Synthesis and characterization of new s-triazine bearing benzimidazole and benzothiazole derivatives as anticancer agents

Article abstract of DOI:10.1007/s00044-015-1430-9

Two new series of s-triazine derivatives appended with benzimidazole (15a-h) and benzothiazole derivatives (16a-h) are synthesized, and structure-activity relationships on anticancer activity of these 15a-h and 16a-h were probed. In vitro inhibitory activity against the growth of six cancer cell lines, viz., MCF-7, MDAMB-231, PC-3, DU-145, HT-29 and HGC-27 was evaluated for synthesized analogues. Among the two series of compounds, derivatives containing benzimidazole scaffold were found to be relatively potent over benzothiazole analogues. In accordance with our previous observation, within benzimidazole derivatives, tri-substituted s-triazine derivatives were found to be more potent over di-substituted derivatives irrespective of cell lines. Structure-activity relationships provided useful insights into these classes of compounds and paved the way to design novel analogues with more potency.

Full text of DOI:10.1007/s00044-015-1430-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1430-9
ORIGINAL RESEARCH
Synthesis and characterization of new s-triazine bearing
benzimidazole and benzothiazole derivatives as anticancer agents
G. Jagadeesh Kumar1,3 S. Naveen Kumar1 Dinesh Thummuri3
•
•
•
Lavanya Bindu Sree Adari3 V. G. M. Naidu3 Kolupula Srinivas3
V. Jayathirtha Rao1,2,3
•
•
•
Received: 17 February 2014 / Accepted: 17 August 2015
Ó Springer Science+Business Media New York 2015
Abstract Two new series of s-triazine derivatives
appended with benzimidazole (15a–h) and benzothiazole
derivatives (16a–h) are synthesized, and structure–activity
relationships on anticancer activity of these 15a–h and
16a–h were probed. In vitro inhibitory activity against the
growth of six cancer cell lines, viz., MCF-7, MDAMB-231,
PC-3, DU-145, HT-29 and HGC-27 was evaluated for
synthesized analogues. Among the two series of com-
pounds, derivatives containing benzimidazole scaffold
were found to be relatively potent over benzothiazole
analogues. In accordance with our previous observation,
within benzimidazole derivatives, tri-substituted s-triazine
derivatives were found to be more potent over di-substi-
tuted derivatives irrespective of cell lines. Structure–ac-
tivity relationships provided useful insights into these
classes of compounds and paved the way to design novel
analogues with more potency.
Keywords s-Triazine benzimidazole derivatives Á
s-Triazine benzothiazole derivatives Á Anticancer activity Á
Structure–activity relationships
Introduction
Cancer is the most deadly disease, and finding remedies for
it is at the forefront of many scientists around the globe. In
this context, s-triazine scaffold has attracted the attention
of many researchers for its therapeutic potential (Sathi-
akumar et al., 2011) and ease of functionalization on it
(Blotny 2006; Therrien 2010). For example, these com-
pounds possess potent antiprotozoal (Klenke et al., 2001),
antimalarial (Manohar et al., 2010; Melato et al., 2008),
antiviral (Maga et al., 2011; Mahajan et al., 2009; Maarouf
et al., 2012; Xiong et al., 2008; Kalyan et al., 2004;
Ludovicia et al., 2001), anticancer (Baindur et al., 2005;
Chua et al., 1999; Leftheris et al., 2004; Manohar et al.,
2010; Moon et al., 2002; Sun et al., 2010; Zheng et al.,
2007), antimicrobial (Bhat et al., 2013; Khan et al., 2013;
McKay et al., 2006; Patel et al., 2013, 2012a, b; Raval
et al., 2011; Singh et al., 2011; Srinivas et al., 2005, 2006;
Desai et al., 2008), antituberculosis (Patel et al., 2013;
Sunduru et al., 2010). Recently, the s-triazine derivatives
were extensively investigated for anticancer activity with a
particular target to mTOR/PI3K pathway (Menear et al.,
2009; Peterson et al., 2011, Poulsen et al., 2012; Richard
et al., 2010; Tanneeru et al., 2012; Venkatesan et al., 2010;
Verheijen et al., 2010; Wurz et al., 2012; Zask et al., 2010;
Zhang et al., 2011). Considering the potent bioactivities of
compounds possessing an s-triazine core, we became
interested to synthesize new s-triazine derivatives as
antibacterial and anticancer agents. Recently, we have
reported s-triazine analogues appended with substituted
& V. G. M. Naidu
vgmnaidu@niperhyd.ac.in
& Kolupula Srinivas
ksrinivas07@yahoo.com
& V. Jayathirtha Rao
jrao@iict.res.in
1
Crop Protection Chemicals Division, CSIR-Indian Institute of
Chemical Technology, Uppal Road Tarnaka,
Hyderabad 500607, India
2
AcSIR-IICT, CSIR-Indian Institute of Chemical Technology,
Uppal Road Tarnaka, Hyderabad 500607, India
3
National Institute of Pharmaceutical Education and Research
(NIPER), Balanagar, Hyderabad 500037, India
123

Med Chem Res
benzoxazoles as anticancer agents (Kumar et al., 2013). In
continuation to the previous work, we herein report newer
s-triazine derivatives appended with benzimidazole and
benzothiazole derivatives in place of benzoxazole deriva-
tives. Synthesized compounds were screened against six
types of cancer cells (MCF-7, MDAMB-231, PC-3, DU-
145, HT-29 and HGC-27), and their potential as anticancer
agents were assessed. Some of them were found to be more
potent than compounds reported in our previous report
(Kumar et al., 2013).
derivatives (15e–h) were synthesized by reacting morpho-
line 17 with di-substituted triazines (15a–d) in the presence
of K2CO3 and DMF at 100 °C. Similarly, compounds 16e–
h were synthesized from 16a–d, respectively (Scheme 4).
All the synthesized compounds were purified using silica gel
column chromatography and characterized by spectroscopic
techniques.
Biology
The anticancer activities of all the synthesized compounds
were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl tetrazolium bromide] method using six cancer cell
lines, viz., MCF-7, MDAMB-231 (breast cancer), PC-3,
DU-145, HT-29 (colon cancer) and HGC-27 (gastric can-
cer). The effect of compounds on the cell viability for each
cell line after exposure to different concentrations is depic-
ted in Fig. 1, and their respective IC50 values are presented in
Table 1. As discussed above, two series of compounds were
synthesized: benzimidazole derivatives and benzothiazole
derivatives. Within these two series of compounds, there
exist di-substituted (15a–d and 16a–d) and tri-substituted
derivatives (15e–h and 16e–h) (di- or tri-substitution w.r.t.
cyanuric chloride). The major difference in di- and tri-sub-
stituted derivatives is the absence and presence of morpho-
line ring, respectively, on s-triazine ring. Compounds 15a,
15c, 15e, 15g, 15h and 16d were found to be more potent
when screened against MCF-7 cell lines. Among the active
compounds, 15e is most potent. Remaining synthesized
compounds were inactive. In case of MDMAB-231 cell
lines, compound 15e and 15g were found to be more potent
with IC50 value of 8.3 1.9 and 10.3 0.2, respectively.
Compounds 15a, 15c, 15f and 15h are moderately active in
MDMAB-231 cell lines, whereas remaining compounds
(15b, 15d, 16a–h) were inactive. Structure–activity rela-
tionships of 15e–h demonstrates that substitution with ‘H’
and ‘F’ on aniline group favours activity as both have similar
size. But in case of 15f and 15h, ‘OCH3’ on aniline and
benzylamine group present, respectively, on triazine ring,
and this relatively disfavours the activity. When all these 16
compounds were screened against PC-3 cancer cell lines,
only compound 15g was active with IC50 value of
13.5 0.5. Compounds 15f–h were active (IC50 values:
18.6 0.4; 10.7 1.7; 20.3 1.6, respectively) against
Chemistry
Common synthetic strategy was followed to make desired
tri-substituted derivatives by sequential nucleophilic
replacement of each chlorine atom on cyanuric chloride
with: (a) aniline derivatives and benzyl amine; (b) substi-
tuted benzimidazoles and substituted benzothiazole;
(c) morpholine. Initially, benzimidazole and benzothiazole
derivatives (4 and 5; Scheme 1) were prepared in gram
quantities according to the published procedure (Chua et al.,
1999). Compound 4 was synthesized by condensation
reaction between benzene-1,2-diamine (1) and p-amino
benzoic acid (3) using polyphosphoric acid (PPA) at 200 °C.
Similarly, compound 5 was synthesized by condensation of
2-aminobenzenethiol (2) with p-amino benzoic acid (3) in
polyphosphoric acid (PPA) at same temperature
(Scheme 1). Mono-substituted triazine derivatives (10–12
and 14) were prepared as per the recent report (Kumar et al.,
2013; Zheng et al., 2007; Hunter et al., 1994; McKay et al.,
2006; Maga et al., 2011) involving a nucleophilic substitu-
tion reaction between cyanuric chloride (6) and various
amines such as aniline (7), p-methoxy aniline (8), p-fluoro
aniline (9) and benzyl amine (13) in the presence of base,
diisopropylethylamine (DIPEA) (Scheme 2). Milder reac-
tion conditions need to be maintained to get desired mono-
substitution on cyanuric chloride. These mono-substituted
triazine derivatives were taken further in making di- and tri-
substituted triazine derivatives. Second nucleophilic sub-
stitution reaction was carried out on mono-substituted tri-
azine derivatives (10–12 and 14) with using benzimidazole
(4) and benzothiazole derivatives (5) in the presence of
K2CO3 and THF at 70–80 °C temperature to get compounds
15a–d and 16a–d (Scheme 3). Tri-substituted triazine
Scheme 1 Synthesis of
compounds 4–5
123

Med Chem Res
Scheme 2 Synthesis of
compounds 10–12 and 14
N
Cl
N
NH2
Cl
N
Y
X
N
N
Y
X
N
N
4
: X = NH
Cl
N
N
H
5: X = S
N
H
N
H
K2CO3 / THF
70-80 ºC / 24 h
X = NH
X = S
10
: Y = H
15a: Y = H
16a: Y = H
11: Y = OCH3
12
15b: Y = OCH3
16b: Y = OCH3
: Y = F
15c
16c
: Y = F
: Y= F
N
X
Cl
NH2
N
Cl
N
N
N
X
4: X = NH
N
N
Cl
N
N
H
5
: X = S
N
H
N
H
K2CO3 / THF
70-80 ºC / 24 h
14
15d:
X = NH
16d: X = S
Scheme 3 Synthesis of compounds 15a–d and 16a–d
DU-145 cell lines. In case of HT-29 cancer cell lines, com-
pounds 15e and 15g were found to be more potent and
compounds 15a, 15c and 15h are moderately active. In case
of HGC-27 cell line, 15a and 15e–h were found to be active
and remaining were inactive. Among the screened 16 com-
pounds, benzimidazole derivatives (15a–h) were found to be
more potent over benzothiazole (16a–h). The difference
between them is –NH– versus –S– group, and this reflected
hugely in anticancer activity. Among benzimidazole
derivatives (15a–h), tri-substituted derivatives (15e–h) were
found to be relatively more potent over di-substituted
derivatives (15a–d); the difference lies in the presence and
absence of morpholine group. This observation reinforces
the previous conclusions presented in recent report from our
group (Kumar et al., 2013), indicating the presence of
morpholine has significant impact on anticancer activity of
these compounds.
Conclusion
In conclusion, two series of s-triazine derivatives bearing
benzimidazole and benzothiazole were synthesized as
anticancer agents. All the synthesized compounds were
screened against six cancer cell lines. Among the two
series of compounds, derivatives containing benzimidazole
scaffold were found to be relatively potent over benzoth-
iazole analogues. This unusual behaviour is a subject of our
future work along with molecular mechanistic studies. In
accordance with our previous observation, within benz-
imidazole derivatives, tri-substituted s-triazine derivatives
were found to be more potent over di-substituted deriva-
tives irrespective of cell lines. Structure–activity relation-
ships in these classes of compounds laid foundations to
develop more potent compounds as leads for cancer
chemotherapy. Focus of our future work includes synthesis
123

Med Chem Res
O
N
H
N
N
N
Cl
N
Y
O
Y
X
X
N
N
N
N
17
N
H
N
H
N
H
N
N
H
K2CO3 / dry DMF
100 ºC / 24 h
X = NH
X = S
X = NH
15e: Y = H
X = S
16e: Y = H
15a
15b
: Y = H
16a: Y = H
16b
15f
16f
: Y = OCH3
: Y = OCH3
15c: Y= F
: Y = OCH3
: Y = OCH3
16c: Y = F
15g: Y = F
16g: Y = F
H
N
O
N
X
Cl
N
O
N
N
N
N
N
17
X
N
N
N
N
H
K2CO3 / dry DMF
100 ºC / 24 h
N
H
N
H
H
15d:
X = NH
15h:
X = NH
16d: X = S
16h: X = S
Scheme 4 Synthesis of compounds 15e–h and 16e–h
of more derivatives of s-triazine with benzimidazoles to
(C, s-triazine-C), 163.8 (C, s-triazine-C), 162.4 (C, N=C–
NH), 149.9 (CAr), 143.7 (CAr), 141.6 (CAr), 139.7 (CAr),
128.3 (CAr), 127.7 (CAr), 124.8 (CAr), 124.5 (CAr), 121.9
(CAr), 120.1 (CAr), 119.5 (CAr), 119.2 (CAr), 118.9 (CAr),
110.5 (CAr); Mass (ESI–MS): m/z 414 [M ? H]?. HRMS
calcd for C22H16ClN7O 414.13641 Found: 414.13452.
evaluate their potential anticancer agents.
Experimental section
General procedure for synthesis of di-substituted
triazines (15a–d and 16a–d)
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-6-chloro-N4-(4-
methoxyphenyl)-1,3,5-triazine-2,4-diamine (15b)
To a solution of mono-substituted triazine derivatives 10–
14 (1 mmol) in dry THF was added K2CO3 (2.5 mmol),
and the reaction mixture was stirred for 5 min at room
temperature, 4 or 5 (1 mmol) was added to the reaction
mixture and stirred for 24 h at reflux temperature. After
completion of the reaction K2CO3 was decanted and the
THF was removed, water was added and extracted with
ethyl acetate. The organic layer was dried over Na2SO4,
concentrated and purified by using silica gel column
chromatography to give the desired di-substituted s-
triazines.
Yield: 89 %; Light red solid; mp 195–197 °C; IR (KBr) m
max: 3390, 3291, 3112, 2925, 1732, 1614, 1575, 1552,
1505, 1476, 1279, 1187, 1109, 1030 cm-1 1H NMR
;
(300 MHz, CDCl3): d 8.07 (m, 3H, ArH), 7.9 (s, 1H, ArH),
7.6 (m, 4H, ArH), 7.29 (s, 2H, ArH), 6.90 (s, 2H, ArH),
3.82 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3 ? DMSO
d6): d 163.8 (C, s-triazine), 163.3 (C, s-triazine), 163.2 (C,
s-triazine), 160.7 (C, N=C–NH), 157.8 (CAr), 155.3 (CAr),
150.7 (CAr), 139.7 (CAr), 137.9 (CAr), 126.5 (CAr), 123.3
(CAr), 122.3 (CAr), 121.5 (CAr), 119.5 (CAr), 113.9 (CAr),
113.0 (CAr), 54.6 (C, O–CH3); Mass (ESI–MS): m/z 444
[M ? H]?. HRMS calcd for C23H18ClN7O 444.13341
Found: 444.13252.
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-6-chloro-N4-
phenyl-1,3,5-triazine-2,4-diamine (15a)
Yield: 85 %; Light red solid; mp 188–190 °C; IR (KBr) m
max: 3853, 3735, 2927, 2360, 1600, 1514, 1430, 1314, 1290,
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-6-chloro-N4-(4-
fluorophenyl)-1,3,5-triazine-2,4-diamine (15c)
1
1188 cm-1; H NMR (300 MHz, CDCl3): d 8.1 (brs, 1H,
NH), 7.9 (d, J = 8.0 Hz, 1H, ArH), 7.6 (m, 5H, ArH), 7.38 (t,
J = 8.0 Hz, 4H, ArH), 7.1 (m, 3H, ArH); 13C NMR
(75 MHz, CDCl3 ? DMSO d6): d 164.5 (C, s-triazine), 163.9
Yield: 83 %; Light red solid; mp 191–193 °C; IR (KBr) m
max: 3404, 3270, 3059, 2924, 1609, 1617, 1575, 1506,
1450, 1410, 1314, 1276, 1210, 1157, 1044, 1016 cm-1; 1H
123

Med Chem Res
Fig. 1 Dose response curve of s-triazine derivatives on human cancer cell lines determined by MTT assay after 48-h treatment
NMR (300 MHz, CDCl3): d 9.43 (brs, 1H, NH), 9.17 (brs,
1H, NH), 8.13 (d, J = 9.4 Hz, 2H, ArH), 8.04 (d,
J = 8.5 Hz, 2H, ArH), 7.77 (t, J = 8.5, 5.6 Hz, 1H, ArH),
7.69 (m, 2H, ArH), 7.58 (m, 1H, ArH), 7.31 (m, 2H, ArH),
7.04 (t, J = 8.5 Hz, 2H, ArH); 13C NMR (75 MHz,
CDCl3 ? DMSO d6): d 162.79 (C, s-triazine), 162.71 (C,
s-triazine), 162.5 (C, s-triazine), 158.9 (C, N=C–NH),
155.6 (CAr), 149.6 (CAr), 136.7 (CAr), 133.1 (CAr), 125.8
123

Med Chem Res
123

Med Chem Res
(CAr), 122.0 (CAr), 121.8 (CAr), 121.7 (CAr), 121.2 (CAr),
119.0 (CAr), 113.9 (CAr), 113.8 (CAr), 113.5 (CAr), 113.2
(CAr); Mass (ESI–MS): m/z 432 [M ? H]?. HRMS calcd
for C22H15ClFN7 432.11343 Found: 432.11254.
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-N4-benzyl-6-
chloro-1,3,5-triazine-2,4-diamine (15d)
Yield: 92 %; Light red solid; mp 194–196 °C; IR (KBr) m
max: 3854, 3734, 3640, 3367, 3260, 3116, 2926, 2852, 2371,
1610, 1575, 1451, 1410, 1353, 1247, 1192, 1120,
1
1060 cm-1; H NMR (300 MHz, CDCl3): d 8.1 (brs, 1H,
NH), 7.9 (d, J = 8.0 Hz, 1H, ArH), 7.6 (m, 5H, ArH), 7.38 (t,
J = 8.0 Hz, 4H, ArH), 7.1 (m, 3H, ArH), 4.5 (m, 2H, Ar–
CH2); 13C NMR (75 MHz, CDCl3 ? DMSO d6): d 168.0 (C,
s-triazine), 165.5 (C, s-triazine), 163.4 (C, s-triazine), 151.3
(C, NH–C=N), 139.9 (CAr), 138.6 (CAr), 138.0 (CAr), 128.0
(CAr), 127.2 (CAr), 126.8 (CAr), 126.6 (CAr), 126.5 (CAr),
123.8 (CAr), 121.7 (CAr), 119.7 (CAr), 114.3 (CAr), 44.0 (C,
Ph–CH2–NH–); Mass (ESI–MS): m/z 428 [M ? H]?.
HRMS calcd for C23H18ClN7 428.13850 Found: 428.13700.
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-6-chloro-N4-phenyl-
1,3,5-triazine-2,4-diamine (16a)
Yield: 88 %; Grey solid; mp 150–152 °C; IR (KBr) m max:
3838, 3735, 3392, 3274, 2924, 1601, 1570, 1507, 1496, 1412,
;
1225, 1181, 988, 966, 836, 802, 756 cm-1 1H NMR
(300 MHz, CDCl3): d 8.01 (m, 5H, ArH), 7.92 (d,
J = 8.1 Hz, 2H, ArH), 7.81 (d, J = 7.6 Hz, 1H, ArH), 7.66
(d, J = 7.6 Hz, 1H, ArH) 7.48 (t, J = 7.6, Hz, 1H, ArH),
7.37 (m, 3H, ArH); 13C NMR (75 MHz, CDCl3 ? DMSO
d6): d 165.8 (C, s-triazine), 163.8 (C, s-triazine), 163.6 (C, s-
triazine), 162.0 (C, S–C=N), 150.0 (CAr), 141.8 (CAr), 141.5
(CAr), 128.5 (CAr), 127.7 (CAr), 125.0 (CAr), 124.6 (CAr),
120.6 (CAr), 120.3 (CAr), 120.1 (CAr), 110.6 (CAr); Mass
(ESI–MS): m/z 431[M ? H]?. HRMS calcd for C22H15
ClN6S 431.08402 Found: 431.08357.
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-6-chloro-N4-(4-
methoxyphenyl)-1,3,5-triazine-2,4-diamine (16b)
Yield: 91 %; Grey solid; mp 156–158 °C; IR (KBr) m max:
3854, 3735, 3397 3274, 3060, 2927, 2360, 1601, 1573,
1
1508, 1411, 1227, 1180, 1034, 829, 755 cm-1; H NMR
(300 MHz, CDCl3): d 8.07 (m, 3H, ArH), 7.9 (s, 1H, ArH),
7.6 (m, 4H, ArH), 7.38 (s, 2H, ArH), 6.9 (s, 2H, ArH), 3.8
(s, 3H, OCH3); 13C NMR (75 MHz, CDCl3 ? DMSO d6):
d 166.8 (C, s-triazine), 166.2 (C, s-triazine), 162.3 (C, s-
triazine), 153.4 (C, S–C=N), 134.0 (CAr), 127.2 (CAr),
125.7 (CAr), 124.4 (CAr), 123.4 (CAr), 123.2 (CAr), 122.5
(CAr), 122.1 (CAr), 121.1 (CAr), 120.2 (CAr), 119.9 (CAr),
113.3 (CAr), 113.2 (CAr), 113.1 (CAr), 54.8 (O–CH3); Mass
123

Med Chem Res
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-6-morpholino-
N4-phenyl-1,3,5-triazine-2,4-diamine (15e)
(ESI–MS): m/z 460 [M]?. HRMS calcd for C23H17ClN6OS
461.09458 Found: 461.09507.
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-6-chloro-N4-(4-
Yield: 89 %; Light red solid; mp 182–184 °C; IR (KBr) m
max: 3459, 3284, 3208, 2947, 2860, 1593, 1559, 1483,
fluorophenyl)-1,3,5-triazine-2,4-diamine (16c)
1
1419, 1305, 1274, 1232, 1108, 1027, 804, 737 cm-1; H
NMR (300 MHz, DMSO d6): d 9.58 (brs, 1H, NH), 8.01
(d, J = 9.0 Hz, 2H, ArH), 7.82 (brs, 1H, NH), 7.74 (d,
J = 9.0 Hz, 2H, ArH), 7.57 (d, J = 8.0 Hz, 2H, ArH),
7.47 (brs, 1H, NH), 7.34 (t, J = 8.0, 7.0 Hz, 3H, ArH),
7.10 (m, 1H, ArH), 6.84 (s, 2H, ArH), 3.85 (t,
J = 5.0 Hz, 4H, O–CH2), 3.77 (t, J = 5.0, 4.0 Hz, 4H,
N–CH2); 13C NMR (75 MHz, CDCl3 ? DMSO d6): d
164.6 (C, s-triazine), 164.1 (C, s-triazine), 164.0 (C, s-
triazine), 151.4 (C, NH–C=N), 143.8 (CAr), 141.8 (CAr),
139.9 (CAr), 134.9 (CAr), 128.4 (CAr), 126.8 (CAr), 123.2
(CAr), 122.1 (CAr), 122.0 (CAr), 121.5 (CAr), 119.6 (CAr),
118.4 (CAr), 111.0 (CAr), 66.0 (2C, CH2–O–CH2), 43.4
(2C, CH2–N–CH2); Mass (ESI–MS): m/z 465 [M ? H]?.
HRMS calcd for C26H24N8O 465.21458 Found:
465.21463.
Yield: 85 %; Grey solid; mp 155–157 °C; IR (KBr) m max:
3853, 3393, 3274, 3058, 2924, 1613, 1573, 1505, 1410,
1314, 1227, 1014, 967, 832, 863, 756, 726, 550, 508 cm-1
;
1H NMR (300 MHz, CDCl3): d 8.01 (m, 5H, ArH), 7.9 (d,
J = 8.0 Hz, 1H, ArH), 7.6 (m, 2H), 7.44 (t, J = 8.0 Hz,
1H, ArH), 7.38 (t, J = 8.0 Hz, 1H, ArH), 7.1 (m, 2H,
ArH); 13C NMR (75 MHz, CDCl3 ? DMSO d6): d 166.7
(C, s-triazine), 153.4 (C, S–C=N), 140.9 (CAr), 134.0 (CAr),
127.4 (CAr), 127.2 (CAr), 125.7 (CAr), 124.4 (CAr), 123.1
(CAr), 122.1 (CAr), 121.1 (CAr), 120.4 (CAr), 120.0 (CAr),
115.0 (CAr), 114.7 (CAr), 114.4 (CAr); Mass (ESI–MS): m/z
449 [M ? H]?. HRMS calcd for C22H14ClFN6S 449.07460
Found: 449.07486.
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-N4-benzyl-6-chloro-
1,3,5-triazine-2,4-diamine (16d)
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-N4-(4-
methoxyphenyl)-6-morpholino-1,3,5-triazine-2,4-diamine
(15f)
Yield: 87 %; Grey solid; mp 222–224 °C; IR (KBr) m max:
3839, 3735, 3264, 3217, 3056, 2832, 2780, 1699, 1628, 1578,
1530, 1393, 1240, 1227, 796, 758, 726, 549, 534 cm-1; H
1
Yield: 92 %; Light red solid; mp 168–170 °C; IR (KBr) m
max: 3276, 2958, 2922, 2853, 2366, 1541, 1491, 1420, 1239,
NMR (300 MHz, CDCl3): d 7.93 (d, J = 8.1 Hz, 2H, ArH),
7.88 (d, J = 8.1 Hz, 2H, ArH), 7.80 (s, 1H), 7.73 (m, 1H,
ArH), 7.42 t, J = 7.6 1H, ArH), 7.3 (m, 5H, ArH) 7.1 (m, 1H,
ArH), 4.5 (m, 2H, Ar–CH2); 13C NMR (75 MHz,
CDCl3 ? DMSO d6): d 165.6 (C, s-triazine), 162.4 (C, s-
triazine), 162.1(C, s-triazine), 150.0(C, S–C=N), 141.6(CAr),
138.7 (CAr), 128.3 (CAr), 127.8 (CAr), 127.2 (CAr), 126.8
(CAr), 125.0 (CAr), 124.8 (CAr), 124.6 (CAr), 119.8 (CAr),
119.6 (CAr), 119.4 (CAr), 119.1 (CAr), 110.6 (CAr), 43.9 (C,
Ph–CH2–NH–); Mass (ESI–MS): m/z 445 [M ? H]?. HRMS
calcd for C23H17ClN6S 445.09967 Found: 445.09997.
1
1181, 1110, 1023, 805, 744 cm-1; H NMR (300 MHz,
DMSO d6): d 8.47 (brs, 1H, NH), 8.11 (d, J = 8.4 Hz, 2H,
ArH), 7.85 (d, J = 8.4 Hz, 2H, ArH), 7.70 (s, 2H, ArH), 7.57
(d, J = 8.7 Hz, 2H, ArH), 7.49 (brs, 1H, ArH), 7.19 (m, 2H,
ArH), 6.87 (d, J = 8.6 Hz, 2H, ArH), 3.83 (s, 4H, O–CH2),
3.80 (s, 3H, OCH3), 3.75 (s, 3H, N–CH2); 13C NMR
(75 MHz, CDCl3 ? DMSO d6): d 164.6 (C, s-triazine),
163.8 (C, s-triazine), 163.7 (C, s-triazine), 154.4 (C, NH–
C=N), 151.4 (CAr), 141.7 (CAr), 141.6 (CAr), 132.6 (CAr),
126.6 (CAr), 122.8 (CAr), 121.6 (CAr), 121.3 (CAr), 119.3
(CAr), 119.2 (CAr), 113.3 (CAr), 110.7 (CAr), 65.9 (2C, CH2–
O–CH2), 54.9 (C, O–CH3), 43.3 (2C, CH2–N–CH2); Mass
(ESI–MS): m/z 495 [M ? H]?. HRMS calcd for
C27H26N8O2 495.22515 Found: 495.22378.
General procedure for synthesis of tri-substituted
triazines (15e–h and 16e–h)
To a solution of di-substituted s-triazine derivatives 15a–
d and 16a–d (1 mmol) in dry DMF, was added K2CO3
(2.5 mmol), and the reaction mixture was stirred for
5 min, at room temperature. Morpholine 17 (1 mmol)
was added to the reaction mixture and stirred at 24 h at
reflux temperature. After completion of the reaction
K2CO3 was decanted and the DMF was removed, water
was added and extracted with EtOAc. The organic layer
was dried over Na2SO4 concentrated and purified by
using silica gel column chromatography to give the
desired tri-substituted triazine derivatives in quantitative
yields.
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-N4-(4-
fluorophenyl)-6-morpholino-1,3,5-triazine-2,4-diamine
(15g)
Yield: 84 %; Light red solid; mp 178–180 °C; IR (KBr) m
max: 3422, 3283, 3190, 2964, 2922, 2855, 1609, 1578,
1542, 1498, 1429, 1265, 1210, 1111, 1014, 899, 744 cm-1
;
1H NMR (300 MHz, DMSO d6): d 12.48 (brs, 1H, NH),
8.99 (brs, 1H, NH), 8.86 (brs, 1H, NH), 8.10 (d,
J = 7.8 Hz, 2H, ArH), 7.90 (d, J = 7.8 Hz, 3H, ArH),
123

Med Chem Res
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-N4-(4-
methoxyphenyl)-6-morpholino-1,3,5-triazine-2,4-diamine
(16f)
7.69 (m, 3H, ArH), 7.48 (s, 1H, ArH), 7.18 (m, 2H, ArH),
7.02 (t, J = 7.8, 9.0 Hz, 2H¸ ArH), 3.83 (t, 4H, O–CH2),
3.74 (t, 4H, N–CH2); 13C NMR (75 MHz, CDCl3 ?
DMSO d6): d 164.6 (C, s-triazine), 163.8 (C, s-triazine),
158.9 (C, s-triazine), 151.4 (C, NH–C=N), 143.7 (CAr),
141.7 (CAr), 136.1 (CAr), 134.8 (CAr), 126.6 (CAr), 123.1
(CAr), 121.8 (CAr), 121.6 (CAr), 121.3 (CAr), 119.4 (CAr),
118.2 (CAr), 114.8 (CAr), 114.5 (CAr), 110.8 (CAr), 65.9
(2C, CH2–O–CH2), 43.3 (2C, CH2–N–CH2); Mass (ESI–
MS): m/z 483 [M ? H]?. HRMS calcd for C26H23FN8O
483.20516 Found: 483.20503.
Yield: 82 %; Grey solid; mp 153–155 °C; IR (KBr) m max:
3394, 3310, 3058, 2957, 2899, 2853, 1601, 1496, 1411,
1
1241, 1179, 1112, 1024, 966, 828, 804 cm-1; H NMR
(300 MHz, DMSO d6): d 9.03 (brs, 1H, NH), 8.54 (brs, 1H,
NH), 7.99 (m, 4H, ArH), 7.94 (d, J = 6.6 Hz, 2H, ArH),
7.60 (d, J = 8.8 Hz, 2H, ArH), 7.48 (t, J = 7.4, 6.6 Hz,
1H, ArH), 7.38 (t, J = 7.4, 6.6 Hz, 2H, ArH), 6.86 (d,
J = 8.8 Hz, 2H, ArH), 3.83 (s, 4H, O–CH2), 3.80 (s, 3H,
OCH3), 3.75 (s, 4H, N–CH2); 13C NMR (75 MHz,
CDCl3 ? DMSO d6): d 167.1 (C, s-triazine), 163.7 (C, s-
triazine), 164.6 (C, s-triazine), 153.6 (C, S–C=N), 154.4
(CAr), 143.2 (CAr), 134.0 (CAr), 132.6 (CAr), 127.3 (CAr),
126.0 (CAr), 125.7 (CAr), 124.5 (CAr), 122.1 (CAr), 121.5
(CAr), 119.3 (CAr), 65.9 (2C, CH2–O–CH2), 54.8 (C, O–
CH3), 43.3 (2C, CH2–N–CH2); Mass (ESI–MS): m/z 512
[M ? H]?. HRMS calcd for C27H25N7O2S 512.18632
Found: 512.18488.
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-N4-benzyl-6-
morpholino-1,3,5-triazine-2,4-diamine (15h)
Yield: 86 %; Light red solid; mp 166–168 °C; IR (KBr) m
max: 3297, 2961, 2921, 2855, 1497, 1430, 1275, 1112,
1
1023, 807, 745 cm-1; H NMR (300 MHz, DMSO d6): d
8.1 (d, J = 9.0 Hz, 1H, ArH), 7.7 (d, J = 9.0 Hz, 1H,
ArH), 7.5 (d, J = 8.0 Hz, 1H, ArH), 7.34 (t, J = 8.0 Hz,
2H, ArH), 7.18 (m, 3H, ArH), 6.90 (m, 3H, ArH), 6.81 (s,
2H, ArH), 4.5 (m, 2H, Ar–CH2), 3.83 (s, 4H, O–CH2),
3.75 (s, 4H); 13C NMR (75 MHz, CDCl3 ? DMSO d6): d
164.5 (C, s-triazine), 163.8 (C, s-triazine), 151.5 (C, s-
triazine), 145.3 (C, NH–C=N), 140.1 (CAr), 127.8 (CAr),
127.8 (CAr), 127.1 (CAr), 126.8 (CAr), 126.7 (CAr), 126.6
(CAr), 126.5 (CAr), 126.2 (CAr), 122.5 (CAr), 121.4 (CAr),
119.0 (CAr), 65.9 (2C, CH2–O–CH2), 48.4 (C, Ph–CH2–
NH–), 43.1 (2C, CH2–N–CH2); Mass (ESI–MS): m/z 478
[M ? H]?. HRMS calcd for C27H26N8O 479.23023
Found: 479.23049.
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-N4-(4-fluorophenyl)-
6-morpholino-1,3,5-triazine-2,4-diamine (16g)
Yield: 89 %; Grey solid; mp 152–154 °C; IR (KBr) m max:
3398, 3296, 2922, 2852, 2367, 2345, 1576, 1498, 1409,
1
1222, 966, 831, 757 cm-1; H NMR (300 MHz, DMSO
d6): d 8.57 (brs, 1H, NH), 8.30 (brs, 1H, NH), 8.12 (d,
J = 8.1 Hz, 2H, ArH), 7.86 (d, J = 8.1 Hz, 2H, ArH),
7.70 (d, J = 7.7 Hz, 2H, ArH), 7.64 (s, 1H, ArH), 7.49
(brs, 1H, NH), 7.31 (t, J = 7.3, 7.7 Hz, 2H, ArH), 7.19 (m,
2H, ArH), 7.01 (t, J = 7.3 Hz, 1H, ArH), 3.85 (s, 4H, O–
CH2), 3.76 (s, 4H, N–CH2); 13C NMR (75 MHz,
CDCl3 ? DMSO d6): d 167.0 (C, s-triazine), 164.5 (C, s-
triazine), 163.8 (C, s-triazine), 153.6 (C, S–C=N), 142.8
(CAr), 134.1 (CAr), 127.4 (CAr), 126.2 (CAr), 126.0 (CAr),
124.6 (CAr), 122.2 (CAr), 121.6 (CAr), 119.8 (CAr), 119.4
(CAr), 114.7 (CAr), 114.6 (CAr), 114.4 (CAr), 114.3 (CAr),
65.9 (2C, CH2–O–CH2), 43.1 (2C, CH2–N–CH2); Mass
(ESI–MS): m/z 500 [M ? H]?. HRMS calcd for C26H22
FN7OS 500.18342 Found: 500.18108.
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-6-morpholino-N4-
phenyl-1,3,5-triazine-2,4-diamine (16e)
Yield: 90 %; Grey solid; mp 149–151 °C; IR (KBr) m max:
3394, 3296, 2922, 2852, 2365, 2345, 1497, 1410, 1312,
1
1226, 1178, 1111, 965, 754 cm-1; H NMR (300 MHz,
DMSO d6): d 9.10 (brs, 1H, NH), 8.69 (brs, 1H, NH), 8.13
(d, J = 9.0 Hz, 2H, ArH), 7.97 (d, J = 9.0 Hz, 2H, ArH),
7.81 (m, 2H, ArH), 7.70 (m, 2H, ArH), 7.59 (m, 1H, ArH),
7.32 (m, 3H, ArH), 7.00 (t, J = 7.1 Hz, 1H, ArH), 3.85 (t,
J = 5.0 Hz, 4H, O–CH2), 3.75 (t, J = 5.0 Hz, 4H, N–
CH2); 13C NMR (75 MHz, CDCl3 ? DMSO d6): d 164.6
(C, s-triazine), 164.0 (C, s-triazine), 163.9 (C, s-triazine),
151.4 (C, S–C=N), 143.8 (CAr), 141.7 (CAr), 139.8 (CAr),
134.8 (CAr), 128.3 (CAr), 126.7 (CAr), 123.2 (CAr), 122.0
(CAr), 121.9 (CAr), 121.4 (CAr), 120.1 (CAr), 118.5 (CAr),
118.4 (CAr), 110.9 (CAr), 65.9 (2C, CH2–O–CH2), 43.3
(2C, CH2–N–CH2); Mass (ESI–MS): m/z 482 [M ? H]?.
HRMS calcd for C26H23N7OS 482.17576 Found:
482.17597.
N2-(4-(benzo[d]thiazol-2-yl)phenyl)-N4-benzyl-6-
morpholino-1,3,5-triazine-2,4-diamine (16h)
Yield: 85 %; Grey solid; mp 158–160 °C; IR (KBr) m max:
3291, 3186, 3058, 2957, 2920, 2851, 1667, 1575, 1478,
1
1249, 1176, 1114, 965, 697 cm-1; H NMR (300 MHz,
DMSO d6): d 8.14 (d, J = 9.0 Hz, 1H, ArH), 7.78 (d,
J = 9.0 Hz, 1H, ArH), 7.52 (d, J = 8.0 Hz, 1H, ArH),
7.34 (t, J = 8.0 Hz, 2H, ArH), 7.16 (m, 3H, ArH), 6.93 (m,
3H, ArH), 6.85 (s, 2H, ArH), 4.50 (m, 2H, Ar–CH2), 3.83
123

Med Chem Res
(s, 4H, O–CH2), 3.75 (s, 4H, N–CH2); 13C NMR (75 MHz,
CDCl3 ? DMSO d6): d 167.1 (C, s-triazine), 165.5 (C, s-
triazine), 164.6 (C, s-triazine), 163.9 (C, S–C=NH), 153.6
(CAr), 140.2 (CAr), 134.0 (CAr), 127.9 (CAr), 127.4 (CAr),
127.2 (CAr), 126.7 (CAr), 126.3 (CAr), 126.1 (CAr), 125.4
(CAr), 124.7 (CAr), 121.7, 119.1 (CAr), 65.9 (2C, CH2–O–
CH2), 43.2 (2C, CH2–N–CH2), 43.0 (C, Ph–CH2–NH–);
Mass (ESI–MS): m/z 496 [M ? H]?. HRMS calcd for
C27H25N7OS 496.19141 Found: 496.19017.
Leftheris K, Ahmed G, Chan R, Dyckman AJ, Hussain Z, Ho K,
Hynes J, Letourneau J, Li W, Lin S, Metzger A, Moriarty KJ,
Riviello C, Shimshock Y, Wen J, Wityak J, Wrobleski ST, Wu
H, Wu J, Desai M, Gillooly KM, Lin TH, Loo D, McIntyre KW,
Pitt S, Shen DR, Shuster DJ, Zhang R, Diller D, Doweyko A,
Sack J, Baldwin J, Barrish J, Dodd J, Henderson I, Kanner S,
Schieven GL, Webb M (2004) The discovery of orally active
triaminotriazine aniline amides as inhibitors of p38 MAP kinase.
J Med Chem 47:6283–6291
Ludovicia DW, Kavash RW, Kukla MJ, Ho CY, Ye H, De Corte BL,
Andries K, de Bethune MP, Azijn H, Pauwels R, Moereels HEL,
Heeres J, Koymans LMH, de Jonge MR, Van Aken KJA,
Daeyaert FFD, Lewi PJ, Das K, Arnolde E, Janssen PAJ (2001)
Evolution of anti-HIV drug candidates part 2: diaryltriazine
(DATA) analogues. Bioorg Med Chem Lett 11:2229–2234
Maarouf AR, Farahat AA, Selim KB, Eisa HM (2012) Synthesis and
antiviral activity of benzimidazolyl and triazolyl-1,3,5-triazines.
Med Chem Res 21:703–710
Acknowledgments Authors thank Director, CSIR-IICT, and Project
Director, NIPER, Hyderabad, for constant support and encourage-
ment. VJR thanks ORIGIN project CSC-0108 for funding. GJK, DT
and LBS thank Department of Pharmaceuticals, India, and SNK
thanks CSIR, India, for fellowship.
Maga G, Falchi F, Radi M, Botta L, Casaluce G, Bernardini M,
Irannejad H, Manetti F, Garbelli A, Samuele A, Zanoli S, Este
JA, Gonzalez E, Zucca E, Paolucci S, Baldanti F, Rijck JD,
Debyser Z, Botta M (2011) Toward the discovery of novel anti-
HIV drugs. Second-generation inhibitors of the cellular ATPase
DDX3 with improved anti-HIV activity: synthesis, structure–
activity relationship analysis, cytotoxicity studies, and target
validation. Chem Med Chem 6:1371–1389
Mahajan DH, Pannecouque C, De Clercq E, Chikhalia KH (2009)
Synthesis and studies of new 2-(Coumarin-4-yloxy)-4,6-(substi-
tuted)-s-triazine derivatives as potential anti-HIV agents. Arch
Pharm 342:281–290
Manohar S, Khan SI, Rawat DS (2010) Synthesis, antimalarial
activity and cytotoxicity of 4-aminoquinoline–triazine conju-
gates. Bioorg Med Chem Lett 20:322–325
McKay GA, Reddy R, Arhin F, Belley A, Lehoux D, Moeck G,
Sarmiento I, Parr T, Gros P, Pelletier J, Fara AR (2006)
Triaminotriazine DNA helicase inhibitors with antibacterial
activity. Bioorg Med Chem Lett 16:1286–1290
Melato S, Prosperi D, Coghi P, Monti D (2008) A combinatorial
approach to 2,4,6-trisubstituted triazines with potent antimalarial
activity: combining conventional synthesis and microwave
assistance. Chem Med Chem 3:873–876
Menear KA, Gomez S, Malagu K, Bailey C, Blackburn K, Cockcroft
XL, Ewen S, Fundo A, Le Gall A, Hermann G, Sebastian L,
Sunose M, Presnot T, Torode E, Hickson I, Martin NMB, Smith
GCM, Pike KG (2009) Identification and optimisation of novel
and selective small molecular weight kinase inhibitors of mTOR.
Bioorg Med Chem Lett 19:5898–5901
References
Baindur N, Chadha N, Brandt BM, Asgari D, Patch RJ, Schalk-HiHi
C, Carver TE, Petrounia IP, Baumann CA, Ott H, Manthey C,
Springer BA, Player MR (2005) 2-Hydroxy-4,6-diamino-[1,3,5]-
triazines: a novel class of VEGF-R2 (KDR) tyrosine kinase
inhibitors. J Med Chem 48:1717–1720
Bhat HR, Pandey PK, Ghosh SK, Singh UP (2013) Development of
4-aminoquinoline-1,3,5-triazine conjugates as potent antibacte-
rial agent through facile synthetic route. Med Chem Res 22:
5056–5065
Blotny G (2006) Recent applications of 2,4,6-trichloro-1,3,5-triazine
and its derivatives in organic synthesis. Tetrahedron 62:
9507–9522 (and references cited therein)
Chua MS, Shi DF, Wrigley S, Bradshaw TD, Hutchinson I, Shaw N,
Barrett DA, Stanley LA, Stevens MFG (1999) Antitumor
benzothiazoles. Synthesis of 2-(4-acylaminophenyl) benzothia-
zoles andinvestigations into the role of acetylation inthe antitumor
activities of the parent amines. J Med Chem 42:381–392
Desai RM, Dodiya DK, Trivedi AR, Shah VH (2008) Simple and
efficient synthetic routes to bioactive s-triazinyl dithiocarbamate
derivatives. Med Chem Res 17:495–506
Hunter A, Renfrew M, Taylor JA, Whitmore JMJ, Williams A (1994)
Nucleophilic aromatic substitution in heterocycles: alcoholysis
and hydrolysis of 2-anilino-4,6-dichloro-l,3,5-triazines. J Perk
Trans 2:2389–2393
Kalyan D, Arthur DCJ, Paul JL, Jan H, RdeJ Marc, Lucien MHK,
Maarten VH, Frederik D, Donald WL, Michael JK, De Bart,
Robert WK, Chih YH, Hong Y, Mark AL, Koen A, Rudi P, de
Be Marie-Pierre, Paul LB, Patrick C, Stephen HH, Paul AJJ,
Eddy A (2004) Roles of conformational and positional adapt-
ability in structure-based design of TMC125 R165335 (Etravir-
ine) and related non-nucleoside reverse transcriptase inhibitors
that are highly potent and effective against wild-type and drug-
resistant HIV-1 variants. J Med Chem 47:2550–2560
Khan FG, Yadav MV, Sagar AD (2013) Synthesis, characterization,
and antimicrobial evaluation of novel trichalcones containing
core s-triazine moiety. Med Chem Res. doi:10.1007/s00044-013-
0837-4
Moon HS, Jacobson EM, Khersonsky SM, Luzung MR, Walsh DP,
Xiong WN, Lee JW, Parikh PB, Lam JC, Kang TW, Rosania
GR, Schier AF, Chang YT (2002) A novel microtubule
destabilizing entity from orthogonal synthesis of triazine library
and zebrafish embryo screening.
11608–11609
J Am Chem Soc 124:
Patel D, Patel R, Kumari P, Patel N (2012a) In vitro antimicrobial
assessment of coumarin-based s-triazinyl piperazines. Med
Chem Res 21:1611–1624
Patel RV, Kumari P, Rajani DP, Chikhalia KH (2012b) Discovery of
2-(4-cyano-3-trifluoromethylphenyl amino)-4-(4-quinazoliny-
loxy)-6-piperazinyl(piperidinyl)-s-triazines as potential antibac-
terial agents. Med Chem Res 21:4177–4192
Patel AB, Patel RV, Kumari P, Rajani DP, Chikhalia KH (2013)
Synthesis of potential antitubercular and antimicrobial s-triazine
based scaffolds via Suzuki cross-coupling reaction. Med Chem
Res 22:367–381
Peterson A, Andrews PS, Be X, Boezio AA, Bush TL, Cheng AC,
Coats JR, Colletti AE, Copeland KW, DuPont M, Graceffa R,
Klenke B, Stewart M, Barrett MP, Brun R, Gilbert IH (2001)
Synthesis and biological evaluation of s-triazine substituted
polyamines as potential new anti-trypanosomal drugs. J Med
Chem 44:3440–3452
Kumar GJ, Bomma HVSS, Srihari E, Shrivastava S, Naidu VGM,
Srinivas K, Rao VJ (2013) Synthesis and anticancer activity of
some new s-triazine derivatives. Med Chem Res 22:5973–5981
123

Med Chem Res
Grubinska B, Harmange JC, Kim JL, Mullady EL, Olivieri P,
Venkatesan AM, Dehnhardt C, Santos ED, Chen Z, Santos OD,
Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R,
Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham RT,
Chaudhary I, Mansour TS (2010) Bis(morpholino-1,3,5-triazine)
derivatives: potent adenosine 50-triphosphate competitive phos-
phatidylinositol-3-kinase/mammalian target of rapamycin inhi-
bitors: discovery of compound 26 (PKI-587), a highly efficacious
dual inhibitor. J Med Chem 53:2636–2645
Schenkel LB, Stanton MK, Teffera Y, Whittington DA, Cai T,
La DS (2011) Discovery of triazine–benzimidazoles as selective
inhibitors of mTOR. Bioorg Med Chem Lett 21:2064–2070
Poulsen A, Williams M, Nagaraj HM, William AD, Wang H, Soh CK,
Xiong ZC, Dymock B (2012) Structure-based optimization of
morpholino-triazines as PI3K and mTOR inhibitors. Bioorg Med
Chem Lett 22:1009–1013
Raval JP, Patel NH, Patel HV, Patel PS (2011) In vitro antimycobac-
terial activity of novel N0-(4-(substituted phenyl amino)-6-
Verheijen JC, Richard DJ, Curran K, Kaplan J, Yu K, Zask A (2010)
2-Arylureidophenyl-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)tri-
azines as highly potent and selective ATP competitive mTOR
inhibitors: optimization of human microsomal stability. Bioorg
Med Chem Lett 20:2648–2653
Wurz RP, Liu L, Yang K, Nishimura N, Bo Y, Pettus LH, Caenepeel
S, Freeman DJ, McCarter JD, Mullady EL, Miguel TS, Wang L,
Zhang N, Andrews KL, Whittington DA, Jiang J, Subramanian
R, Hughes PE, Norman MH (2012) Synthesis and structure–
activity relationships of dual PI3K/mTOR inhibitors based on a
4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold. Bioorg
Med Chem Lett 22:5714–5720
Xiong YZ, Chen FE, Balzarini J, De Clercq E, Pannecouque C (2008)
Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 11:
structural modulations of diaryltriazines with potent anti-HIV
activity. Eur J Med Chem 43:1230–1236
Yaguch S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H,
Hirono S, Yamazaki K, Yamori T (2006) Antitumor activity of
ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl
Cancer Inst 98:545–556
(pyridin-2-ylamino)-1,3,5-triazin-2-yl)isonicotino
Med Chem Res 20:274–279
hydrazide.
Richard DJ, Verheijen JC, Yu K, Zask A (2010) Triazines incorpo-
rating (R)-3-methylmorpholine are potent inhibitors of the
mammalian target of rapamycin (mTOR) with selectivity over
PI3K alpha. Bioorg Med Chem Lett 20:2654–2657
Sathiakumar N, MacLennan PA, Mandel J, Delzell E (2011) A review
of epidemiologic studies of triazine herbicides and cancer. Crit
Rev Toxicol 41:1–34
Singh UP, Singh RK, Bhat HR, Subhashchandra YP, Kumar V,
Kumawat MK, Gahtori P (2011) Synthesis and antibacterial
evaluation of series of novel tri-substituted-s-triazine derivatives.
Med Chem Res 20:1603–1610
Srinivas K, Srinivas U, Jayathirtha Rao V, Bhanuprakash K, Kishore HK,
Murthy USN (2005) Synthesis and antibacterial activity of 2,4,6-tri
substituted s-triazine. Bioorg Med Chem Lett 15:1121–1123
Srinivas K, Srinivas U, Jayathirtha Rao V, Bhanuprakash K, Kishore
HK, Murthy USN (2006) Synthesis and antibacterial activity of
various substituted s-triazines. Eur J Med Chem 41:1240–1246
Sun D, Melman G, Le Torneau NJ, Hays AM, Melman A (2010)
Synthesis and antiproliferating activity of iron chelators of
hydroxyamino-1,3,5-triazine family. Bioorg Med Chem Lett
20:458–460
Zask A, Verheijen JC, Richard DJ, Kaplan J, Curran K, Toral-Barza
L, Lucas J, Hollander I, Yu K (2010) Discovery of 2-urei-
dophenyltriazines bearing bridged morpholinesas potent and
selective ATP-competitive mTOR inhibitors. Bioorg Med Chem
Lett 20:2644–2647
Sunduru N, Gupta L, Chaturvedi V, Dwivedi R, Sinha S, Chauhan
PMS (2010) Discovery of new 1,3,5-triazine scaffolds with
potent activity against Mycobacterium tuberculosis H37Rv. Eur
J Med Chem 45:3335–3345
Tanneeru K, Reddy BM, Guruprasad L (2012) Three-dimensional
quantitative structure–activity relationship (3D-QSAR) analysis
and molecular docking of ATP-competitive triazine analogs of
human mTOR inhibitors. Med Chem Res 21:1207–1217
Therrien B (2010) Coordination chemistry of 2,4,6-tri(pyridyl)-1,3,5-
triazine ligands. J Organomet Chem 696:637–651
Zhang YJ, Duan Y, Zheng XFS (2011) Targeting the mTOR kinase
domain: the second generation of mTOR inhibitors. Drug Discov
Today 16:325–331
Zheng M, Xu C, Ma J, Sun Y, Du F, Liu H, Lin L, Li C, Dian J (2007)
Synthesis and antitumor evaluation of a novel series of triamino-
triazine derivatives. Bioorg Med Chem Lett 15:1815–1827
123