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Preliminary CommuniCation

The inexorable march of several multidrug-resistant (MDR) pathogenic microbes has posed a threat in many countries around the world. Due to an increase in the number of immuno-suppressed patients in recent decades [1], the inci-dence of systemic microbial infections has been increasing dramatically. The increased use of antibacterial and antifungal drugs in recent years has resulted in the development of resistance to current antimicrobial agents [2–5]; possible microbial implications for morbidity and mor-tality, as well as healthcare costs, have become a serious concern. Moreover, the development of drug-resistant strains of Mycobacterium species has contributed to the inefficiency of conven-tional anti-TB therapy; thus, it is still necessary to search for new antimycobacterial agents. The 2010 statistics from the WHO indicated that 1.3 million MDR–TB cases will need to be treated in the 27 high MDR–TB burden countries between 2010 and 2015 [2,101–103]. The mortal-ity and spread of this disease has been further aggravated by its synergy with HIV. The reverse transcriptase (RT) enzyme of HIV converts sin-gle-stranded viral RNA into a double-stranded proviral DNA and, thus, reverse transcription is a necessary step in the HIV-1 replication cycle.

Therefore, the inhibition of RT has been an important target and non-nucleoside RT inhibi-tors (NNRTIs) are first-line selective drugs in the fight against HIV-AIDS. By destroying the

two most important cells to the containment of Tubercle bacilli (macrophages and CD4-receptor-bearing lymphocytes), HIV vigorously promotes the progression of recent, or remotely acquired, TB infection to active disease [3–5].

The affiliated multiple bioactivities in a sin-gle molecular scaffold remain an intriguing scientific endeavor. Fluorine has been claimed to exhibit a key role in novel drug discovery to enhance metabolic stability and membrane per-meation, thereby increasing the binding affin-ity of the drug candidate to the targeted site [6]. With this in mind, incorporating 4-amino-2-trifluoromethyl-benzonitrile, a part of bicaluta-mide drug (Figure 1), to the s-triazine core was contemplated [7]. In this study, an attempt has been made to identify the efficacy of the newly synthesized compounds against the DU-145 prostate cancer cell line. In addition, some piperazine-substituted analogues were also found to display activity against the prostate cancer cell line DU-145 [8–10]. The title compounds were also screened for their cytotoxicity against the MCF-7 breast cancer cell line, in order to gain more information about their anticancer efficacy.

BicalutamideBeing involved in a research program aimed at discovering new potentially active 1,3,5-triazines [11–13], we report herein the synthesis and pharma-cological activities of novel 1,3,5-triazines. Several

Antimicrobial, anti-TB, anticancer and anti-HIV evaluation of new s-triazine-based heterocycles

Background: The acquirement of resistance by microorganisms to the antimicrobial arsenal is a threat to public health. A recent WHO report estimated that 1.3 million HIV-negative people and 0.38 million HIV-positive people died from TB in 2009. Various forms of cancer account for a high percentage of deaths in both women (breast cancer) and men (prostate cancer). Results & discussion: In vitro activity assessment of newly constructed s-triazines against a panel of microorganisms including bacteria, fungi and Mycobacteria demonstrated that the compounds are of immense attraction for impending drug discovery. They were further examined for in vitro activity against breast cancer and prostate cancer cell lines, as well as HIV-1 (IIIB) and HIV-2 (ROD) viral strains. Proposed structural confirmation studies by IR, 1H NMR, 13C NMR, 19F NMR spectroscopy and elemental analysis were in accordance. Conclusion: Activity profiles of the products may contribute considerably to future drug-discovery studies.

Rahul V Patel*1, Premlata Kumari1, Dhanji P Rajani2, Christophe Pannecouque3, Erik De Clercq3 & Kishor H Chikhalia4

1Department of Applied Chemistry, S.V. National Institute of Technology, Surat 395 007, India2Microcare Laboratory, Surat 395 001, India 3Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium 4Department of Chemistry, School of Science, Gujarat University, Ahmedabad 380 009, India *Author for correspondence: Tel.: +91 971 275 5525 E-mail: rahul.svnit11@gmail.com

1053ISSN 1756-8919Future Med. Chem. (2012) 4(9), 1053–106510.4155/FMC.12.57 © 2012 Future Science Ltd

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FUTURE SCIE

NCE GROUPearlier observations suggest that 1,3,5-triazine

analogues are extensively studied heterocyclics representing significant antimicrobial [14–16], anticancer [17,18] and antimalarial [19] effects, and as antiviral NNRTIs [20]. Profound medicinal applications associated with piperazine hetero-cycles make them useful structural units in drug research [21–27]. It has been recently suggested that several s-triazine derivatives bearing mor-pholine, piperidine and some piperazine moieties are effective against the Mycobacterium tubercu-losis H37Rv strain [28], while the quinoline- based anti-TB compound TMC207 (Figure 2) possess a very promising activity against MDR-TB [29,30]. Recently, several bromo-quinoline- and pipera-zine-functionalized scaffolds have been reported to exert potent pharmacological activities [31–33]. In addition, a quinoline and piperazine combina-tion is also found in the well-known antimicro-bial drugs fluoroquinolones, for example cipro-floxacin (Figure 2). Studying the pharmacological importance of the above-mentioned scaffolds, it was proposed to synthesize a compact system that involves different active pharmacophores. This approach is, thus, less likely to induce drug resistance.

Recently, we have discovered other s-triazine analogues incorporating 4-amino-benzonitrile, 4-amino-2-trifluoromethyl-benzonitrile and sim-ple aniline, as well as substitution of 8-hydroxy-quinoline, 4-hydroxyquinoline and 4-hydroxy-coumarin [34–36] as biologically active agents. Moreover, we have also studied the biological activities of the systems with the substitutions of

4-amino-benzonitrile and 6-bromo-4-hydroxy-quinoline [37], as well as 4-amino-2-trifluorome-thyl-benzonitrile and 4-hydroxyquinoline [38]. The compounds have shown promising anti-microbial activity, representing a promising lead for further optimization. In order to investigate the activity profiles of such analogues, additional research efforts were required to investigate to what extent the particular structural modifica-tion in s-triazine core conserves their potency in spite of various substitutions. Hence, we have designed and synthesized a novel series based upon 4-amino-2-trifluoromethyl-benzonitrile- and 6-bromo-4-hydroxyquinoline-incorporated s-triazines. We have introduced similar pipera-zine bases in both systems in order to identify the difference between the biological profiles of the resultant series, in which activity was found to be increased significantly against most of the studied strains of bacteria and fungi in terms of MIC (Figure 3).

ExperimentalThe following reagents were used in the synthesis of new s-triazine-based heterocycles: 2,4,6-trichloro-1,3,5-triazine (Sigma Aldrich Chemicals Pvt. Ltd, Mumbai, India); 6-bromo-4-hydroxyquinoline (a gift from Silica Hetero Cyclics, Hyderabad, India); 4-amino-2-trifluoromethyl-benzonitrile (a gift from Ramdev Chemicals Pvt. Ltd, Boisar, India); acetone, tetrahydrofuran and 1,4-dioxane of HPLC grade (purchased from Rankem, Surat, India); TLC plates (silica gel 60 F254; Merck, Germany); and substituted piperazine derivatives (gifts from Prem’s Molecules Pvt. Ltd, Vadodara, India; Modepro India Pvt. Ltd, Mumbai, India; Trichem Pvt. Ltd, Mumbai, India; Siddharth Interchem Pvt. Ltd, Ankleshwar, India; and Mahrshee Laboratories, Bharuch, India).

Melting points were determined in open capil-laries on a Veego electronic apparatus VMP-D (Veego Instrument Corporation, Mumbai, India) and are uncorrected. IR spectra (4000–400 cm-1) of synthesized compounds were recorded on a Shimadzu 8400-S FT-IR spectrophotometer (Shimadzu India Pvt. Ltd, Mumbai, India) using KBr pellets. TLC was performed on object glass slides (2 × 7.5 cm) coated with silica gel-G, and spots were visualized under UV irradiation. 1H NMR and 13C NMR spectra were recorded on a Varian 400 MHz model spectrometer (Varian India Pvt. Ltd, Mumbai, India) using DMSO as a solvent and TMS as an internal standard, with 1H resonant frequency of 400 MHz and 13C resonant frequency of 100 MHz. 19F NMR spectra were

CN

F3CHN

O

HOS

O

O

F

Figure 1. Bicalutamide.

TMC207 Ciprofloxacin

N

BrOH

N

HN

N

F

N

O

COOH

Figure 2. TMC207 and ciprofloxacin.

Key Terms

Non-nucleoside RT inhibitors: Well-known class of anti-HIV drugs.

Metabolic stability: The susceptibility of compounds to biotransformation in designing drugs with favorable pharmacokinetic properties.

TMC207: Diarylquinoline with 6-bromo substituent, first compound of a new class of anti-TB drugs that are currently being evaluated in Phase II clinical trials.

Fluoroquinolones: Well-known class of quinoline-based antibacterial drugs.

Preliminary CommuniCation | Patel, Kumari, Rajani, Pannecouque, De Clercq & Chikhalia

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NCE GROUP

obtained on the same spectrometer using CDCl3

as a solvent and CFCl3 as an external standard,

positive for downfield shift with 19F resonant fre-quency of 400 MHz. The 1H NMR, 13C NMR and 19F NMR chemical shifts were reported as parts per million downfield from TMS (Me

4Si)

and CFCl3 and were conducted at the Centre for

Excellence, Vapi, India. The splitting patterns are designated as follows; singlet (s); broad sin-glet (br s); doublet (d); multiplet (m). Elemental analyses (C, H and N) were performed using a Heraeus Carlo Erba 1180 CHN analyzer (Hanau, Germany).

4-[4,6-dichloro-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (1) was synthesized as reported previously (Figure 4) [39].

� 4-(4-(6-bromoquinolin-4-yloxy)-6-chloro-1,3,5-triazin-2-ylamino)-2-trifluoromethyl-benzonitrile (3)To a stirred solution of 6-bromo-4-hydroxyquino-line (8 g, 0.035 mol) in anhydrous THF (150 ml) 60% NaH (0.84 g, 0.035 mol) was added at room temperature over 1 h and 1 (12.04 g, 0.035 mol) was then added to the mixture. Stirring continued for another 20 h at 45°C. Progress of the reaction was monitored by TLC using toluene:acetone (7:3) as eluent. The mixture was treated with crushed ice, filtered and dried to make 3 [40]. Yield 82%, melting point (m.p.) 273–275°C. IR (KBr, cm-1): 2221 (C≡N), 1261 (C-O-C).

Preparation of compounds 5a–uTo a solution of 3 (0.01 mol) in 1,4-dioxane (30 ml), the respective substituted piperazine derivative was added and the reaction mixture was refluxed for 13–25 h. Potassium carbonate (0.01 mol) was used for neutralization of the reac-tion mixture. Progress of the reaction was moni-tored by TLC using toluene:acetone (8:2) as elu-ent. The mixture was then treated with crushed

ice and neutralized by dilute HCl. The precipitate thus obtained was filtered, dried and recrystallized from THF to afford the desired compounds 5a–u.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-(4-methyl-piperazin-1-yl)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5a)Light-brown solid, recrystallization from THF (yield 4.74 g, 81%), m.p. 217–218°C. IR (KBr, cm-1): 3311 (-NH), 2218 (C≡N), 1263 (C-O-C), 809 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.22 (s, 1H, C

tri-NH), 8.91 (d,

N

N

N

R

NH

N

Increased activity of some molecules by lowering MICs

Contribute constant activity

Where R = piperazine or piperidine base

• Decreased MIC levels significantly• Increased total number of active molecules against DU-145

ONCF3

CN

N

N

R

NH

N

ON CF3

C

Br

N

N

N

R

NH

N

ON

C

Br

Figure 3. The comparison and influence of different substituent pattern on biological activities.

N

N

N

Cl Cl

Cl

NH2

CF3

NC

Et3N

N

N

N

NH

NC

Cl

Cl CF3

N

OH

BrNaH

N

N

N

NH

N

ON

C

Br Cl

CF3

XHN R

K2CO3

N

N

N

NH

N

3

435

6

4 3

2

2

1

3

4

55

6

67

8

9

1

21

ON

C

BrN

R1

X

R

+

+1

+3

2

4a-u

THF

THF

1,4-dioxane

2,4,6-trichloro-1,3,5-triazine

4-amino-2-trifluoromethyl-benzonitrile

1

6-bromo-4-hydroxyquinoline

X = N or H or O and R1 = aliphatic or substituted aromatic or heterocyclic functional groups

5a–u

Figure 4. Synthesis of final s-triazine derivatives. Synthetic protocol for the compounds 5a–u.

Evaluation of new s-triazine-based heterocycles | Preliminary CommuniCation

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J = 2.3 Hz, 1H, H-5qui

), 8.72 (d, J = 7.9 Hz, 1H, -N=CH-, H-2

qui), 8.58 (s, 1H, H-3

qui), 8.41 (d,

J = 7.5 Hz, 1H, H-8qui

), 8.11 (dd, J = 7.3, 1.6 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.52–7.43 (m, 4H, Ar-H), 3.81 (br s, 4H

pip), 3.51 (br s, 4H

pip),

1.92 (s, 1H, N-CH3). 13C NMR (100 MHz,

DMSO-d6): δ 175.9 (1C, C

tri-N

pip), 166.2 (1C,

Ctri

-O-Cqui

), 163.8 (1C, C-2, Ctri

-NH-), 153.9, 152.5 (2C, C

2 and C

9, quinoline), 148.0, 147.2,

145.9, 142.6, 139.9, 137.4, 136.8, 133.9, 130.2 (C-CF

3), 127.8, 126.3, 124.9 (CF

3), 124.6 (13C,

Ar. C), 105.7 (1C, C≡N), 98.2 (1C, -C-C≡N), 50.2, 47.9 (4C

pip), 20.8 (1C, -CH

3). Anal. calcd

for C25

H20

BrF3N

8O: C, 51.29; H, 3.44; N,

19.14. Found: C, 51.16; H, 3.30; N, 19.29.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-(4-ethyl-piperazin-1-yl)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5b) Light-brown solid, recrystallization from THF (yield 4.56 g, 76%), m.p. 224–226°C. IR (KBr, cm-1): 3310 (-NH), 2220 (C≡N), 1260 (C-O-C), 814 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.41 (s, 1H, C

tri-NH),

8.84 (d, J = 1.4 Hz, 1H, H-5qui

), 8.68 (d, J = 8.1 Hz, 1H, -N=CH-, H-2

qui), 8.54 (s, 1H,

H-3qui

), 8.39 (d, J = 7.4 Hz, 1H, H-8qui

), 8.15 (dd, J = 7.6, 1.6 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.49–7.43 (m, 2H, Ar-H), 3.87 (br s, 4H

pip), 3.44

(br s, 4Hpip

), 2.29 (q, J = 7.1 Hz, 2H, N-CH2),

1.90 (t, J = 6.8 Hz, 3H, N-CH2-CH

3). 13C

NMR (100 MHz, DMSO-d6): δ 174.5 (1C, C

tri-

Npip

), 165.5 (1C, Ctri

-O-Cqui

), 164.2 (1C, C-2, C

tri-NH-), 155.4, 152.1 (2C, C

2 and C

9, quino-

line), 147.4, 144.8, 141.7, 140.2, 137.8, 136.3, 134.0, 131.9, 130.5 (C-CF

3), 128.7, 127.1, 125.3

(CF3), 123.3 (13C, Ar. C), 105.1 (1C, C≡N),

98.1 (1C, -C-C≡N), 48.8, 45.3, 39.2 (5C, 4C of piperazine and 1C of N-CH

2-CH

3), 19.4 (1C,

N-CH2-CH

3). Anal. calcd for C

26H

22BrF

3N

8O:

C, 52.10; H, 3.70; N, 18.69. Found: C, 52.24; H, 3.55; N, 18.83.

� 4-{4-(6-bromo-quinolin-4-yloxy)-6-[4-(2-chloro-phenyl)-piperazin-1-yl]-1,3,5-triazin-2-ylamino}-2-trifluoromethyl-benzonitrile (5c)Dark-yellow solid, recrystallization from DMF (yield 5.46 g, 80%), m.p. 209–211°C. IR (KBr, cm-1): 3298 (-NH), 2219 (C≡N), 1252 (C-O-C), 819 (s-triazine C-N str.), 772 (C-Cl). 1H NMR (400 MHz, DMSO-d

6): δ 9.34 (s, 1H,

Ctri

-NH), 8.90 (d, J = 1.9 Hz, 1H, H-5qui

), 8.72 (d, J = 8.5 Hz, 1H, -N=CH-, H-2

qui), 8.63 (s,

1H, H-3qui

), 8.36 (d, J = 7.3 Hz, 1H, H-8qui

),

8.13 (dd, J = 7.2, 1.5 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.51–7.34 (m, 6H, Ar-H), 3.89 (br s, 4H

pip), 3.51 (br s, 4H

pip). 13C NMR (100 MHz,

DMSO-d6): δ 176.4 (1C, C

tri-N

pip), 165.8 (1C,

Ctri

-O-Cqui

), 164.2 (1C, C-2, Ctri

-NH-), 153.7, 151.2 (2C, C

2 and C

9, quinoline), 149.1, 148.2,

146.8, 145.1, 142.9, 139.8, 137.6, 136.1, 133.4, 131.9, 129.8 (C-CF

3), 128.2, 126.7, 124.9 (CF

3),

123.5, 121.9, 120.7, 119.4, 118.4 (19C, Ar. C), 104.9 (1C, C≡N), 99.1 (1C, -C-C≡N), 52.2, 43.9 (4C

pip). Anal. calcd for C

30H

21BrClF

3N

8O:

C, 52.84; H, 3.10; N, 16.43. Found: C, 52.72; H, 2.98; N, 16.31.

� 4-{4-(6-bromo-quinolin-4-yloxy)-6-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-1,3,5-triazin-2-ylamino}-2-trifluoromethyl-benzonitrile (5d) Brown solid, recrystallization from DMF (yield 5.37 g, 75%), m.p. 231–232°C. IR (KBr, cm-1): 3294 (-NH), 2224 (C≡N), 1257 (C-O-C), 810 (s-triazine C-N str.), 763 (C-Cl). 1H NMR (400 MHz, DMSO-d

6): δ 9.47 (s, 1H, C

tri-NH),

8.88 (d, J = 2.1 Hz, 1H, H-5qui

), 8.77 (d, J = 8.3 Hz, 1H, -N=CH-, H-2

qui), 8.55 (s, 1H,

H-3qui

), 8.39 (d, J = 7.4 Hz, 1H, H-8qui

), 8.09 (dd, J = 7.2, 1.3 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.52–7.33 (m, 5H, Ar-H), 3.82 (br s, 4H

pip), 3.55 (br s, 4H

pip). 13C NMR (100 MHz,

DMSO-d6): δ 174.5 (1C, C

tri-N

pip), 167.0 (1C,

Ctri

-O-Cqui

), 164.9 (1C, C-2, Ctri

-NH-), 156.2, 153.4 (2C, C

2 and C

9, quinoline), 149.3, 142.7,

141.2, 139.9, 137.6, 136.2, 134.8, 133.1, 131.9, 130.5 (C-CF

3), 128.9, 127.3, 126.2, 125.0 (CF

3),

123.6, 121.3, 120.8, 119.1, 118.3 (19C, Ar. C), 106.7 (1C, C≡N), 95.6 (1C, -C-C≡N), 52.2, 44.8 (4C

pip). Anal. calcd for C

30H

20BrCl

2F

3N

8O:

C, 50.30; H, 2.81; N, 15.64. Found: C, 50.54; H, 3.01; N, 15.49.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-piperidin-1-yl-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5e)Light-yellow solid, recrystallization from THF (yield 4.16 g, 73%), m.p. 192–194°C. IR (KBr, cm-1): 3316 (-NH), 2224 (C≡N), 1265 (C-O-C), 806 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.32 (s, 1H, C

tri-NH), 8.83 (d,

J = 1.6 Hz, 1H, H-5qui

), 8.69 (d, J = 8.0 Hz, 1H, -N=CH-, H-2

qui), 8.59 (s, 1H, H-3

qui), 8.36 (d,

J = 7.2 Hz, 1H, H-8qui

), 8.18 (dd, J = 7.8, 1.7 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.55–7.42 (m, 2H, Ar-H), 3.80 (t, J = 4.9 Hz, 4H

pip), 3.67 (t,

J = 5.8 Hz, 4Hpip

), 1.59–1.63 (m, 2Hpip). 13C NMR (100 MHz, DMSO-d

6): δ 176.2 (1C,

Preliminary CommuniCation | Patel, Kumari, Rajani, Pannecouque, De Clercq & Chikhalia

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NCE GROUP

Ctri

-Npip

), 165.2 (1C, Ctri

-O-Cqui

), 164.4 (1C, C-2, C

tri-NH-), 154.0, 151.7 (2C, C

2 and C

9,

quinoline), 146.7, 144.8, 141.7, 139.3, 136.9, 133.1, 130.1 (C-CF

3), 128.9, 126.7, 125.2 (CF

3),

123.7, 122.8, 121.0 (13C, Ar. C), 105.4 (1C, C≡N), 98.1 (1C, -C-C≡N), 51.9, 49.7, 37.9 (5C

pip). Anal. calcd for C

25H

19BrF

3N

7O: C,

52.64; H, 3.36; N, 17.19. Found: C, 52.78; H, 3.48; N, 16.99.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-morpholin-4-yl-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5f)Light-brown solid, recrystallization from THF (yield 4.64 g, 81%), m.p. 200–202°C. IR (KBr, cm-1): 3304 (-NH), 2222 (C≡N), 1431 (morpholine C-O-C str.), 1249 (C-O-C), 806 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.51 (s, 1H, C

tri-NH), 8.87 (d,

J = 1.8 Hz, 1H, H-5qui

), 8.68 (d, J = 7.9 Hz, 1H, -N=CH-, H-2

qui), 8.61 (s, 1H, H-3

qui), 8.49 (d,

J = 7.8 Hz, 1H, H-8qui

), 8.16 (dd, J = 7.6, 1.7 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.49–7.40 (m, 2H, Ar-H), 2.45–2.37 (m, 4H, -CH

2, morpho-

line), 1.81–1.84 (m, 2H, -CH2, morpholine),

1.29–1.33 (m, 2H, -CH2, morpholine). 13C

NMR (100 MHz, DMSO-d6): δ 175.4 (1C,

C-6, Ctri

-Nmor

), 165.9 (1C, Ctri

-O-Cqui

), 163.5 (1C, C-2, C

tri-NH-), 151.3, 150.1 (2C, C

2 and

C9, quinoline), 147.6, 145.2, 142.0, 140.5,

137.6, 136.1, 132.9, 130.6 (C-CF3), 129.1,

127.6, 126.2, 124.9 (CF3), 123.1 (13C, Ar. C),

105.9 (1C, C≡N), 96.4 (1C, -C-C≡N), 59.8, 56.2 (4C

mor). Anal. calcd for C

24H

17BrF

3N

7O

2:

C, 50.36; H, 2.99; N, 17.13. Found: C, 50.22; H, 3.11; N, 17.01.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-(4-phenyl-piperazin-1-yl)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5g)Off-white solid, recrystallization from DMF (yield 4.92 g, 76%), m.p. 252–253°C. IR (KBr, cm-1): 3299 (-NH), 2220 (C≡N), 1258 (C-O-C), 812 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.40 (s, 1H,

Ctri

-NH), 8.82 (d, J = 1.4 Hz, 1H, H-5qui

), 8.74 (d, J = 8.2 Hz, 1H, -N=CH-, H-2

qui),

8.63 (s, 1H, H-3qui

), 8.38 (d, J = 7.5 Hz, 1H, H-8

qui), 8.13 (dd, J = 7.3, 1.4 Hz, 1H), 7.76

(d, J = 1.7 Hz, 1H), 7.47–7.33 (m, 7H, Ar-H), 3.85 (br s, 4H

pip), 3.57 (br s, 4H

pip). 13C NMR

(100 MHz, DMSO-d6): δ 176.8 (1C, C

tri-

Npip

), 166.4 (1C, Ctri

-O-Cqui

), 164.3 (1C, C-2, C

tri-NH-), 155.3, 152.4 (2C, C

2 and C

9, quino-

line), 146.1, 145.2, 143.3, 141.4, 140.9, 138.2,

136.7, 135.4, 133.0, 132.8, 130.0 (C-CF3),

129.1, 127.8 (CF3), 126.4, 124.8, 123.5, 122.1,

121.6, 120.5 (19C, Ar. C), 106.1 (1C, C≡N), 97.8 (1C, -C-C≡N), 50.2, 41.8 (4C

pip). Anal.

calcd for C30

H22

BrF3N

8O: C, 55.65; H, 3.42;

N, 17.31. Found: C, 55.81; H, 3.29; N, 17.19.

� 4-[4-(4-acetyl-piperazin-1-yl)-6-(6-bromo-quinolin-4-yloxy)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5h) Light-brown solid, recrystallization from THF (yield 4.91 g, 80%), m.p. 219–221°C. IR (KBr, cm-1): 3312 (-NH), 2219 (C≡N), 1722 (-C=O), 1482 (-CH

3),

1254 (C-O-C),

809 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.32 (s, 1H, C

tri-NH), 8.85 (d,

J = 1.7 Hz, 1H, H-5qui

), 8.70 (d, J = 7.9 Hz, 1H, -N=CH-, H-2

qui), 8.63 (s, 1H, H-3

qui), 8.36

(d, J = 7.3 Hz, 1H, H-8qui

), 8.10 (dd, J = 7.3, 1.3 Hz, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.44–7.35 (m, 2H, Ar-H), 3.79 (br s, 4H

pip), 3.41 (br

s, 4Hpip

), 2.44 (s, 3H, N-COCH3). 13C NMR

(100 MHz, DMSO-d6): δ 174.6 (1C, C

tri-

Npip

), 167.8, 166.2 (2C, 1C at Ctri

-O-Cqui

and 1C at N-COCH

3), 163.9 (1C, C-2, C

tri-NH-),

153.7, 153.1 (2C, C2 and C

9, quinoline), 146.9,

145.2, 142.8, 140.4, 137.9, 135.3, 133.8, 132.6, 130.5 (C-CF

3), 127.9, 126.2, 124.8 (124.8),

122.7 (13C, Ar. C), 106.1 (1C, C≡N), 97.2 (1C, -C-C≡N), 49.2, 46.1 (4C

pip), 23.7 (1C,

N-COCH3). Anal. calcd for C

26H

20BrF

3N

8O

2:

C, 50.91; H, 3.29; N, 18.27. Found: C, 51.14; H, 3.13; N, 18.13.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-(4-isopropyl-piperazin-1-yl)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5i)Light-brown solid, recrystallization from DMF (yield 4.91 g, 80%), m.p. 211–212°C. IR (KBr, cm-1): 3296 (-NH), 2218 (C≡N), 1370 (isopro-pyl), 1255 (C-O-C), 819 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.44 (s,

1H, Ctri

-NH), 8.84 (d, J = 1.8 Hz, 1H, H-5qui

), 8.77 (d, J = 8.6 Hz, 1H, -N=CH-, H-2

qui),

8.57 (s, 1H, H-3qui

), 8.41 (d, J = 7.6 Hz, 1H, H-8

qui), 8.07 (dd, J = 7.4, 1.3 Hz, 1H), 7.74 (d,

J = 1.4 Hz, 1H), 7.49–7.44 (m, 2H, Ar-H), 3.83 (br s, 4H

pip), 3.49 (br s, 4H

pip), 2.90–2.93 (m,

1H, N-CH), 1.91 (d, J = 6.6 Hz, 6H, -2CH3).

13C NMR (100 MHz, DMSO-d6): δ 175.5 (1C,

Ctri

-Npip

), 165.4 (1C, Ctri

-O-Cqui

), 164.1 (1C, C-2, C

tri-NH-), 153.1, 150.9 (2C, C

2 and C

9,

quinoline), 147.2, 146.0, 143.8, 139.8, 138.1, 136.3, 134.1, 132.9, 129.7 (C-CF

3), 127.6,

126.0, 125.4 (CF3), 122.6 (13C, Ar. C), 105.7

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(1C, C≡N), 96.6 (1C, -C-C≡N), 55.2, 52.3, 46.9 (5C, 4C

pip and 1C of N-CH), 22.8 (2C,

2CH3). Anal. calcd for C

27H

24BrF

3N

8O: C,

52.86; H, 3.94; N, 18.27. Found: C, 52.71; H, 3.79; N, 18.20.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-(4-pyridin-2-yl-piperazin-1-yl)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5j) Light-brown solid, recrystallization from DMF (yield 4.80 g, 74%), m.p. 246–247°C. IR (KBr, cm-1): 3311 (-NH), 2223 (C≡N), 1264 (C-O-C), 806 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.48 (s, 1H,

Ctri

-NH), 8.94 (d, J = 2.3 Hz, 1H, H-5qui

), 8.73 (d, J = 8.3 Hz, 1H, -N=CH-, H-2

qui), 8.54 (s,

1H, H-3qui

), 8.44 (d, J = 7.6 Hz, 1H, H-8qui

), 8.16 (dd, J = 7.6, 1.7 Hz, 1H), 8.04 (dd, J = 7.5, 1.5 Hz, 1H, pyridyl), 7.74 (d, J = 1.6 Hz, 1H), 7.50–7.36 (m, 5H, Ar-H), 3.84 (br s, 4H

pip), 3.53

(br s, 4Hpip

). 13C NMR (100 MHz, DMSO-d6):

δ 177.1 (1C, Ctri

-Npip

), 166.3 (1C, Ctri

-O-Cqui

), 164.7 (1C, C-2, C

tri-NH-), 157.5, 156.7, 153.9,

151.5 (4C, 2C of C2 and C

9, quinoline and 2C

of Npip

-C-Npy

-CH or 1C of Npip

-C-Npy

-CH), 145.9, 143.7, 142.3, 140.9, 137.8, 136.0, 135.2, 133.1, 130.1 (C-CF

3), 127.9, 126.5, 125.7 (CF

3),

123.9, 122.0, 120.6, 119.1 (16C, Ar. C), 105.5 (1C, C≡N), 96.2 (1C, -C-C≡N), 50.2, 42.6 (4C

pip). Anal. calcd for C

29H

21BrF

3N

9O: C,

53.72; H, 3.26; N, 19.44. Found: C, 53.54; H, 3.38; N, 19.59.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-(4-pyrimidin-2-yl-piperazin-1-yl)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5k) Light-brown solid, recrystallization from DMF (yield 5.19 g, 80%), m.p. 253–255°C. IR (KBr, cm-1): 3318 (-NH), 2218 (C≡N), 1261 (C-O-C), 811 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.33 (s, 1H,

Ctri

-NH), 8.90 (d, J = 1.8 Hz, 1H, H-5qui

), 8.69 (d, J = 7.8 Hz, 1H, -N=CH-, H-2

qui), 8.57 (s,

1H, H-3qui

), 8.51–8.53 (m, 2H, pyrimidyl), 8.37 (d, J = 7.2 Hz, 1H, H-8

qui), 8.11 (dd,

J = 7.3, 1.5 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.47–7.39 (m, 2H, Ar-H), 6.82 (t, J = 6.9 Hz, 1H, pyrimidyl), 3.83 (br s, 4H

pip), 3.46 (br s,

4Hpip

). 13C NMR (100 MHz, DMSO-d6): δ

174.2 (1C, Ctri

-Npip

), 167.1 (1C, Ctri

-O-Cqui

), 164.1 (1C, C-2, C

tri-NH-), 159.7, 157.3, 156.6,

150.8 (5C, 2C of -C2H=N-C

9 or 1C of C

2 and

C9, quinoline and 3C

py), 147.9, 145.7, 142.2,

138.6, 136.2, 134.0, 132.7, 130.0 (C-CF3),

127.9, 126.1, 124.9 (CF3), 123.5, 121.0, 119.5

(14C, Ar. C), 105.9 (1C, C≡N), 97.9 (1C, -C-C≡N), 49.7, 44.1 (4C

pip). Anal. calcd for

C28

H20

BrF3N

10O: C, 51.78; H, 3.10; N, 21.57.

Found: C, 51.66; H, 2.97; N, 21.63.

� 4-[4-(4-benzyl-piperazin-1-yl)-6-(6-bromo-quinolin-4-yloxy)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5l) Off-white solid, recrystallization from DMF (yield 5.09 g, 77%), m.p. 222–223°C. IR (KBr, cm-1): 3309 (-NH), 2221 (C≡N), 1251 (C-O-C), 817 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.41 (s, 1H,

Ctri

-NH), 8.82 (d, J = 1.3 Hz, 1H, H-5qui

), 8.71 (d, J = 8.1 Hz, 1H, -N=CH-, H-2

qui),

8.58 (s, 1H, H-3qui

), 8.39 (d, J = 7.3 Hz, 1H, H-8

qui), 8.15 (dd, J = 7.8, 1.3 Hz, 1H), 7.76 (d,

J = 1.5 Hz, 1H), 7.53–7.37 (m, 7H, Ar-H), 3.87 (br s, 4H

pip), 3.52 (br s, 4H

pip), 2.80 (s, 2H,

Npip

-CH2). 13C NMR (100 MHz, DMSO-d

6):

δ 175.5 (1C, Ctri

-Npip

), 165.3 (1C, Ctri

-O-Cqui

), 164.6 (1C, C-2, C

tri-NH-), 154.7, 153.2 (2C,

C2 and C

9, quinoline), 148.1, 147.0, 144.3,

140.2, 139.3, 136.9, 135.5, 133.2, 132.8, 129.6 (C-CF

3), 128.1, 127.0, 126.7, 124.7 (CF

3),

123.1, 122.9, 121.7, 120.2, 118.7 (19C, Ar. C), 106.6 (1C, C≡N), 98.2 (1C, -C-C≡N), 66.1 (1C, N-CH

2), 51.4, 42.9 (4C

pip). Anal. calcd for

C31

H24

BrF3N

8O: C, 56.29; H, 3.66; N, 16.94.

Found: C, 56.43; H, 3.50; N, 17.08.

� 4-[4-(4-benzyl-piperidin-1-yl)-6-(6-bromo-quinolin-4-yloxy)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5m)Light-brown solid, recrystallization from DMF (yield 4.83 g, 73%), m.p. 240–241°C. IR (KBr, cm-1): 3316 (-NH), 2221 (C≡N), 1267 (C-O-C), 808 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.36 (s, 1H, C

tri-NH), 8.91 (d,

J = 2.0 Hz, 1H, H-5qui

), 8.70 (d, J = 7.9 Hz, 1H, -N=CH-, H-2

qui), 8.62 (s, 1H, H-3

qui), 8.46

(d, J = 7.5 Hz, 1H, H-8qui

), 8.08 (dd, J = 7.4, 1.4 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.51–7.35 (m, 7H, Ar-H), 3.84 (4H, t, J = 6.6 Hz, pip-eridine), 3.69 (4H, t, J = 8.9 Hz, piperidine), 2.45 (2H, s, -CH

2), 1.87 (1H, t, J = 7.5 Hz,

-CHpip

). 13C NMR (100 MHz, DMSO-d6):

δ 174.7 (1C, Ctri

-Npip

), 166.0 (1C, Ctri

-O-Cqui

), 163.4 (1C, C-2, C

tri-NH-), 152.7, 150.1 (2C, C

2

and C9, quinoline), 147.1, 146.3, 145.2, 142.3,

140.7, 138.4, 1136.9, 135.1, 133.8, 132.4, 130.8 (C-CF

3), 128.9, 127.7, 126.0, 125.4 (CF

3),

123.5, 122.6, 121.9, 119.1 (19C, Ar. C), 104.9 (1C, C≡N), 96.6 (1C, -C-C≡N), 49.3, 41.9, 38.1, 29.3 (6C, 5C

pip and 1C of N-CH

2). Anal.

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NCE GROUP

calcd for C32

H25

BrF3N

7O: C, 58.19; H, 3.82;

N, 14.84. Found: C, 58.32; H, 3.71; N, 14.99.

� 4-[4-(6-bromo-quinolin-4-yloxy)-6-(3,5-dimethyl-piperidin-1-yl)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5n)Light brown solid, recrystallization from DMF (yield 4.67 g, 78%), m.p. 263–264°C. IR (KBr, cm-1): 3314 (-NH), 2220 (C≡N), 1250 (C-O-C), 818 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.39 (s, 1H, C

tri-NH), 8.89 (d,

J = 1.9 Hz, 1H, H-5qui

), 8.77 (d, J = 8.4 Hz, 1H, -N=CH-, H-2

qui), 8.54 (s, 1H, H-3

qui), 8.43 (d,

J = 7.4 Hz, 1H, H-8qui

), 8.12 (dd, J = 7.5, 1.2 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.52–7.43 (m, 2H, Ar-H), 3.73 (dd, J = 12.3, 7.5 Hz, 2Hpip), 2.97 (dd, J = 12.4, 7.8 Hz, 2Hpip), 1.82–1.88 (m, 4H, piperidne), 1.45 (d, J = 6.8 Hz, 6H, 2CH

3).

13C NMR (100 MHz, DMSO-d6): δ 176.2 (1C,

Ctri

-Npip

), 166.4 (1C, Ctri

-O-Cqui

), 164.1 (1C, C-2, C

tri-NH-), 153.2, 152.1 (2C, C

2 and C

9,

quinoline), 144.2, 142.8, 139.0, 136.8, 135.7, 133.5, 132.9, 131.7, 129.8 (C-CF

3), 127.9, 126.3,

124.8 (CF3), 123.1, 120.7 (13C, Ar. C), 106.1

(1C, C≡N), 96.9 (1C, -C-C≡N), 49.1, 37.9, 29.9 (5C

pip), 23.2 (2C, 2CH

3). Anal. calcd for

C27

H23

BrF3N

7O: C, 54.19; H, 3.87; N, 16.38.

Found: C, 54.02; H, 3.98; N, 16.22.

� 4-[4-(4-benzhydryl-piperazin-1-yl)-6-(6-bromo-quinolin-4-yloxy)-1,3,5-triazin-2-ylamino]-2-trifluoromethyl-benzonitrile (5o) Off-while solid, recrystallization from DMF (yield 5.16 g, 70%), m.p. 279–281°C. IR (KBr, cm-1): 3309 (-NH), 2224 (C≡N), 1253 (C-O-C), 809 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.33 (s, 1H,

Ctri

-NH), 8.92 (d, J = 2.2 Hz, 1H, H-5qui

), 8.71 (d, J = 8.0 Hz, 1H, -N=CH-, H-2

qui),

8.58 (s, 1H, H-3qui

), 8.36 (d, J = 7.1 Hz, 1H, H-8

qui), 8.17 (dd, J = 7.7, 1.6 Hz, 1H), 7.73 (d,

J = 1.3 Hz, 1H), 7.55–7.26 (m, 12H, Ar-H), 4.47 (s, 1H, N-CH), 3.81 (br s, 4H

pip), 3.50 (br

s, 4Hpip

). 13C NMR (100 MHz, DMSO-d6): δ

177.1 (1C, Ctri

-Npip

), 166.2 (1C, Ctri

-O-Cqui

), 163.7 (1C, C-2, C

tri-NH-), 154.3, 151.7 (2C,

C2 and C

9, quinoline), 147.5, 146.1, 143.9,

142.1, 140.3, 139.6, 137.9, 136.4, 135.1, 134.0, 132.8, 131.7, 130.7 (C-CF

3), 129.0, 128.3,

127.9, 126.4, 125.5 (CF3), 124.2, 123.8, 122.0,

121.9, 120.5, 119.3, 118.1 (25C, Ar. C), 105.9 (1C, C≡N), 97.1 (1C, -C-C≡N), 75.6 (1C, -N

pip-CH), 46.5, 42.7 (4C

pip). Anal. calcd for

C37

H28

BrF3N

8O: C, 60.25; H, 3.83; N, 15.19.

Found: C, 60.36; H, 3.72; N, 14.96.

� 4-(4-(6-bromo-quinolin-4-yloxy)-6-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-1,3,5-triazin-2-ylamino)-2-trifluoromethyl-benzonitrile (5p)Yellow solid, recrystallization from DMF (yield 5.87 g, 76%), m.p. 270–272°C. IR (KBr, cm-1): 3297 (-NH), 2222 (C≡N), 1256 (C-O-C), 811 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.45 (s, 1H, C

tri-NH), 8.83 (d,

J = 1.5 Hz, 1H, H-5qui

), 8.69 (d, J = 7.8 Hz, 1H, -N=CH-, H-2

qui), 8.60 (s, 1H, H-3

qui), 8.44 (d,

J = 7.6 Hz, 1H, H-8qui

), 8.09 (dd, J = 7.2, 1.4 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.51–7.27 (m, 11H, Ar-H), 4.09 (s, 1H, N-CH), 3.89 (br s, 4H

pip), 3.56 (br s, 4H

pip). 13C NMR (100 MHz,

DMSO-d6): δ 176.1 (1C, C

tri-N

pip), 166.1

(1C, Ctri

-O-Cqui

), 164.7 (1C, C-2, Ctri

-NH-), 152.9, 151.3 (2C, C

2 and C

9, quinoline), 146.6,

145.2, 143.7, 142.4, 141.6, 140.1, 139.2, 138.0, 136.7, 135.0, 134.9, 133.1, 132.2, 131.9, 130.8 (C-CF

3), 129.1, 128.4, 127.3, 126.5, 125.2

(CF3), 123.9, 122.5, 121.8, 120.9, 120.1 (25C,

Ar. C), 106.1 (1C, C≡N), 95.9 (1C, -C-C≡N), 75.8 (1C, -N

pip-CH), 48.1, 45.7 (4C

pip). Anal.

calcd for C37

H27

BrClF3N

8O: C, 57.56; H, 3.53;

N, 14.51. Found: C, 57.69; H, 3.41; N, 14.67.

� 4-{4-(6-bromo-quinolin-4-yloxy)-6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-1,3,5-triazin-2-ylamino}-2-trifluoromethyl-benzonitrile (5q)Brown solid, recrystallization from DMF (yield 5.26 g, 79%), m.p. 225–226°C. IR (KBr, cm-1): 3303 (-NH), 2223 (C≡N), 1263 (C-O-C), 814 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.32 (s, 1H, C

tri-NH), 8.83 (d,

J = 1.6 Hz, 1H, H-5qui

), 8.74 (d, J = 8.3 Hz, 1H, -N=CH-, H-2

qui), 8.63 (s, 1H, H-3

qui), 8.48

(d, J = 7.5 Hz, 1H, H-8qui

), 8.11 (dd, J = 7.4, 1.3 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.58–7.38 (m, 9H, Ar-H), 6.99 (dd, J = 12.7, 7.1 Hz, 2H), 6.83–6.85 (m, 1H), 6.59 (dd, J = 12.9, 7.2 Hz, 1H), 3.81 (br s, 4H

pip), 3.45 (br s, 4H

pip). 13C

NMR (100 MHz, DMSO-d6): δ 174.6 (1C, C

tri-

Npip

), 166.2 (1C, Ctri

-O-Cqui

), 164.8 (1C, C-2, C

tri-NH-), 154.1, 153.4, 150.8 (3C, 2C of C

2

and C9, quinoline

and 1C of C-F), 146.2, 145.3,

143.9, 140.9, 137.9, 136.1, 135.4, 132.9, 131.7, 131.1 (C-CF

3), 128.9, 128.1, 127.5, 126.0, 125.6

(CF3), 124.0, 123.6, 122.7 (18C, Ar. C), 105.7

(1C, C≡N), 97.2 (1C, -C-C≡N), 50.1, 44.9 (4C

pip). 19F NMR (400 MHz, CDCl

3): δ -65.8

(s, 3F, CF3). Anal. calcd for C

30H

21BrF

4N

8O: C,

54.15; H, 3.18; N, 16.84. Found: C, 54.04; H, 3.33; N, 17.01.

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� 4-{4-(6-bromo-quinolin-4-yloxy)-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-1,3,5-triazin-2-ylamino}-2-trifluoromethyl-benzonitrile (5r)Light-brown solid, recrystallization from DMF (yield 4.92 g, 74%), m.p. 255–256°C. IR (KBr, cm-1): 3318 (-NH), 2224 (C≡N), 1265 (C-O-C), 806 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.37 (s, 1H,

Ctri

-NH), 8.90 (d, J = 2.0 Hz, 1H, H-5qui

), 8.70 (d, J = 8.0 Hz, 1H, -N=CH-, H-2

qui),

8.55 (s, 1H, H-3qui

), 8.41 (d, J = 7.4 Hz, 1H, H-8

qui), 8.17 (dd, J = 7.6, 1.6 Hz, 1H), 7.80

(d, J = 1.9 Hz, 1H), 7.49–7.34 (m, 9H, Ar-H), 7.23 (dd, J = 12.8, 7.9 Hz, 2H), 6.74–6.76 (m, 1H), 6.63 (dd, J = 12.9, 6.2 Hz, 1H), 3.86 (br s, 4H

pip), 3.53 (br s, 4H

pip). 13C NMR (100 MHz,

DMSO-d6): δ 176.0 (1C, C

tri-N

pip), 166.2 (1C,

Ctri

-O-Cqui

), 164.2 (1C, C-2, Ctri

-NH-), 153.7, 151.8, 149.9 (3C, 2C of C

2 and C

9, quinoline

and 1C of C-F), 147.9, 146.4, 145.2, 143.2, 139.8, 137.6, 135.0, 134.2, 133.7, 131.8, 130.3 (C-CF

3), 127.9, 126.3, 124.9 (CF

3), 123.2,

122.7, 121.1, 119.4 (18C, Ar. C), 105.2 (1C, C≡N), 97.2 (1C, -C-C≡N), 49.1, 45.6 (4C

pip).

19F NMR (400 MHz, CDCl3): δ -118.3 (1F,

s, C-F), -66.2 (s, 3F, CF3). Anal. calcd for

C30

H21

BrF4N

8O: C, 54.15; H, 3.18; N, 16.84.

Found: C, 53.98; H, 3.26; N, 16.97.

� 4-{4-(6-bromo-quinolin-4-yloxy)-6-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3,5-triazin-2-ylamino}-2-trifluoromethyl-benzonitrile (5s)Light-brown solid, recrystallization from DMF (yield 5.79 g, 81%), m.p. 282–283°C. IR (KBr, cm-1): 3310 (-NH), 2219 (C≡N), 1267 (C-O-C), 806 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.40 (s, 1H, C

tri-NH), 8.94 (d,

J = 2.3 Hz, 1H, H-5qui

), 8.77 (d, J = 8.5 Hz, 1H, -N=CH-, H-2

qui), 8.63 (s, 1H, H-3

qui), 8.37 (d,

J = 7.3 Hz, 1H, H-8qui

), 8.18 (dd, J = 7.6, 1.8 Hz, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.44–7.33 (m, 5H, Ar-H), 3.81 (br s, 4H

pip), 3.47 (br s, 4H

pip). 13C NMR (100 MHz,

DMSO-d6): δ 176.2 (1C, C

tri-N

pip), 165.8 (1C,

Ctri

-O-Cqui

), 164.4 (1C, C-2, Ctri

-NH-), 153.1, 151.8 (2C, C

2 and C

9, quinoline), 148.2, 146.9,

145.6, 143.8, 142.1, 140.2, 139.3, 137.5, 136.8, 135.1, 133.9, 132.6, 130.7 (C-CF

3), 130.1

(C-CF3), 127.5, 125.8 (CF

3), 125.0 (CF

3), 123.7,

121.1, 119.2 (20C, Ar. C), 106.1 (1C, C≡N), 97.4 (1C, -C-C≡N), 50.5, 42.9 (4C

pip). 19F NMR

(400 MHz, CDCl3): δ -65.9 (3F, s, -CF

3), -65.1

(3F, s, -CF3). Anal. calcd for C

31H

21BrF

6N

8O:

C, 52.04; H, 2.96; N, 15.66. Found: C, 52.23; H, 3.11; N, 15.43.

� 4-{4-(6-bromo-quinolin-4-yloxy)-6-[4-(2,3,4-trimethoxy-benzyl)-piperazin-1-yl]-1,3,5-triazin-2-ylamino}-2-trifluoromethyl-benzonitrile (5t)Dark-yellow solid, recrystallization from DMF (yield 5.64 g, 75%), m.p. 277–279°C. IR (KBr, cm-1): 3299 (-NH), 2218 (C≡N), 1486 (-CH

2),

1249 (C-O-C), 818 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.46 (s, 1H,

Ctri

-NH), 8.86 (d, J = 1.7 Hz, 1H, H-5qui

), 8.74 (d, J = 8.4 Hz, 1H, -N=CH-, H-2

qui),

8.55 (s, 1H, H-3qui

), 8.45 (d, J = 7.5 Hz, 1H, H-8

qui), 8.13 (dd, J = 7.5, 1.6 Hz, 1H), 7.79

(d, J = 7.6 Hz, 1H), 7.52–7.41 (m, 4H, Ar-H), 6.91 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 3.81 (br s, 4H

pip), 3.78 (s, 1H, N-CH

2),

3.73 (s, 9H, 3OCH3), 3.55 (br s, 4H

pip). 13C

NMR (100 MHz, DMSO-d6): δ 176.2 (1C,

Ctri

-Npip

), 165.7 (1C, Ctri

-O-Cqui

), 164.9 (1C, C-2, C

tri-NH-), 154.1, 152.1 (2C, C

2 and C

9,

quinoline), 149.1, 148.1, 146.7, 144.9, 141.7, 139.0, 136.8, 135.3, 133.9, 132.6, 131.4, 130.5 (C-CF

3), 128.9, 127.1, 126.5, 124.7 (CF

3),

123.1, 122.9, 119.1 (19C, Ar. C), 106.4 (1C, C≡N), 97.1 (1C, -C-C≡N), 66.6, 61.9, 56.2 (4C, 3C of 3OCH

3 and 1C of N

pip-CH

2), 49.1,

44.1 (4Cpip

). Anal. calcd for C34

H30

BrF3N

8O

4:

C, 54.34; H, 4.02; N, 14.91. Found: C, 54.47; H, 3.91; N, 14.80.

� 4-{4-(6-bromo-quinolin-4-yloxy)-6-[4-(4-methoxy-phenyl)-piperazin-1-yl]-1,3,5-triazin-2-ylamino}-2-trifluoromethyl-benzonitrile (5u)Light-brown solid, recrystallization from DMF (yield 5.62 g, 83%), m.p. 249–251°C. IR (KBr, cm-1): 3302 (-NH), 2220 (C≡N), 1260 (C-O-C), 809 (s-triazine C-N str.). 1H NMR (400 MHz, DMSO-d

6): δ 9.34 (s, 1H,

Ctri

-NH), 8.92 (d, J = 1.9 Hz, 1H, H-5qui

), 8.72 (d, J = 7.9 Hz, 1H, -N=CH-, H-2

qui),

8.57 (s, 1H, H-3qui

), 8.39 (d, J = 7.3 Hz, 1H, H-8

qui), 8.14 (dd, J = 7.4, 1.6 Hz, 1H), 7.74 (d,

J = 7.2 Hz, 1H), 7.50–7.40 (m, 4H, Ar-H), 7.27 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 4.29 (s, 3H, OCH

3), 3.84 (br s, 4H

pip), 3.56

(br s, 4Hpip

). 13C NMR (100 MHz, DMSO-d6):

d 174.2 (1C, Ctri

-Npip

), 165.2 (1C, Ctri

-O-Cqui

), 163.9 (1C, C-2, C

tri-NH-), 153.4, 151.8 (2C, C

2

and C9, quinoline), 147.1, 145.6, 144.5, 143.2,

140.9, 139.2, 137.6, 135.4, 134.1, 133.2, 131.9, 129.9 (C-CF

3), 128.4, 126.8, 125.2 (CF

3),

Key Terms

Sulforhodamine B colorimetric assay: Method describing the toxicity screening of compounds to cancerous cells in a 96-well format.

Mitochondrial dehydrogenase: Enzyme located in the inner mitochondrial membrane.

Cytopathic effect: Degenerative changes in cells, especially in tissue culture, and associated with the multiplication of certain viruses.

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124.3, 123.7, 121.8, 117.7 (19C, Ar. C), 105.8 (1C, C≡N), 97.1 (1C, -C-C≡N), 58.8 (1C, -OCH

3), 47.1, 43.9 (4C

pip). Anal. calcd for

C31

H24

BrF3N

8O

2: C, 54.96; H, 3.57; N, 16.54.

Found: C, 55.14; H, 3.42; N, 16.72.

PharmacologyIn order to characterize the antimicrobial properties of the new analogues, several bacte-rial (Staphylococcus aureus MTCC 96, Bacillus cereus MTCC 430, Escherichia coli MTCC 739, Pseudomonas aeruginosa MTCC 741, Klebsiella pneumoniae MTCC 109, Salmonella typhi MTCC 733, Proteus vulgaris MTCC 1771 and Shigella flexneria MTCC 1457) and fun-gal (Aspergillus niger MTCC 282, Aspergillus fumigatus MTCC 343, Aspergillus clavatus MTCC 1323 and Candida albicans MTCC 183) species were selected and assayed in vitro using the paper disc diffusion technique for obtaining the zone of inhibition [41]. The MIC of the compound was determined by the agar streak dilution method [42]. The preliminary antimycobacterial assessment for the final syn-thesized compounds was carried out using the BACTEC™ MGIT™ method [43] and the secondary antimycobacterial screening for test compounds was obtained for M. tuberculosis H37Rv, by using the Lowenstein and Jensen MIC method [44]. The in vitro anticancer screening was performed using the sulforhod-amine B colorimetric assay [45]. Methods of pharmacological evaluations were as described earlier [38].

In vitro evaluation of anti-HIV assay Evaluation of the antiviral activity of the test compounds against HIV-1 strain (III

B) and

HIV-2 strain (ROD) in MT-4 cells were per-formed using the MTT assay method as pre-viously described [46,47]. Briefly, stock solu-tions (10-times final concentration) of test compounds were added in 25-µl volumes to two series of triplicate wells so as to allow simultaneous evaluation of their effects on mock- and HIV-infected cells at the begin-ning of each experiment. Serial fivefold dilu-tions of test compounds were made directly in flat-bottomed 96-well microtiter trays using a Biomek 3000 robot (Beckman Instruments). Untreated control HIV- and mock-infected cell samples were included for each sample. HIV-1(III

B) [48] or HIV-2 (ROD) [49] stock (50 µl) at

100–300 CCID50

(50% cell culture infectious dose) or culture medium was added to either the

infected or mock-infected wells of the microtiter tray. Mock-infected cells were used to evaluate the effect of the test compound on uninfected cells in order to assess the cytotoxicity of the test compound. Exponentially growing MT-4 cells [50] were centrifuged for 5 min at 1000 rpm (220 g) and the supernatant was discarded. The MT-4 cells were resuspended at 6 × 105 cells ml-1 and 50 µl volumes were transferred to the microtiter tray wells. Five days after infection, the viability of mock- and HIV-infected cells was examined spectrophotometrically by the MTT assay.

The MTT assay is based on the reduction of yellow coloured MTT (Acros Organics) by mitochondrial dehydrogenase of metaboli-cally active cells to a blue–purple formazan that can be measured spectrophotometrically. The absorbances were read in an eight-channel com-puter-controlled photometer (Safire, Tecan), at two wavelengths (540 and 690 nm). All data were calculated using the median optical den-sity value of tree wells. The 50% cytotoxic con-centration was defined as the concentration of the test compound that reduced the absorbance (optical density 540) of the mock-infected con-trol sample by 50%. The concentration achiev-ing 50% protection from the cytopathic effect of the virus in infected cells was defined as the 50% effective concentration.

Results & discussion � Chemistry

The designed target compounds were obtained as outlined in Figure 4. This reaction proceeded with good yields and is applicable for different substituted piperazines and piperidines. The correct synthesis of 5a–u was confirmed on the basis of 1H NMR, 13C NMR and 19F NMR spectra [51] of synthesized compounds and the purity was ascertained by elemental analysis.

� PharmacologyAntimicrobial activityThe biological assay summarized in SuPPlementary tableS 1–4 revealed that all the newly synthe-sized compounds indicated varied bioactivities against the microorganism or cell line studied. However, it can be seen that biological activi-ties vary with the differences in the functional group(s) or atom(s) attached to the piperazine moiety condensed to the nucleus. In the present studies, these newer molecules are found to pos-sess higher activity than those analogues stud-ied previously. A possible explanation of this improvement in bioactivity is the incorporation

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of two key elements as trifluoromethyl- and bromo-functional groups. We have previously introduced the said functional groups one by one within the similar structural pattern and examined the bioassays mentioned here, and found both elements with combined form are more beneficial.

From the bioassay results it can be stated that all new analogues showed appreciable antimi-crobial activity. Compounds 5n, 5s & 5t were potentially active against both the Gram-positive bacteria (S. aureus and B. cereus) at 3.12 µg/ml of MIC as well as against P. aeruginosa and S. flexneri at 6.25 µg/ml and 12.5 µg/ml of MIC, respectively. Compounds 5s & 5t with tri-func-tionality appeared with significant inhibition of E. coli and P. vulgaris, as well as S. typhi, at 6.25 and 12.5 µg/ml of MIC, respectively, whereas compound 5n was effective against K. pneumo-niae at 12.5 µg/ml of MIC along with similar efficacy of analogue 5s. Derivatives with single electron-withdrawing chloro (5p) or fluoro (5q) substituent had excellent activity against P. vul-garis at an MIC level of 6.25 µg/ml, along with equal potency of compound 5u with electron-donating alkoxy substituent towards the same bacteria. Compound 5q was also active against S. typhi, while 5u was remarkably active against P. aeruginosa and S. flexneri at an MIC of 6.25 and 12.5 µg/ml, respectively. Analogues 5q, 5r, 5s & 5t had diminished activity against A. niger at 12.5 µg/ml, as well as against A. fumigatus and C. albicans at 25 µg/ml of MIC, whereas compounds 5s  &  5t were also active against A. clavatus at an MIC of 12.5 µg/ml. Analogues (5d & 5p) with a chloro subtituent displayed strong activity against A. fumigatus at an MIC of 25 µg/ml. Compound 5u with methoxy sub-stituent showed inhibition of C. albicans at an MIC of 25 µg/ml. Some analogues were found to display moderate activity at >25 µg/ml of MIC; however, the activity level of many ana-logues was found to increase within the scaffolds studied in the research work presented here than those scaffolds studied previously. Furthermore, the total number of the most potent analogues against a particular microorganism improved significantly in comparison with earlier studies.

� Anti-TB activityIn vitro anti-TB results provided in SuPPlementary table 3 indicated that s-triazines 5n, 5s & 5t displayed complete inhibition (99%) of M. tuberculosis H37Rv at an MIC of 3.12 µg/ml. Compounds 5p & 5u appeared with a good

inhibitory effect at an MIC of 6.25 µg/ml, while all the remaining derivatives were found to exert MIC values ranging from 12.5 to 500 µg/ml. From this bioassay it is appropriate to state that the numbers of total active analogues increase when lowering the MIC profiles when compared with that of control drugs.

� Anticancer activityThe activity of new compounds against breast cancer (MCF-7) cell proliferation reported in SuPPlementary table 4 suggest that four com-pounds (5c, 5j, 5n & 5s) were active in terms of GI

50, in which compound 5n showed heist

activity at 37.3 µg/ml of GI50

. In vitro anti-

prostate cancer activity results indicated that 15 compounds (5a–c, 5e, 5f–g, 5h–i, 5j–l, 5n, 5s & 5t) displayed significant growth inhibition in terms of GI

50. The compound 5e with the

morpholine ring system gave the highest activ-ity against the DU-145 cell line at 19.8 µg/ml of GI

50. Four compounds (5a, 5b, 5e & 5i) conferred

total inhibition of DU-145 cell growth (TGI) at the concentration level of 49.2–58.9 µg/ml and were found equally potent as the standard drug (ADR: TGI >100 µg/ml) in terms of TGI.

� Anti-HIV activityIn vitro anti-HIV activity results for the newer analogues are presented in SuPPlementary table 5. From this bioassay results it can be observed that the final analogues did not show selective activity against any type of the HIV viral strains studied.

ConclusionIn conclusion, the main goal of our study was to develop new s-triazines with broad therapeutic windows. The results obtained revealed that the nature of substituents and substitution pattern on the s-triazine ring may have a considerable impact on the biological activities of the target products. Out of the 21 compounds screened, compounds 5d, 5h, 5n, 5p, 5q, 5r, 5s, 5t & 5u exhibited promising in vitro anti bacterial, anti-fungal and antimycobacterial inhibitory effects. In general, the compounds showed improved antibacterial activity when compared to their antifungal activity. Among these compounds, a clear trend of improved activity has been shown to be due to the chloro, acetyl linkage and dime-thyl, mono-fluoro, trifluoromethyl, trimethoxy and mono-methoxy functionality at the nitro-gen atom of piperazine bases condensed to the nucleus. Interestingly, derivatives that showed

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potent antimicrobial as well as antimycobacte-rial activities at lower MICs were devoid of anti-cancer activity. Piperazine bases with aliphatic linkage (5a, 5b, 5h & 5i) or unsubstituted aro-matic or heterocyclic rings (5e, 5f, 5g, 5j, 5k & 5l) are more essential for anticancer activity (with the exception of 5m & 5o) than the final derivatives bearing electron-withdrawing or -releasing functional groups (5d, 5n, 5p–u). It is worth concluding that insertion of 4-amino-2-trifluoromethyl benzonitrile and 6-bromo-4-hydroxyquinoline is essential to increase the pharmacological activities of the resultant scaffolds by lowering the MICs in all the cases evaluated. In short, our findings might be ben-eficial as leads for designing new compounds with potential bioactivities.

Future perspectiveOver the next few years, among the trend of random screening of library of analogues versus multiple biological targets, the objective of the present work will be beneficial to increase under-standing of how the modification of basic struc-tural entities by different functionality affects the pharmacological profiles of basic heteronu-clei. By comparing anti microbial activities of the current products with previously developed products as the MICs against a broad spec-trum of microorganisms, cancerous cells and

viral strains, similarities and differences can be identified and may be utilized to derive potent drug candidates with a desired site of action. This article has described the most powerful method of structural optimization leading to the improved bioactive candidates – essential for further accomplishments and achievements.

Supplementary dataTo view the supplementary data that accompany this article please visit the journal website at: www.future-science.com/fmc/10.4155/FMC.12.57

Financial & competing interests disclosureThe authors are thankful to Applied Chemistry Department of S.V. National Institute of Technology, Surat, India for scholarship, encouragement and facilities. The authors wish to offer their deep gratitude to the Microcare Laboratory, Surat, India and Tata Memorial Advanced Centre for Treatment, Research and Education in Cancer, Mumbai, India for carrying out the biological screenings. The authors are also thankful to the Centre of Excellence, Vapi, India for carrying out 1H NMR, 13C NMR and 19F NMR analy-ses. The authors have no other relevant affiliations or finan-cial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Executive summary � A new class of s-triazine derivatives was designed and synthesized.

� In connection with our pre-established studies, we have repeated a set of modified analogues with improved bioefficacies.

� Synthesized compounds have been characterized. � FT-IR, 1H NMR, 13C NMR, 19F NMR and elemental analysis techniques were adopted.

� Some of the final analogues exhibited promising antimicrobial potency. � Lowest MIC values of 3.12–25 µg/ml were observed against bacteria, fungi and mycobacteria, and were equipotent to control drugs.

� The majority of the final analogues demonstrated higher or equipotent anticancer activity. � Compound concentration dose required for total growth inhibition of cancerous cells for some analogues was found to be lower (<100 µg/ml) in the anticancer assay when compared with the control drug (>100 µg/ml).

� Some analogues showed potential multiple bioactivities. � Some of the final products exerted constant activity in all the bioassays studied.

� New analogues warrant further study. � We faced considerable cytotoxicity in anti-HIV activity assays. Some possible modifications to the present structures may lead to molecules having higher selectivity as anti-HIV targets. One possible way is to reduce the bulk of the substituent to any one of three positions to observe whether this influences the activity or not. Hence, we believe that new hope for medical advances arise from the discovery of such products that may act as efficient leads in the development of novel therapeutic agents.

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Evaluation of new s-triazine-based heterocycles | Preliminary CommuniCation

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