C. H.; Huang, R.; Jiang, S.; Lee, K. H.; Xie,

L. J. Med. Chem. 2010, 53, 4906; (c) Tian, X.; Qin, B.; Wu, Z.; Wang, X.; Lu, H.;

Morris, N. S. L.; Chen, C. H.; Jiang, S.; Lee, K. H.; Xie, L. J. Med. Chem. 2010, 53,

8287; (d) Chen, X.; Zhan, P.; Li, D.; De Clercq, E.; Liu, X. Curr. Med. Chem. 2011,

18, 359; (e) Bode, M. L.; Gravestock, D.; Moleele, S. S.; Van der Westhuyzen, C.

W.; Pelly, S. C.; Steenkamp, P. A.; Hoppe, H. C.; Khan, T.; Nkabinde, L. A. Bioorg.

Med. Chem. 2011, 19, 4227; (f) Alexandre, F.; Amador, A.; Bot, S.; Caillet, C.;

Convard, T.; Jakubik, J.; Musiu, C.; Poddesu, B.; Vargiu, L.; Liuzzi, M.; Roland, A.;

Seifer, M.; Standring, D.; Storer, R.; Dousson, C. B. J. Med. Chem. 2011, 54, 392;

(g) Tang, G.; Kertesz, D. J.; Yang, M.; Lin, X.; Wang, Z.; Li, W.; Qiu, Z.; Chen, J.;

Mei, J.; Chen, L.; Mirzadegan, T.; Harris, S. F.; Villaseñor, A. G.; Fretland, J.; Fitch,

W. L.; Hang, J. Q.; Heilek, G.; Klumpp, K. Bioorg. Med. Chem. Lett. 2010, 20, 6020;

(h) Zeng, Z.; He, Q.; Liang, Y.; Feng, X.; Chen, F.; Clercq, E. D.; Balzarini, J.;

Pannecouque, C. Bioorg. Med. Chem. 2010, 18, 5039; (i) Kertesz, D. J.;

Brotherton-Pleiss, C.; Yang, M.; Wang, Z.; Lin, X.; Qiu, Z.; Hirschfeld, D. R.;

Gleason, S.; Mirzadegan, T.; Dunten, P. W.; Harris, S. F.; Villaseñor, A. G.; Hang,

J. Q.; Heilek, G. M.; Klumpp, K. Bioorg. Med. Chem. Lett. 2010, 20, 4215; (j) Liang,

Y.; He, Q.; Zeng, Z.; Liu, Z.; Feng, X.; Chen, F.; Balzarini, J.; Pannecouque, C.;

Clercq, E. D. Bioorg. Med. Chem. 2010, 18, 4601; (k) Leung, C. S.; Zeevaart, J. G.;

Domaoal, R. A.; Bollini, M.; Thakur, V. V.; Spasov, K. A.; Anderson, K. S.;

Jorgensen, W. L. Bioorg. Med. Chem. Lett. 2010, 20, 2485; (l) Feng, X.; Zeng, Z.;

Liang, Y.; Chen, F.; Pannecouque, C.; Balzarini, J.; Clercq, E. D. Bioorg. Med. Chem.

2010, 18, 2370; (m) Rotili, D.; Tarantino, D.; Artico, M.; Nawrozkij, M. B.;

Gonzalez-Ortega, E.; Clotet, B.; Samuele, A.; Este, J. A.; Maga, G.; Mai, A. J. J. Med.

Chem. 2011, 54, 3091.

Acknowledgments

The research leading to these results has received funding from

the European Community’s Seventh Framework programme (FP7/

2007-2013) under grant agreement no. 242135 (CHAARM). J.M. is

thankful to Research Foundation Flanders (FWO-Vlaanderen) for

the award of Ph.D grant. This work was supported by BOF (Re-

search Council of University of Antwerp), IOF-POC (Industrial Re-

search Fund-Proof of Concept) and Hercules Foundation. P.V.V.,

K.K.A. and G.V. are indebted to the Flemish Fund for Scientiﬁc re-

search (FWO-Vlaanderen) for ﬁnancial support. The Laboratory of

Medicinal Chemistry belongs to the Department of Pharmaceutical

Sciences and is also a partner of the Antwerp Drug Discovery Net-

work (ADDN). The excellent technical assistance of S. Lyssens is

greatly appreciated.

References and notes

12. Ekkati, A. R.; Bollini, M.; Domaoal, R. A.; Spasov, K. A.; Anderson, K. S.;

Jorgensen, W. L. Bioorg. Med. Chem. Lett. 2012, 22, 1565.

13. CHAARM project, Combined Highly Active Anti-Retroviral Microbicides, http://

www.chaarm.eu/.

1. De Corte, B. L. J. Med. Chem. 2005, 48, 1689.

2. Tantillo, C.; Ding, J.; Jacobo-Molina, A.; Nanni, R. G.; Boyer, P. L.; Hughes, S. H.;

Pauwels, R.; Andries, K.; Janssen, P. A.; Arnold, E. J. Mol. Biol. 1994, 243, 369.

3. Pauwels, R. Curr. Opin. Pharmacol. 2004, 4, 437.

14. Characterization of all the newly synthesized compounds was done with ¹H

NMR and mass spectrometry. ¹H NMR spectra were measured on Bruker

Avance DRX-400 spectrometer and coupling constants (J) are reported in Hz.

Column chromatography was performed on a Flashmaster II instrument (Jones

Chromatography) with Isolute columns pre-packed with silica gel, using a

30 min gradient of 0–70% EtOAc in hexanes. Electrospray ionization (ESI) mass

spectra were acquired on an ion trap mass spectrometer (Bruker Daltonics

Esquire^TM3000plus). LC–MS spectra were recorded on an Agilent 1100 Series

LC Series LC system equipped with a C18 column (2.1 Â 50 mm, 5 mm, Supelco,

Sigma–Aldrich) coupled to the mass spectrometer; solvent A: H₂O + 0.1%

formic acid, solvent B: CH₃CN + 0.1% formic acid; gradient: 5% B ? 100% B over

23 min at 0.2 mL min^À1. The purity of all the compounds was P 95% and yield

of the compounds was in the range of 20–65%. As an example the experimental

4. Sahlberg, C.; Zhou, X. Anti-Infect. Agents Med. Chem. 2008, 7, 101.

5. (a) Merluzzi, V. J.; Hargrave, K. D.; Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J.

C.; Shih, C. K.; Eckner, K.; Hattox, S.; Adams, J.; Rosenthal, A. S.; Faanes, R.;

Eckner, R. J.; Koup, R. A.; Sullivan, J. L. Science 1990, 250, 1411; (b) Dueweke, T.

J.; Poppe, S. M.; Romero, D. L.; Swaney, S. M.; So, A. G.; Downey, K. M.; Althaus,

I. W.; Reusser, F.; Busso, M.; Resnick, L.; Mayers, D. L.; Lane, J.; Aristoff, P. A.;

Thomas, R. C.; Tarpley, W. G. Antimicrob. Agents Chemother. 1993, 37, 1127; (c)

Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W. C.; Lyle, T. A.;

Huff, J. R.; Anderson, P. S.; Olsen, D. B.; Carroll, S. S.; Pettibone, D. J.; O’Brien, J.

A.; Ball, R. G.; Balani, S. K.; Lin, J. H.; Chen, I. W.; Schleif, W. A.; Sardana, V. V.;

Long, W. J.; Byrnes, V. W.; Emini, E. A. Antimicrob. Agents Chemother. 1995, 39,

2602.

and analytical data for

5 are given: To a solution of 4-(4-chloro-6-

(mesitylamino)-1,3,5-triazin-2-ylamino)benzonitrile (2.2 g, 6 mmol) in

dioxane (50 mL) was added DIPEA (1 mL, 6 mmol) and ethane-1,2-diamine

(0.2 mL, 3 mmol) and allowed to reﬂux for 48 h. Removal of solvent and

puriﬁcation by column chromatography using 70% EtOAc in hexanes afforded

white powder (0.45 g, 21%); ¹H NMR (MeOD, 400 MHz) d 7.95 (br s, 2H), 7.61

(br s, 4H), 7.32 (br s, 2H), 6.90 (br s, 4H), 3.69–3.61 (m, 4H), 2.33 (br s, 6H), 2.17

(br s, 12H); MS (ESI) m/z 718 [M+H]⁺; LC–MS (214 nm) t_r20.7 min, 100%.

15. Venkatraj, M.; Ariën, K. K.; Heeres, J.; Dirié, B.; Joossens, J.; Van Goethem, S.;

Van der Veken, P.; Michiels, J.; Vande Velde, C. M. L.; Vanham, G.; Lewi, P. J.;

Augustyns, K. Bioorg. Med. Chem. 2011, 19, 5924.

6. Ren, J.; Stammers, D. K. Virus Res. 2008, 134, 157.

7. (a) Andries, K.; Azijn, H.; Thielemans, T.; Ludovici, D.; Kukla, M.; Heeres, J.;

Janssen, P.; De Corte, B.; Vingerhoets, J.; Pauwels, R.; de Béthune, M. P.

Antimicrob. Agents Chemother. 2004, 48, 4680; Das, K.; Clark, A. D.; Lewi, P. J.;

Heeres, J.; De Jonge, M. R.; Koymans, L. M. H.; Vinkers, H. M.; Daeyaert, F.;

Ludovici, D. W.; Kukla, M. J.; De Corte, B.; Kavash, R. W.; Ho, C. Y.; Ye, H.;

Lichtenstein, M. A.; Andries, K.; Pauwels, R.; De Bethune, M. P.; Boyer, P. L.;

Clark, P.; Hughes, S. H.; Janssen, P. A. J.; Arnold, E. J. J. Med. Chem. 2004, 47, 2550.

8. (a) Janssen, P. A. J.; Lewi, P. J.; Arnold, E.; Daeyaert, F.; de Jonge, M.; Heeres, J.;

Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.;

Andries, K.; de Bethune, M. P.; Pauwels, R.; Das, K.; Clark, A. D.; Frenkel, Y. V.;

Hughes, S. H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.;

Williams, P.; Stoffels, P. J. Med. Chem. 2005, 48, 1901; (b) Guillemont, J.;

Pasquier, E.; Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P. J.; Heeres, J.; de

Jonge, M. R.; Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M. H.; Arnold, E.;

Das, K.; Pauwels, R.; Andries, K.; de Bethune, M. P.; Bettens, E.; Hertogs, K.;

Wigerinck, P.; Timmerman, P.; Janssen, P. A. J. J. Med. Chem. 2005, 48, 2072; (c)

Mordant, C.; Schmitt, B.; Pasquier, E.; Demestre, C.; Queguiner, L.; Masungi, C.;

Peeters, A.; Smeulders, L.; Bettens, E.; Hertogs, K.; Heeres, J.; Lewi, P.;

Guillemont, J. Eur. J. Med. Chem. 2007, 42, 567.

16. Daelemans, D.; Pauwels, R.; De Clercq, E.; Pannecouque, C. Nat. Protoc. 2011, 6,

925.

17. A time-of-drug addition assay¹⁶was performed using a modiﬁed protocol. In

brief, 2 Â 10⁴TZM-bl cells were plated in a 96-well plate and exposed to 0.4

MOI of virus, with or without compound for 1 h. Unbound virus was washed

away and fresh medium with or without compound was added. Next, each

hour compound was added (at 50–500 Â EC₅₀) for a consecutive 12 h. Gag p24

production was quantiﬁed using an in-house p24 antigen capture ELISA after

24 h, ensuring

a single round of viral replication. The CD4 bindings site

inhibitor M48U1, the NRTI azidothymidine (AZT), the NNRTI TMC120 and the

integrase inhibitor raltegravir were used as reference compounds, alongside a

negative control (cells + medium) and positive control (cells + virus). EC₅₀and

CC₅₀values were determined for each of the reference compounds and

compound 5, prior to executing the TOA.

9. (a) Ludovici, D. W.; De Corte, B. L.; Kukla, M. J.; Ye, H.; Ho, C. Y.; Lichtenstein, M.

A.; Kavash, R. W.; Andries, K.; de Bethune, M. P.; Azijn, H.; Pauwels, R.; Lewi, P.

J.; Heeres, J.; Koymans, L. M. H.; de Jonge, M. R.; Van Aken, K. J. A.; Daeyaert, F. F.

D.; Das, K.; Arnold, E.; Janssen, P. A. J. Bioorg. Med. Chem. Lett. 2001, 11, 2235; (b)

Products guided by the article

Product name:4,4'-((6,6'-(hexane-1,6-diylbis(azanediyl))bis(4-(mesitylamino)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile

Cas No:1415319-62-8

R&D Labs maybe for 1415319-62-8

A-Chem Technologies Co.,Ltd.

Contact:+86-512-69561895

Address:No.111, Building A4, 218 Xinghu Street, Suzhou Industrial Park, P. R. China
Beijing Chemdow Co., Ltd

website:http://www.chemdow.com

Contact:0086-10-82435335

Address:Room 401,Unit 3,4th Floor,Shangdijiayuan,Shangdi East Road, Haidian District,Beijing
Li's chemicals

Contact:+86-15850770348

Address:51 OF XIANGFANGCUN ROAD, Nanjing 210002, China
Hangzhou Chemfar Ltd.

Contact:+86-571-87859231, 87859237, 87859239

Address:1606,Huarong Times Mansion, No.3880 Jiangnan Avenue, Binjiang District, Hangzhou, China, 310053
Ningbo Huajia Chemicals

Contact:+86-574-87065746

Address:10th Floor, No.787 Baizhang East Road,

Relevant to this article

Synthesis of homoallylic amines and acylhydrazides by tin powder-promoted multicomponent one-pot allylation reactions

Doi:10.1002/aoc.3472
(2016)
Cooperative N-heterocyclic carbene/Br?nsted acid catalysis for the tail-to-tail (co)dimerization of methacrylonitrile

Doi:10.1021/jo500514e
(2014)
Synthesis of spiro[indolizidine-1,3′-oxindole] from L-glutamic acid

Doi:10.1016/j.tet.2020.131261
(2020)
α-MsO/TsO/Cl ketones as oxidized alkyne equivalents: Redox-neutral rhodium(III)-catalyzed C-H activation for the synthesis of N-heterocycles

Doi:10.1002/anie.201310272
(2014)
Doi:10.1002/hlca.660280186
(1945)
Discovery of M₃Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease

Doi:10.1021/acs.jmedchem.1c00204
(2021)

Article Doi

Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents

DOI: 10.1016/j.bmcl.2012.09.066

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.bmcl.2012.09.066

Full text of DOI:10.1016/j.bmcl.2012.09.066

Products guided by the article

R&D Labs maybe for 1415319-62-8

Relevant to this article

Hot Product