Design, synthesis and SAR exploration of hybrid 4-chlorophenylthiazolyl-s-triazine as potential antimicrobial agents

Figures & data

Figure 1.  Hybrid phenylthiazolyl-s-triazine derivatives.

Figure 2.  Hybrid diethylamino-chloro (series C) and diethylamino-dichloro (series D) phenylthiazolyl-s-triazine derivatives.

Table 1.  Some physicochemical properties and spectral data of diethylamino-chlorophenylthiazolyl-s-triazine derivatives (series C)

Compound	X	m.p.^a (°C)	Yield (%)	Rf (silica gel GF254)^b	FTIR (KBr, cm^−1)	^1H NMR (400 MHz, DMSO-d6, δ ppm)	Anal. Calcd./found
19c	–Cl	142–144	82.59	0.5172	1076 (Ar–Cl), 1324 (C–N), 1669 (C=N), 1447(C=C Ar bending), 2880 (methyl C–H sym. stretch), 2970 (methyl C–H asy. stretch), 3057 (Ar–CH), 3309 (sec. N–H broad peak)	1.19 (t, 6H, 2×−CH3), 3.29 (m, 4H, N–CH2), 4.38 (m, 2H, NH), 6.61 (s, 1H, 1-CH thiazole), 7.44 (d, 2H, 3-Ar–H), 7.54 (d, 2H, 2-Ar–H)	C-48.61, H-4.08, N-21.26/C-48.89, H-4.02, N-21.28
20c		63–65	68.84	0.7684	1347 (C–N), 1679 (C=N), 1664 (C=C cis/vinyl), 1468 (C=C Ar bending), 2885 (methyl C–H sym. stretch), 2975 (methyl C–H asy. stretch), 3034 (Ar–CH), 3300 (sec. N–H broad peak)	1.10 (t, 6H, 2×−CH3), 3.22 (m, 4H, N–CH2), 3.66 (t, 2H, CH2), 4.35 (m, 1H, NH), 4.64 (s, 1H, NH), 5.11 (d, 2H, J = 9, CH2=C ethylene), 5.73–5.88 (m, 1H, CH=C ethylene), 6.22 (s, 1H, 1-CH thiazole), 6.82 (d, 2H, Ar–H), 7.12 (d, 2H, Ar–H)	C-54.86, H-5.33, N-23.57/C-54.75, H-5.34, N-23.68
21c		28–30	93.38	0.7941	1100 (Ar–Cl), 1355(C–N), 1682 (C=N), 1471 (C=C Ar bending), 2876 (CH2 stretch), 3018 (Ar–CH), 3312 (sec. NH broad peak)	1.01 (t, 3H,−CH3), 1.05 (t, 6H, 2×−CH3), 1.33 (m, 2H,−CH2–), 1.53 (m, 2H,−CH2–), 3.15 (m, 2H, N–CH2–), 3.18 (m, 4H, N–CH2), 3.45 (s, 2H, NH2), 4.16 (m, 1H, NH), 4.66 (s, 1H, NH), 6.54 (s, 1H, 1-CH thiazole), 6.82 (d, 2H, Ar–H), 7.05 (d, 2H, Ar–H)	C-55.61, H-6.07, N-22.70/C-55.55, H-6.11, N-22.78
22c		32–34	73.38	0.8827	640 (C–S str. thiazole), 730 (C–Cl str.), 1360 (C–N str.), 1680 (C=N), 1580 & 1440 (aromatic ring), 1630 (C=C str.), 3024 (sym. C–H str.), 3040 (asy. C–H str.), 3270 (sec. NH broad peak)	1.14 (t, 6H, 2×−CH3), 3.26 (m, 4H, N–CH2), 4.50 (s, 1H, NH), 4.71 (s, 1H, NH), 6.34 (s, 1H, 1-CH thiazole), 6.78 (d, 2H, Ar–H), 6.94 (d, 2H, Ar–H), 7.18 (d, 1H, Ar–H), 7.29 (t, 2H, Ar–H), 7.45 (d, 2H, Ar–H)	C-58.46, H-4.91, N-21.69/C-58.84, H-4.52, N-22.50
23c		28–29	93.38	0.8620	640 (C–S str. thiazole), 731 (C–Cl str.), 1360 (C–N str.), 1475 & 1675 (aromatic ring), 1630(C=C str.), 1685 (C=N), 3021 (sym. C–H str.), 3040 (asy. C–H str.), 3320 (sec. NH broad peak)	1.13 (t, 6H, 2×−CH3); 2.14 (s, 1H, 1×−NH thiazole); 3.06 (s, 2H, 1×−CH2 methyl furan); 3.52 (m, 4H, 2×−CH2 ethyl amine); 4.53 (t, 1H, 1×−NH methyl furan); 6.14 (s, 1H, 1×−CH thiazole); 6.23 (d, 1H,−CH furan); 7.28 (t, 1H,−CH furan); 7.33 (d, 1H, 2×−CH phenyl); 7.66 (d, 1H, 2×−CH phenyl); 7.69 (d, 1H,−CH furan)	C-55.32, H-4.86, N-21.50/C-55.42, H-4.58, N-21.58
24c		98–100	54.22	0.7772	1050 (Ar–Cl), 1347 (C–N), 1644 (C=N), 1441 (C=C Ar bending), 3018 (sym. C–H str.), 3037 (asy. C–H str.), 3041 (Ar–CH) 3287 (sec. NH broad peak).	1.03 (t, 6H, 2×−CH3 ethyl amine), 3.62 (t, 2H, CH2), 4.29 (s, 1H, NH), 5.02 (d, 2H, J = 9, CH2=C ethylene), 5.58 (m, 1H, CH=CH2 ethylene), 6.25 (s, 1H, 1-CH thiazole), 6.89 (d, 2H, Ar–H), 7.02 (d, 2H, Ar–H)	C-52.70, H-4.89, N-19.41/C-52.89, H-4.67, N-19.50
25c		82–84	55.34	0.7984	1046 (Ar–Cl), 1352 (C–N), 1630 (C=N), 1429 (C=C Ar bending), 2845 (CH2 stretching), 3014 (sym. C–H str.), 3018 (Ar–CH), 3034 (asy. C–H str.), 3290 (sec. NH broad peak)	0.83 (t, 6H, 2×−CH3 ethyl amine), 0.96 (t, 3H,−CH3), 1.25 (m, 2H,−CH2–), 1.34 (m, 2H,−CH2–), 3.58 (m, 2H, N–CH2-), 6.46 (s, 1H, 1-CH thiazole), 6.83 (d, 2H, Ar–H), 7.02 (d, 2H, Ar–H)	C-53.50, H-5.61, N-18.72/C-53.41, H-5.70, N-18.61
26c		78–80	84.35	0.8965	640 (C–S str. thiazole), 731 (C–Cl str.), 1359 (C–N), 1678 & 1477 (aromatic ring), 1629 (C=C str.), 1674 (C=N), 3022 (sym. C–H str.), 3041 (asy. C–H str.), 3300 (sec. NH broad peak)	1.36 (t, 6H, 2×−CH3 ethyl amine), 2.37 (s, 1H, 1×−NH thiazole), 3.75 (m, 4H, 2×−CH2 ethyl amine), 7.53 (d, 2H, 2×−CH thiophenyl), 7.57 (t, 1H, 1×−CH thiophenyl), 7.64 (t, 2H, 2×−CH thiophenyl), 7.89 (d, 2H, 2×−CH phenyl), 7.93 (d, 2H, 2×−CH phenyl), 8.81 (s, 1H, 1×−CH thiazole)	C-56.34, H-4.51, N-17.92/C-56.38, H-4.53, N-17.78
27c		97–99	56.67	0.8004	1076 (Ar–Cl), 1360 (C–N), 1669 (C=N), 1447 (C=C Ar bending), 3020 (sym. C–H str.), 3035 (asy. C–H str.), 3057 (Ar–CH), 3310 (sec. N–H broad peak)	1.26 (t, 6H, 2×−CH3 ethyl amine), 3.20 (s, 2H,−CH2), 3.68 (m, 4H, 2×−CH2 ethyl amine), 4.42 (s, 1H, NH), 5.74 (d, 1H, 3′CH-furan), 6.01 (t, 1H, 4′CH-furan), 6.18 (s, 1H, 1-CH thiazole), 6.61 (d, 1H, 5′CH-furan), 6.78 (d, 2H, Ar–H), 6.78 (d, 2H, Ar–H)	C-53.32, H-4.47, N-17.77/C-53.10, H-4.65, N-17.58

^a25c liquid b.p. ^b19c (benzene:ethyl acetate:0.1 M alcoholic KOH 2:3:5) and others 20c–27c (benzene:ethyl acetate:0.1 M alcoholic KOH 3:3:4). FTIR, Fourier transform infrared.

Table 2 . Some physicochemical properties and spectral data of diethyl amino dichlorophenylthiazolyl-s-triazine derivatives (series D).

Compound	X	m.p.^a (°C)	Yield (%)	Rf (silica gel GF254)^b	FTIR (KBr, cm^−1)	^1H NMR (400 MHz, DMSO-d6, δ ppm)	Anal. Calcd./found
28d	–Cl	154–156	85.34	0.5576	1041 (Ar–Cl), 1215 (tert. C–N), 1271 (C–N), 1675 (C=N), 1459 (C=C Ar bending), 3022 (sym. C–H str.), 3038 (asy. C–H str.), 3100 (Ar–CH), 3322 (sec. N–H broad peak)	1.25 (t, 6H, 2×−CH3 ethyl amine), 3.18 (s, 2H,−CH2), 3.86 (m, 4H, 2×−CH2 ethyl amine), 4.29 (m, 2H, N–CH2), 5.02 (s, 1H, NH), 6.69 (s, 1H, 1-CH thiazole), 7.32 (d, 1H, Ar–H), 7.55 (d, 1H, Ar–H), 7.65(s, 1H, Ar–H)	C-44.72, H-3.52, N-19.56/C-44.80, H-3.60, N-19.38
29d		54–56	76.34	0.7498	1103 (Ar–Cl), 1218 (tert. C–N), 1252 (C–N), 1654 (C=N), 1679 (C=C), 1492 (C=C Ar bending), 3014 (sym. C–H str.), 3018 (Ar–CH), 3034 (asy. C–H str.), 3184 (sec. N–H broad peak)	1.14 (t, 6H, 2×−CH3 ethyl amine), 3.67 (m, 4H, 2×−CH2 ethyl amine), 3.80 (t, 2H, N–CH2), 5.22 (d, 2H, CH2=CH2), 5.85 (m, 1H, C–HC=CH2), 4.62 (m, 1H, NH), 6.60 (s, 1H, 1-CH thiazole), 7.20 (d, 1H, 3-Ar–H), 7.25 (d, 1H, 2-Ar–H), 7.41 (s, 1H, 5-Ar–H)	C-50.67, H-4.70, N-21.77/C-50.42, H-4.54, N-21.89
30d		58–59	65.62	0.7512	1050 (Ar–Cl), 1227 (tert. C–N), 1645 (C=N), 1471 (C=C Ar bending), 2852 (CH2 stretching), 3021 (sym. C–H str.), 3031 (asy. C–H str.), 3041 (Ar–CH), 3196 (sec. N–H broad peak)	1.05 (t, 6H, 2×−CH3 ethyl amine), 1.27 (t, 3H, CH3), 1.53 (m, 2H, CH2), 1.80 (m, 2H, CH2), 3.22 (m, 4H, N–CH2), 3.49 (m, 2H, N–CH2), 3.77 (s, 2H, NH2), 4.78 (m, 1H, NH), 6.53 (s, 1H, 1-CH thiazole), 7.31 (d, 1H, 3-Ar–H), 7.51 (d, 1H, 2-Ar–H), 7.47 (s, 1H, 5-Ar–H)	C-51.50, H-5.40, N-21.02/C-51.70, H-5.52, N-21.13
31d		60–62	67.72	0.7584	1074 (Ar–Cl), 1258 (tert. C–N), 1680 (C=N), 1408 (C=C Ar bending), 3016 (Ar–CH), 3032 (asy. C–H str.), 3085 (Ar–CH), 3320 (sec. N–H broad peak)	1.18 (t, 6H, 2×−CH3 ethyl amine), 3.72(m, 4H, 2×−CH2 ethyl amine), 4.29 (s, 2H, NH2), 4.60 (s, 1H, NH), 5.00 (s, 1H, NH), 6.44 (s, 1H, 1-CH thiazole), 7.22 (d, 2H, Ar–H), 7.25 (t, 1H, Ar–H), 7.38 (t, 2H, Ar–H), 7.58 (d, 1H, 3-Ar–H), 7.68 (d, 1H, 2-Ar–H), 7.79 (s, 1H, 5-Ar–H)	C-54.32, H-3.47, N-20.16/C-54.69, H-3.22, N-20.04
32d		73–75	89.71	0.7613	1044 (Ar–Cl), 1255 (tert. C–N), 1624 (C=N), 1440 (C=C Ar bending), 3018 (sym. C–H str.), 3031 (asy. C–H str.), 3095 (Ar–CH), 3301 (sec. N–H broad peak)	1.11 (t, 6H, 2×−CH3 ethyl amine), 3.49 (m, 4H, 2×−CH2 ethyl amine), 4.39 (s, 2H, NH2), 4.61 (m, 1H, NH), 4.78 (s, 1H, NH), 6.09 (d, 1H, 3′CH-furan), 6.21 (m, 1H, 4′CH-furan), 6.46 (s, 1H, 1-CH thiazole), 7.28 (d, 1H, 5 ′CH-furan), 7.25 (d, 1H, 3-Ar–H), 7.32 (d, 1H, 2-Ar–H), 7.41 (s, 1H, 5-Ar–H)	C-51.43, H-4.32, N-19.99/C-51.23, H-4.19, N-20.28
33d		89–91	44.45	0.7832	1050 (Ar–Cl), 1251 (tert. C–N), 1662 (C=N), 1666 (C=C), 1473 (C=C Ar bending), 3021 (sym. C–H str.), 3030 (asy. C-H str.), 3121 (Ar–CH), 3301 (sec. N–H broad peak)	1.14 (t, 6H, 2×−CH3 ethyl amine), 3.52 (m, 4H, 2×−CH2 ethyl amine), 3.55 (d, 2H, S–CH2), 5.01 (d, 2H, C=CH2), 5.92 (m, 1H, HC=C), 4.38 (m, 1H, NH), 6.57 (s, 1H, 1-CH thiazole), 7.20 (d, 1H, 3-Ar–H), 7.21 (d, 1H, 2-Ar–H), 7.40 (s, 1H, 5-Ar–H)	C-48.82, H-4.32, N-17.98/C-48.62, H-4.45, N-17.75
34d		71–73	78.33	0.8054	1040 (Ar–Cl), 1262 (tert. C–N), 1650 (C=N), 1424 (C=C Ar bending), 3012 (sym. C–H str.), 3021 (asy. C–H str.), 3062 (Ar–CH), 3304 (sec. N–H broad peak)	0.90 (t, 3H, CH3), 1.04 (t, 6H, 2×−CH3 ethyl amine), 1.21 (m, 2H, CH2), 1.28 (m, 2H, CH2), 2.89 (m, 2H, S–CH2), 3.60 (m, 4H, 2× −CH2 ethyl amine), 4.60 (s, 1H, NH), 6.40 (s, 1H, 1-CH thiazole), 7.17 (d, 1H, 3-Ar–H), 7.27 (d, 1H, 2-Ar–H), 7.37 (s, 1H, 5-Ar–H)	C-49.68, H-5.00, N-17.38/C-49.53, H-5.25, N-17.19
35d		78–80	76.83	0.8783	1090 (Ar–Cl), 1279 (tert. C–N), 1669 (C=N), 1441 (C=C Ar bending), 3018 (sym. C–H str.), 3031 (asy. C–-H str.), 3080 (Ar–CH), 3298 (sec. N–H broad peak)	1.38 (t, 6H, 2×−CH3 ethyl amine), 3.64 (m, 4H, 2×−CH2 ethyl amine), 4.20 (s, 2H, aqNH2), 4.40 (s, 1H, NH), 6.51 (s, 1H, 1-CH thiazole), 7.08 (m, 2H, Ar′–H), 7.03 (m, 1H, Ar′–H), 7.16 (m, 2H, Ar′–H), 7.30 (d, 1H, 3-Ar–H), 7.36 (d, 1H, 2-Ar–H), 7.41 (s, 1H, 5-Ar–H)	C-52.48, H-4.01, N-16.69/C-52.29, H-4.21, N-16.45
36d		85–86	55.88	0.8448	1072 (Ar–Cl), 1265 (tert. C–N), 1664 (C=N), 1445 (C=C Ar bending), 3014 (Ar–CH), 3020 (sym. C–H str.), 3033 (asy. C–H str.), 3052 (Ar–CH), 3306 (sec. N–H broad peak)	1.32 (t, 6H, 2×−CH3 ethyl amine), 3.69 (m, 4H, 2×−CH2 ethyl amine), 4.25 (m, 2H, N–CH2), 4.04 (s, 2H, NH2), 4.31 (m, 2H, NH), 6.02 (d, 1H, 3′CH-furan), 6.20 (m, 1H, 4′CH-furan), 6.36 (s, 1H, 1-CH thiazole), 7.22 (d, 1H, 5′CH-furan), 7.30 (d, 1H, 3-Ar–H), 7.38 (d, 1H, 2-Ar–H), 7.41 (s, 1H, 5-Ar–H)	C-49.71, H-3.97, N-16.56/C-49.80, H-3.79, N-16.39

^a34d liquid b.p. ^b28d (benzene:ethyl acetate:0.1 M alcoholic KOH 2:3:5) and others 29d–36d (benzene:ethyl acetate:0.1 M alcoholic KOH 3:3:4).

FTIR, Fourier transform infrared.

Scheme 1.  Reagents and condition: (a) Na2CO3 0 -5°C; (b) 4-chloro-phenylthiazole-2-amine and 3,4-dichlorophenylthiazolyl-2-amine, NaHCO₃, aqueous dioxane 45–50°C; (c) Alkenyl/alkyl/aryl/hetro alkyl–aryl amines or thiols in NaHCO₃, dioxane 90–100°C under nitrogen atmosphere.

Table 3 . MIC values of series C and D against gram-positive/negative bacteria.

Compound	MIC (µg/ml)
	Gram positive			Gram negative
	Lactobacillus casei (NCIM-2651)	Bacillus cereus (NCIM-2458)	Staphylococcus aureus (NCIM-2120)	Salmonella typhimurium (NCIM-2501)	Escherichia coli (NCIM-2065)	Klebsiella aerogenes (NCIM-2098)
Series C
19c	100	100	50	100	100	100
20c	50	25	25	50	100	100
21c	25	25	25	50	50	100
22c	6.25	12.5	12.5	6.25	25	50
23c	6.25	6.25	6.25	12.5	25	50
24c	25	12.5	6.25	25	50	50
25c	25	12.5	50	25	100	50
26c	12.5	12.5	12.5	12.5	25	50
27c	25	25	25	50	25	50
Series D
28d	100	50	50	100	100	100
29d	12.5	12.5	6.25	6.25	12.5	50
30d	12.5	6.25	6.25	12.5	6.25	50
31d	3.125	1.562	1.562	6.25	6.25	50
32d	1.562	3.125	3.125	3.125	6.25	50
33d	50	25	25	25	25	100
34d	25	25	12.5	12.5	6.25	25
35d	25	25	12.5	25	25	50
36d	50	25	25	50	50	100
Penicillin G	1.562	1.562	3.125	12.5	12.5	12.5
Streptomycin	12.5	6.25	6.25	1.562	3.125	1.562

Table 4 . Brine shrimp cytotoxicity assay for compounds 31d and 32d.

Concentration (μg/ml)	Mortality^a
	31d	32d
1000.00	4	4
Control	1	1
LD50	>1000 μg/ml	>1000 μg/ml
Toxicity	Non-toxic	Non-toxic

^aTen larvae (Artemia salina) for each test concentration.

Table 5 . Molinspiration calculations of compounds.

Compound	Molinspiration calculations (series C & D)
	milogP	TPSA	natoms	MW	nON	nOHNH	nViolations	nrotb	Volume
31d	7.65	78.86	32	486.43	7	2	1	8	403.74
32d	6.59	92.00	32	490.42	8	2	1	9	402.11

^aFor average MIC.

MIC, minimum inhibitory concentration; MW, molecular weight; nOHNH, number of hydrogen bond donors; nON, number of hydrogen bond acceptors; TPSA, topological polar surface area.

Table 6 . Osiris calculations of compounds.

Compound	Toxicity level				Osiris calculations
	Mutagenic	Tumorigenic	Irritant	RE	DL	DS
19c	±	±	+	±	2.11	0.09
20c	−	±	−	−	1.59	0.22
21c	−	±	−	−	2.50	0.20
22c	−	±	−	−	2.49	0.17
23c	−	±	−	−	4.13	0.21
24c	−	±	−	−	1.48	0.19
25c	−	±	−	−	1.72	0.17
26c	−	±	−	−	2.36	0.17
27c	−	±	−	−	4.12	0.18
28d	±	±	+	±	1.47	0.07
29d	−	−	−	−	0.99	0.21
30d	−	−	−	−	1.92	0.21
31d	−	−	−	−	1.86	0.19
32d	−	−	−	−	3.53	0.22
33d	−	−	−	−	0.88	0.19
34d	−	−	−	−	1.13	019
35d	−	−	−	−	1.76	0.19
36d	−	−	−	−	3.52	0.20
Penicillin G	−	−	−	−	11.28	0.91

DL, drug likeness; DS, drug score; RE, reproductive effect; S, solubility; +, high toxic effects; −, drug-conform behaviour; ±, undesired effect.

Figure 3.  Straight-line correlation between average MIC and volume. MIC, minimum inhibitory concentration.