Synthesis, characterization, and antimicrobial screening of s-triazines linked with piperazine or aniline scaffolds

Article abstract of DOI:10.1515/hc-2013-0077

Two series of s-triazines linked with piperazine or aniline scaffolds (4a-i and 5a-j) were synthesized and evaluated for their in vitro biological efficacy against Gram positive and Gram negative bacteria (Klebsiella pneumoniae MTCC 109, Pseudomonas aerug

Full text of DOI:10.1515/hc-2013-0077

ꢁꢁꢁꢂ
DOI 10.1515/hc-2013-0077ꢀ
ꢀHeterocycl. Commun. 2013; 19(5): 351–355
Harshad P. Lakum, Dhara V. Desai and Kishor H. Chikhalia*
Synthesis, characterization, and antimicrobial
screening of s-triazines linked with piperazine
or aniline scaffolds
Abstract: Two series of s-triazines linked with piperazine The achievements of novel drugs are put at risk by AMR.
or aniline scaffolds (4a–i and 5a–j) were synthesized and Without efficient antimicrobials for care and avoidance
evaluated for their in vitro biological efficacy against Gram of infections, the success of treatments such as organ
positive and Gram negative bacteria (Klebsiella pneumo- transplantation, cancer chemotherapy, and major surgery
niae MTCC 109, Pseudomonas aeruginosa MTCC 741, Staph- would be compromised. Infections caused by resistant
ylococcus aureus MTCC 96, Bacillus cereus MTCC 619) and microorganisms pose a serious challenge to the medical
fungi (Candida albicans MTCC 183 and Aspergillus niger community and the need for an effective therapy has led
MTCC 282) using a broth dilution technique. Compounds to a search for novel antimicrobial agents.
most active against certain bacteria and fungi are 4e, 4g,
i, 5d, and 5i.
According to a literature survey, many s-triazine
derivatives have been found to possess good antimicro-
bial properties and diverse pharmacological activities
4
Keywords: aniline; antimicrobial screening; piperazine; showing broadly active herbicidal [2] and antimicrobial
s-triazine.
[3] properties. Some are also used for the treatment of
HIV infection [4–6]. Several workers have investigated
s-triazine derivatives in the scope of potential therapeutic
agents for diseases due to bacteria [7–10], cancer [11–13],
antitumor [14, 15], and malaria [16, 17]. This literature
survey led us to consider the s-triazine system as a pos-
sible scaffold. Various substituted piperazine and aniline
derivatives linked with s-triazine moiety possess potential
antimicrobial [18], antituberculosis [18], and antimalarial
*
Corresponding author: Kishor H. Chikhalia, Department of
Chemistry, School of Sciences, Gujarat University, Ahmedabad
3
80 009, India, e-mail: chikhalia_kh@yahoo.com
Harshad P. Lakum and Dhara V. Desai: Department of Chemistry,
School of Sciences, Gujarat University, Ahmedabad 380 009, India
[
19, 20] activity. Several morpholine-substituted s-triazine
Introduction
derivatives also display good biological activity.
Drug-resistant strength of various disease-causing
microbes to well-known antibiotics has increased in
recent decades. Antimicrobial resistance (AMR) is resist-
ance of a microorganism to an antimicrobial medicine
Results and discussion
to which it was originally sensitive. Resistant organisms Chemistry
(
they include bacteria, fungi, viruses, and some parasites)
are able to withstand attack by antimicrobial medicines, The desired compounds 4a–i and 5a–j were synthesized
such as antibiotics, antifungals, antivirals, and antima- as outlined in Scheme 1. This synthetic route is practi-
larials, so that standard treatments become ineffective cal, amendable to scale-up, and offers a general modus
and infections persist, increasing the risk of spread. Some operandi for the preparation of a diversity of s-triazine
infections are caused by highly resistant bacteria such derivatives. Synthesis of compound 2 was achieved by the
as methicillin-resistant Staphylococcus aureus (MRSA). treatment of cyanuric chloride (1) with anisole in the pres-
According to the World Health Organization (WHO), ence of AlCl . The next step to compound 3 was a nucleo-
3
approximately 8.7 million people have been infected and philic displacement of the second chloride in compound 2
1
.4 million people have died from tuberculosis (TB) in by the reaction with morpholine in the presence of sodium
the year 2011 [1]. Diseases caused by resistant microbial bicarbonate. The third chloride was replaced by the reac-
flora often fail to respond to standard drug treatment, tion of 3 with aniline, substituted aniline, piperazine, or
resulting in prolonged illness and greater risk of death. substituted piperazine. All synthesized compounds were

3
52ꢀꢁꢁꢁꢂꢀH.P. Lakum et al.: s-Triazine scaffolds as potential antimicrobial agents
Cl
Cl
Cl
N
N
a
N
N
b
N
N
Cl
N
Cl
N
Cl
N
N
O
MeO
2
MeO
1
3
c
d
R2
N
R1
HN
N
N
N
N
N
N
N
N
N
O
O
MeO
MeO
4a-i
5a-j
1
4f: R1 = 4-Cl
5a: R2 = H
5f: R2 = 2-Cl-3-Cl-C H
6 3
4
4
4
4
4
a: R = H
1
1
2
2
i
b: R = 3-NO2
4g: R = 2-Me
5b: R = Me
5g: R = Pr
1
1
5c: R2 = Et
2
c: R = 4-NO
4h: R = 3-Me
5h: R = 2-F-C H
2
6
4
1
4i: R1 = 4-Me
2
2
d: R = 2-Cl
5d: R = OCOMe
5i: R = 4-F-C H
6
4
1
5e: R2 = 3-Cl-C H
2
e: R = 3-Cl
5j: R = 4-MeO-C H
6
4
6
4
Scheme 1ꢀReagents and conditions: (A) anisole, anhydrous AlCl , 0–5°C, acetone; (B) morpholine, acetone, NaHCO , 35–40°C; (C)
3
3
arylamine, DMF, NaHCO , 80–90°C; (D) piperazine derivative, DMF, NaHCO , 80–90°C.
3
3
characterized by IR and NMR and purity was established
with elemental analysis.
Experimental
General
Antimicrobial activity
Melting points were recorded using an open capillary melting point
1
apparatus and are uncorrected. H NMR spectra (400 MHz) were
The antimicrobial screening was performed for all synthe-
recorded in DMSO-d on a Bruker WM 400 instrument. IR spectra
6
sized s-triazine derivatives. Compounds were evaluated were recorded in KBr pellets on a Shimadzu FTIR spectrophotometer.
in vitro for their biological efficacy against Gram posi- Elemental analyses were carried out on a Carlo Erba-1108 elemen-
tal analyzer. The purity of all synthesized compounds was checked
tive and Gram negative bacteria (Klebsiella pneumoniae
MTCC 109, Pseudomonas aeruginosa MTCC 741, Staphy-
lococcus aureus MTCC 96, Bacillus cereus MTCC 619) and
fungi (Candida albicans MTCC 183 and Aspergillus niger
MTCC 282) using a broth dilution technique. Ciproflaxin
using thin layer chromatography (TLC) on silica gel-coated sheets
(
Merck Kiesel 60 GF-254, 0.2 mm thickness).
Synthesis of 2,4-dichloro-6-(4-
methoxyphenyl)-1,3,5-triazine (2)
(
an antibacterial antibiotic) and ketoconazole (an anti-
fungal antibiotic) were used at a concentration of 3.1 μg/
mL as reference drugs. Several compounds were found to
be active at a similar concentration level against particu-
A stirred solution of cyanuric chloride (1, 0.108 mol, 20 g) and anisole
(
0.108 mol, 11.8 g) in acetone (50 mL) was treated portion-wise with
lar bacteria and fungi. Whereas none of the compounds AlCl (0.108 mol, 14.4 g) at 0–5°C for 2 h. The mixture was stirred for
3
show activity at this concentration against K. pneumo- an additional 15 h at room temperature. The progress of reaction was
monitored by TLC using hexane/ethyl acetate (3:2) as an eluent. Af er
nia or P. aeruginosa, agents 4e and 5d show compar-
able activity against B. cereus and S. aureus, respectively.
Compound 4g is active against fungi C. albicans, and two
compounds 4i and 5i show activity at this concentration
against A. niger.
completion of the reaction the mixture was treated with 50% HCl.
The solid product obtained was filtered, washed with water, dried,
-1 1
and crystallized from acetone: yield 55%; IR: 1250, 3070 cm ; H NMR:
δ 3.85 (s, 3H), 7.10 (m, 2H), 7.90 (m, 2H); mp 132–136°C (dec). (Lit. mp
133–136°C [21].)

H.P. Lakum et al.: s-Triazine scaffolds as potential antimicrobial agentsꢀꢂꢁꢁꢁꢀ353
N-(4-Chlorophenyl)-4-(4-methoxyphenyl)-6-morpholino-1,3,5-
Synthesis of 2-chloro-4-(4-methoxyphenyl)-
-morpholino-1,3,5-triazine (3)
triazine-2-amine (4f)ꢀThis compound was obtained in 62% yield;
6
-1
1
mp 140–142°C (dec); IR: 3262, 1245, 1333, 3065, 842 cm ; H NMR: δ
.23 (s, 3H), 3.62 (m, 4H), 6.26 (s, 1H), 3.88 (m, 4H), 6.87 (m, 8H). Anal.
3
Morpholine (0.195 mol, 17.0 g) in acetone (50 mL) was slowly added
Calcd for C H ClN O : C, 60.38; H, 5.07; N, 17.60. Found: C, 60.33; H,
2
0
20
5
2
to a well-stirred slurry of compound 2 (0.195 mol, 50 g) and NaHCO
3
5.03; N, 17.65.
(
3
18 g, 0.215 mol) in acetone (50 mL) at a controlled temperature of
5–40°C. The reaction mixture was stirred for 6 h. The progress of
4
-(4-Methoxyphenyl)-6-morpholino-N-(o-tolyl)-1,3,5-triazine-
reaction was monitored by TLC using acetone/toluene (4:1) as an
eluent. Af er completion of the reaction, the solution was poured
onto crushed ice. The solid product obtained was filtered, dried, and
recrystallized from acetone: yield 60% yield; mp 70–75°C (dec); IR:
2
-amine (4g)ꢀThis compound was obtained in 56% yield; mp 137–
-1 1
1
39°C (dec); IR: 3255, 1239, 1339, 3045, 855 cm ; H NMR: δ 3.25 (s, 3H),
.24 (s, 3H), 3.66 (m, 4H), 6.24 (s, 1H), 3.83 (m, 4H), 6.87–7.98 (m, 8H).
Anal. Calcd for C H N O : C, 66.83; H, 6.14; N, 18.55. Found: C, 66.87;
2
-
1
1
21 23
5
2
1
251, 1315, 3067, 844 cm ; H NMR: δ 3.80 (s, 3H), 3.59–3.63 (t, J ꢀ= ꢀ 5.2
H, 6.12; N, 18.50.
Hz), 3.87 (t, 4H, J ꢀ= ꢀ 5.2 Hz), 7.10 (m, 2H), 7.90 (m, 2H).
4
-(4-Methoxyphenyl)-6-morpholino-N-(m-tolyl)-1,3,5-triazine-
2
-amine (4h)ꢀThis compound was obtained in 58% yield; mp 122–
-1 1
1
26°C (dec); IR: 3251, 1259, 1359, 3041, 825 cm ; H NMR: δ 3.22 (s, 3H),
.26 (s, 3H), 3.68 (m, 4H), 6.22 (s, 1H), 3.81 (m, 4H), 7.01–8.18 (m, 8H).
Anal. Calcd for C H N O : C, 66.83; H, 6.14; N, 18.55. Found: C, 66.80;
Synthesis of compounds 4a–i
An aniline (53.7 mmol) in dimethylformamide (DMF, 50 mL) was
allowed to react with compound 3 (16.5 g, 53.7 mmol) in DMF (50 mL)
2
21 23
5
2
H, 6.15; N, 18.57.
in the presence of NaHCO (4.96 g, 59.1 mmol) at 80–90°C for 5–10 h.
3
4
-(4-Methoxyphenyl)-6-morpholino-N-(p-tolyl)-1,3,5-triazine-
The progress of reaction was monitored by TLC using hexane/ethyl
acetate (4:1) as eluent. Af er completion of the reaction, the mixture
was poured onto crushed ice. The solid product thus obtained was
filtered, dried, and crystallized from methanol.
2
-amine (4i)ꢀThis compound was obtained in 63% yield; mp 129–
-1 1
1
31°C (dec); IR: 3239, 1270, 1328, 3027, 843 cm ; H NMR: δ 3.25 (s, 3H),
.29 (s, 3H), 3.64 (m, 4H), 6.15 (s, 1H), 3.84 (m, 4H), 7.14–8.10 (m, 8H);
mp 129–131°C (dec). Anal. Calcd for C H N O : C, 66.83; H, 6.14; N,
2
2
1
23
5
2
1
8.55. Found: C, 66.88; H, 6.19; N, 18.60.
4
-(4-Methoxyphenyl)-6-morpholino-N-phenyl-1,3,5-triazine-
2
-amine (4a)ꢀThis compound was obtained in 70% yield; mp
-1 1
1
14–116°C (dec); IR: 3279, 1246, 1325, 3085, 836 cm . H NMR: δ 3.25
(
s, 3H), 3.65 (m, 4H), 6.0 (s, 1H), 3.82 (m, 4H), 6.85 (m, 9H). Anal.
Calcd for C H N O : C, 66.10; H, 5.82; N, 19.27. Found: C, 66.14; H,
2
0
21
5
2
Synthesis of compounds 5a–j
5.85; N, 19.21.
Compound 3 (18.45 g, 60.14 mmol) in DMF (50 mL) was allowed to
4
-(4-Methoxyphenyl)-6-morpholino-N-(3-nitrophenyl)-1,3,5-tri- react with a piperazine (60.14 mmol) in the presence of NaHCO3
azine-2-amine (4b)ꢀThis compound was obtained in 65% yield; mp (5.56 g, 66.15 mmol) at 80–90°C for 5–10 h. The progress of reaction
-1
-1 1
1
3
20–124°C (dec); IR: (cm ): 3285, 1211, 1315, 3067, 844 cm ; H NMR: δ was monitored by TLC using hexane/ethyl acetate (4:1) as an elu-
.22 (s, 3H), 3.61 (m, 4H), 6.07 (s, 1H), 3.87 (m, 4H), 7.90 (m, 8H). Anal. ent. Af er completion of the reaction, the mixture was poured onto
Calcd for C H N O : C, 58.82; H, 4.94; N, 20.58. Found: C, 58.89; H, crushed ice, and the resultant precipitate was filtered, dried, and
2
0
20
6
4
4.95; N, 20.52.
crystallized from tetrahydrofuran (THF).
4
-(4-Methoxyphenyl)-6-morpholino-N-(4-nitrophenyl)-1,3,5- 2-(4-Methoxyphenyl)-4-morpholino-6-piperazino-1,3,5-triazine
triazine-2-amine (4c)ꢀThis compound was obtained in 62% yield; (5a)ꢀThis compound was obtained in 64% yield; mp 178–180°C
-1
1
-1 1
mp 131–133°C (dec); IR: 3276, 1244, 1310, 3061, 849 cm ; H NMR: δ (dec); IR: 3239, 1279, 1321, 3029, 849 cm ; H NMR: δ 3.25 (s, 3H), 3.31
.28 (s, 3H), 3.68 (m, 4H), 6.11 (s, 1H), 3.81 (m, 4H), 6.85 (m, 8H). Anal. (m, 4H), 3.63 (m, 4H), 3.79 (m, 4H), 4.15 (s, 1H), 3.84 (m, 4H), 6.84–7.30
Calcd for C H N O : C, 58.82; H, 4.94; N, 20.58. Found: C, 58.88; H, (m, 4H). Anal. Calcd for C H N O : C, 60.66; H, 6.79; N, 23.58. Found:
3
2
0
20
6
4
18 24
6
2
4.96; N, 20.60.
C, 60.68; H, 6.80; N, 23.60.
N-(2-Chlorophenyl)-4-(4-methoxyphenyl)-6-morpholino-1,3,5- 2-(4-Methoxyphenyl)-4-(4-methylpiperazino)-6-mor-
triazine-2-amine (4d)ꢀThis compound was obtained in 58% yield; pholino-1,3,5-triazine (5b)ꢀThis compound was obtained in 68%
-
1
1
-1
1
mp 128–130°C (dec); IR: 3259, 1255, 1323, 3056, 834 cm ; H NMR: δ yield; mp 184–186°C (dec); IR: 3231, 1272, 1325, 3047, 863 cm ; H
3
.24 (s, 3H), 3.69 (m, 4H), 6.01 (s, 1H), 3.82 (m, 4H), 8.04 (m, 8H). Anal. NMR: δ 3.27 (s, 3H), 3.32 (m, 4H), 3.69 (m, 4H), 3.84 (m, 4H), 3.31 (s,
Calcd for C H ClN O : C, 60.38; H, 5.07; N, 17.60. Found: C, 60.30; H, 3H), 3.84 (m, 4H), 6.88–7.36 (m, 4H). Anal. Calcd for C H N O : C,
2
0
20
5
2
19 26
6
2
5.13; N, 17.64.
61.60; H, 7.07; N, 22.69. Found: C, 61.61; H, 7.05; N, 22.73.
N-(3-Chlorophenyl)-4-(4-methoxyphenyl)-6-morpholino-1,3,5- 2-(4-Ethylpiperazino)-(4-methoxyphenyl)-6-morpholino-1,3,5-
triazine-2-amine (4e)ꢀThis compound was obtained in 64% yield; triazine (5c)ꢀThis compound was obtained in 69% yield; mp 166–
-
1
1
-1 1
mp 150–152°C (dec); IR: 3252, 1256, 1329, 3052, 831 cm ; H NMR: δ 168°C (dec); IR: 3255, 1265, 1329, 3024, 844 cm ; H NMR: δ 3.22 (s, 3H),
3
.28 (s, 3H), 3.64 (m, 4H), 6.21 (s, 1H), 3.87 (m, 4H), 6.81–8.03 (m, 8H). 3.36–3.40 (m, 4H), 3.68 (m, 4H), 3.77 (m, 4H), 1.92 (t, 3H), 2.94 (q, 2H),
Anal. Calcd for C H ClN O : C, 60.38; H, 5.07; N, 17.60. Found: C, 3.89 (m, 4H), 6.94–7.38 (m, 4H). Anal. Calcd for C H N O : C, 62.48;
2
0
20
5
2
20 28
6
2
6
0.45; H, 5.13; N, 17.53.
H, 7.34; N, 21.86. Found: C, 62.46; H, 7.38; N, 21.84.

3
54ꢀꢁꢁꢁꢂꢀH.P. Lakum et al.: s-Triazine scaffolds as potential antimicrobial agents
-
1
1
2
-(4-Acetoxypiperazino)-4-(4-methoxyphenyl)-6-mor- yield; mp 180–182°C (dec); IR: 3242, 1287, 1361, 3058, 848 cm ; H
pholino-1,3,5-triazine (5d)ꢀThis compound was obtained in 55% NMR: δ 3.21 (s, 3H), 3.34 (m, 4H), 3.65 (m, 4H), 3.72 (m, 4H), 3.86 (m,
yield; mp 170–172°C (dec); IR: 3240, 1270, 1358, 3077, 821 cm ; H NMR: 4H), 6.98 (m, 8H). Anal. Calcd for C H FN O : C, 63.98; H, 6.04; N,
-
1 1
24
27
6
2
δ 3.22 (s, 3H), 3.35 (m, 4H), 3.63 (m, 4H), 3.93 (s, 3H), 3.74 (m, 4H), 18.65. Found: C, 63.97; H, 6.03; N, 18.63.
.88 (m, 4H), 6.86–7.39 (m, 4H). Anal. Calcd for C H N O : C, 57.96;
3
2
0
26
6
4
H, 6.32; N, 20.28. Found: C, 57.97; H, 6.30; N, 20.32.
2-(4-Fluorophenylpiperazino)-4-(4-methoxyphenyl)-6-mor-
pholino-1,3,5-triazine (5i)ꢀThis compound was obtained in 79%
-1
1
2
-(3-Chlorophenylpiperazino)-4-(4-methoxyphenyl)-6-mor- yield; mp 202–205°C (dec); IR: 3248, 1282, 1368, 3052, 841 cm ; H
pholino-1,3,5-triazine (5e)ꢀThis compound was obtained in 60% NMR: δ 3.26 (s, 3H), 3.38 (m, 4H), 3.61 (m, 4H), 3.76 (m, 4H), 3.82 (m,
-1
1
yield. IR (KBr, cm ): 3248 (NH), 1272 (C-O-C), 1355 (CN), 3059, 831. H 4H), 7.07–7.79 (m, 8H). Anal. Calcd for C H FN O : C, 63.98; H, 6.04;
NMR (400 MHz, DMSO-d ) δ ppm: 3.25 (s, 3H, Ar-OCH ), 3.32–3.36 N, 18.65. Found: C, 63.97; H, 6.03; N, 18.63.
24
27
6
2
6
3
(
m, 4H, piperazine), 3.59–3.63 (m, 4H, piperazine), 3.70–3.74 (m, 4H,
morpholine), 3.85–3.89 (m, 4H, morpholine), 6.84–7.39 (m, 8H, Ar-H), 2-(4-Methoxyphenyl)-4-(4-methoxyphenylpiperazino)-6-mor-
mp 160–163°C (dec). Anal. Calcd for C H ClN O : C, 61.73; H, 5.83; N, pholino-1,3,5-triazine (5j)ꢀThis compound was obtained in 66%
2
4
27
6
2
-
1
1
1
8.00. Found: C, 61.76; H, 5.86; N, 18.05.
yield; mp 192–198°C (dec); IR: 3245, 1284, 1364, 3055, 844 cm ; H
NMR: δ 3.21 (s, 3H), 3.32 (m, 4H), 3.67 (m, 4H), 3.71 (m, 4H), 3.86 (m,
2
-(2,3-Dichlorophenylpiperazino)-4-(4-methoxyphenyl)-6-mor- 4H), 3.39 (s, 3H), 7.12–7.76 (m, 8H). Anal. Calcd for C H N O : C, 64.92;
25 30 6 3
pholino-1,3,5-triazine (5f)ꢀThis compound was obtained in 58% H, 6.54; N, 18.17. Found: C, 64.90; H, 6.53; N, 18.16.
-1 1
yield; mp 179–181°C (dec); IR: 3240, 1279, 1351, 3051, 841 cm ; H NMR:
δ 3.24 (s, 3H), 3.37 (m, 4H), 3.67 (m, 4H), 3.74 (m, 4H), 3.87 (m, 4H),
Acknowledgments: The authors are thankful to Prof.
Nisha Shah, Head, Department of Chemistry, School
of Sciences, Gujarat University, Ahmedabad, India, for
6
1
.94–7.49 (m, 7H). Anal. Calcd for C H Cl N O : C, 57.49; H, 5.23; N,
24 26 2 6 2
6.76. Found: C, 57.23; H, 5.25; N, 16.73.
2
-(4-Isopropylpiperazino)-4-(4-methoxyphenyl)-6-mor- her kind cooperation in providing support and research
pholino-1,3,5-triazine (5g)ꢀThis compound was obtained in 67%
facilities. The authors also express their sincere thanks
to the Sophisticated Analytical Instrumentation Facility
SAIF), Punjab University and Chandigarh for spectral
-1
1
yield; mp 180–182°C (dec); IR: 3230, 1266, 1344, 3065, 843 cm ; H
NMR: δ 3.22 (s, 3H), 3.32 (m, 4H), 3.66 (m, 4H), 2.86 (m, 1H), 2.02 (d,
(
6
H, J ꢀ= ꢀ 6.5 Hz), 3.71 (m, 4H), 3.82 (m, 4H), 7.12–7.59 (m, 4H). Anal.
Calcd for C H N O : C, 63.29; H, 7.59; N, 21.09. Found: C, 63.28; H,
analysis.
2
1
30
6
2
7.58; N, 21.08.
2
-[4-(2-Fluorophenyl)piperazino]-4-(4-methoxyphenyl)-6-mor-
pholino-1,3,5-triazine (5h)ꢀThis compound was obtained in 67% Received May 23, 2013; accepted August 23, 2013
References
[
1] World Health Organization. Fact Sheet: A Short Update to the
013 Report; available at: http://www.who.int/mediacentre/
factsheets/fs104/en/ (Accessed 4 May, 2013).
2] Garmoura, M.; Blanchoud, H.; Teil, M.; Blanchard, M.; Chevreuil, M.
anti-HIV evaluation and molecular modeling of piperidine-
linked amino-triazine derivatives as potent non-nucleoside
reverse transcriptase inhibitors. Bioorg. Med. Chem. 2012, 20,
3856–3864.
2
[
Triazines in the marne and the seine rivers (France): longitudinal
evolution and flows. Water Air Soil Pollut. 2000, 132, 1–17.
3] Patel, R.; Kumari, P.; Rajani, D.; Chikhalia, K. Synthesis and
studies of novel 2-(4-cyano-3-trifluoromethylphenyl amino)-
[7] Srinivas, K.; Srinivas, U.; Jayathirtha Rao, V.; Bhanuprakash, K.;
Hara Kishore, K.; Murty, U. S. N. Synthesis and antibacterial
activity of 2,4,6-trisubstituted s-triazines. Bioorg. Med. Chem.
Lett. 2005, 15, 1121–1123.
[8] Patel, R.; Kumari, P.; Rajani, D.; Chikhalia, K. Synthesis,
characterization and pharmacological activities of
2-[4-cyano-(3-trifluoromethyl)phenylamino]-4-(4-quinoline/
coumarin-4-yloxy)-6-(fluoropiperazinyl)-s-triazines. J. Fluorine
Chem. 2011, 132, 617–627.
[9] Srinivas, K.; Srinivas, U.; Jayathirtha Rao, V.; Bhanuprakash, K.;
Hara Kishore, K.; Murty, U. S. N.; Jayathirtha Rao, V. Synthesis
and antibacterial activity of various substituted s-triazines.
Eur. J. Med. Chem. 2006, 41, 1240–1246.
[10] Gahtori, P.; Ghosh, S.; Singh, B.; Singh, B.; Singh, U.; Bhat, H.;
Uppal, A. Synthesis, SAR and antibacterial activity of hybrid
chloro, dichloro-phenylthiazolyl-s-triazines. Saudi Pharm. J.
2012, 20, 35–43.
[
4
(quinolin-4-yloxy)-6-(piperazinyl/piperidinyl)-s-triazines
as potential antimicrobial, antimycobacterial and anticancer
agents. Eur. J. Med. Chem. 2011, 46, 4354–4365.
[
[
[
4] Chen, X.; Zhan, P.; Pannecouque, C.; Balzarini, J.; Clercq, E.;
Liu, X. Synthesis and biological evaluation of piperidine-
substituted triazine derivatives as HIV-1 non-nucleoside reverse
transcriptase inhibitors. Eur. J. Med. Chem. 2012, 51, 60–66.
5] Patel, R.; Kumari, P.; Rajani, D.; Pannecouque, C.; Clercq, E.;
Chikhalia, K. Antimicrobial, anti-TB, anticancer and anti-HIV
evaluation of new s-triazine-based heterocycles. Future Med.
Chem. 2012, 4, 1053–1065.
6] Chen, X.; Zhan, P.; Liu, X.; Cheng, Z.; Meng, C.; Shao, S.;
Pannecouque, C.; Clercq, E.; Liu, X. Design, synthesis,

H.P. Lakum et al.: s-Triazine scaffolds as potential antimicrobial agentsꢀꢂꢁꢁꢁꢀ355
[
11] Machakanur, S.; Patil, B.; Badiger, D.; Bakale, R.; Gudasi, K.;
biological evaluation of novel 2,N6-disubstituted 1,2-dihydro-
1,3,5-triazine-4,6-diamines as potential antimalarials. Eur. J.
Med. Chem. 2011, 46, 2022–2030.
Annie Bligh, S. W. Synthesis, characterization and anticancer
evaluation of novel tri-arm star shaped 1,3,5-triazine
hydrazones. J. Mol. Struct. 2012, 1011, 121–127.
[17] Gahtori, P.; Ghosh, S.; Parida, P.; Prakash, A.; Gogoi, K.;
Bhat, H. R.; Singh, U. P. Antimalarial evaluation and docking
studies of hybrid phenylthiazolyl-1,3,5-triazine derivatives: a
novel and potential antifolate lead for Pf-DHFR-TS inhibition
Exp. Parasitol. 2012, 130, 292–299.
[18] Solankee, A.; Kapadia, K.; Cirić, A.; Soković, M.; Doytchinova, I.;
Geronikaki, A. Synthesis of some new s-triazine based
chalcones and their derivatives as potent antimicrobial agents.
Eur. J. Med. Chem. 2010, 45, 510–518.
[19] Kumar, A.; Srivastava, K.; Kumar, S. R.; Puri, S. K.; Chauhan,
P. M. S. Synthesis of 9-anilinoacridine triazines as new class of
hybrid antimalarial agents. Bioorg. Med. Chem. Lett. 2009, 19,
6996–6999.
[20] Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S.
Syntheses of 2,4,6-trisubstituted triazines as antimalarial
agents. Bioorg. Med. Chem. Lett. 2005, 15, 531–533.
[21] Richard, H.; Luppi, B. Novel s-triazine compounds bearing
at least one para-aminobenzalmalonic salt substituted and
photoprotective cosmetic compositions comprised thereof.
United State Patent Application Publication. Pub. No.: US
7534421B2, 2009.
[
12] Kumar, R.; Gupta, L.; Pal, P.; Khan, S.; Singh, N.; Katiyar, S.;
Meena, S.; Sarkar, J.; Sinha, S.; Kanaujiya, J.; et al. Synthesis
and cytotoxicity evaluation of (tetrahydro-b-carboline)-1,3,5-
triazine hybrids as anticancer agents. Eur. J. Med. Chem. 2010,
45, 2265–2276.
[
13] Patel, R.; Kumari, P.; Rajani, D.; Chikhalia, K. Synthesis and
studies of novel 2-(4-cyano-3-trifluoromethylphenylamino)-
4
-(quinolin-4-yloxy)-6-(piperazinyl/piperidinyl)-s-triazines
as potential antimicrobial, antimycobacterial and anticancer
agents. Eur. J. Med. Chem. 2011, 46, 4354–4365.
[
[
[
14] Brzozowski, Z.; Sączewski, F. Synthesis and antitumor
activity of novel 2-amino-4-(3,5,5-trimethyl-2-pyrazolino)-1,3,5-
triazine derivatives. Eur. J. Med. Chem. 2002, 37,
7
09–720.
15] Brzozowski, Z.; Saczewski, F.; Gdaniec, M. Synthesis,
structural characterization and antitumor activity of novel
2
,4-diamino-1,3,5-triazine derivatives. Eur. J. Med. Chem.
000, 35, 1053–1064.
2
16] Gravestock, D.; Rousseau, A.; Lourens, A. C. U.; Moleele, S.;
van Zyl, R. L.; Steenkamp, P. A. Expeditious synthesis and

Copyright of Heterocyclic Communications is the property of De Gruyter and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.