Med Chem Res
It has also been observed that the electron donating
groups with secondary nitrogen viz. Cyclopropyl (6a),
propyl (6b), methyl (6d), and aromatic amines (6e)
enhanced antimalarial activity, whereas tertiary amine sub-
stituted compounds showed no antimalarial activity. Further
in case of aromatic amines there should not be any other
substitution (6h, 6i) on the ring.
All the synthesized compounds were found to have a
higher dock score than that of WR99210 and chloroquine.
But the docked pose of chloroquine had shown only the
presence of weak pi-cationic interaction with Phe 58. It may
be due to noninvolvement of chloroquine with Pf-DHFR-
TS in its mechanism of action making its in-silico in-vitro
correlation insignificant.
(N–H stretch), 2959.66, 2929.77 (C–H aromatic stretch),
1631.70 (N–H bend), 1470.53, 1442.89 (C–C aromatic
stretch), 1326.27, 1294.63, 1271.99 (C–N aromatic stretch);
1H NMR (400 MHz, CDCl3) δ (ppm): 7.4159, 7.3785,
7.2590 (CH, benzene, J = 2.31 Hz), 6.9908 (CH, thiazole,
J = 1.11 Hz), 3.5699 (NH, aromatic, J = 1.62 Hz), 1.6941
(CH2 methylene, J = 3.80 Hz), 1.0118 (CH3 methyl, J =
3.02 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm): 165.64,
162.19, 161.43, 149.82, 135.24, 128.55, 127.78, 126.55,
107.78, 43.31, 23.21, 11.57; Mass: 370.23 (M+H)+.
N2, N2, N4, N4-tetramethyl-N6-(4-phenylthiazol-2-yl)-1,3,5-
triazine-2,4,6-triamine (6c)
Moreover if the binding pattern of the synthesized
compounds were compared with that of WR99210 (Fig. 2),
it can be seen that Asp 54 was the only common residue
between WR99210 and 6d. Compounds 12b, 29d and 21c
of same hybrid synthesized previously by our group
(Gahtori et al., 2012) had also shown H-bonded interaction
with Asp 54 and Ile 164, which supports this claim. The
best compound 34d reported by Gahtori et al. (2012) had
shown interaction with Arg 122. Presence of such residues
in the binding site of the synthesized compounds 6a and 6d
can also be the reason for their good antimalarial activity.
Enhancement of antimalarial activity in the compounds 6a,
6b, 6d, and 6e well justifies the selection of amines over
mercapto analog present in the previously reported lead
compound 34d.
Color: white; M.p.: 204–207 °C; Rf. 0.54 (Hexane: CHCl3::
4:1); UV λmax (CHCl3): 262 nm; FTIR (cm−1): 3237.07
(N–H stretch), 3098.98, 2922.58, 2859.34 (C–H aromatic
stretch), 1586.25 (N–H bend), 1454.34, 1442.57 (C–C
aromatic stretch), 1299.96, 1275.95 (C–N aromatic stretch);
1H NMR (400 MHz, CDCl3) δ (ppm): 7.4038, 7.3853,
7.2603 (CH, benzene, J = 2.28 Hz), 7.0331 (CH, thiazole,
J = 1.13 Hz), 3.1703 (NH, aromatic), 2.1710 (CH3 methyl,
J = 3.22 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm):
165.27, 161.67, 159.33, 134,86, 128.57, 127.61, 125.99,
106.87, 36.18; Mass: 342.12 (M+H)+.
N2, N4-dimethyl-N6-(4-phenylthiazol-2-yl)-1,3,5-triazine-
2,4,6-triamine (6d)
Color: yellow; M.p: 115–119 °C; Rf. 0.47 (Hexane: CHCl3::
4:1); UV λmax (CHCl3): 270 nm; FTIR (cm−1): 3265.41
(N–H stretch), 3011.43, 2931.03 (C–H aromatic stretch),
1597.54 (N–H stretch), 1467.66, 1438.44 (C–C aromatic
stretch), 1333.74, 1276.57 (C–N aromatic stretch); 1H NMR
(400 MHz, DMSO) δ (ppm): 7.4684, 7.3450, 7.3255,
7.2454 (CH, benzene, J = 5.42 Hz), 6.8560 (CH, thiazole,
J = 0.53 Hz), 3.7137 (NH, aromatic, J = 2.54 Hz), 2.5773
(CH3 methyl, J = 2.32 Hz); 13C NMR (100 MHz, DMSO) δ
(ppm): 168.38, 148.72, 134.12, 133.93, 128.20, 127.14,
125.41, 101.11, 26.99; Mass: 314.19 (M+H)+.
Spectroscopic data
N2, N4-dicyclopropyl-N6-(4-phenylthiazol-2-yl)-1,3,5-
triazine-2,4,6-triamine (6a)
Color: cream; M.p: 124–127 °C; Rf. 0.45 (Hexane: CHCl3::
4:1); UV λmax (CHCl3): 262 nm; FTIR (cm−1): 3432.87,
3235.42 (N–H stretch), 3113.05, 3014.26 (C–H aromatic
stretch), 1593.56 (N–H bend), 1482.39, 1440.94 (C–C
aromatic stretch), 1329.50, 1306.57, 1279.96 (C–N aro-
matic stretch); 1H NMR (400 MHz, CDCl3) δ (ppm):
7.4043, 7.3283, 7.2617 (CH, benzene, J = 1.11 Hz), 7.0153
(CH, thiazole, J = 0.43 Hz), 4.1484 (NH, aromatic, J = 0.77
Hz), 1.2541 (CH, cyclopropyl, J = 1.05 Hz), 0.6607, 0.5187
(CH2, cyclopropyl, J = 2.82 Hz); 13C NMR (100 MHz,
CDCl3) δ (ppm): 149.89, 134.8, 128.47, 127.77, 126.68,
24.07, 23.59, 7.66, 6.99, Mass: 366.12 (M+H)+.
N2, N4-diphenyl-N6-(4-phenylthiazol-2-yl)-1,3,5-triazine-
2,4,6-triamine (6e)
Color: white; M.p: 253–256 °C; Rf. 0.55 (Hexane: CHCl3::
4:1); UV λmax (CHCl3): 210 nm; FTIR (cm−1): 3404.30
(N–H stretch), 3023.18, 2871.90 (C–H aromatic stretch),
1593.02 (N–H bend), 1466.57, 1432.12 (C–C aromatic
stretch), 1324.61, 1297.53, 1203.23 (C–N aromatic stretch);
1H NMR (400 MHz, DMSO) δ (ppm): 7.3903, 7.3756,
7.3101, 7.0209 (CH, benzene, J = 4.95 Hz), 6.9160 (CH,
thiazole), 3.3748, 3.4250 (NH, aromatic); 13C NMR (100
MHz, DMSO) δ (ppm): 163.76, 162.13, 159.29, 149.11,
N2-(4-phenylthiazol-2-yl)-N4,N6-dipropyl-1,3,5-triazine-
2,4,6-triamine (6b)
Color: white; M.p.: 163–167 °C; Rf. 0.55 (Hexane: CHCl3::
4:1); UV λmax (CHCl3): 265 nm; FTIR (cm−1): 3261.07