K. El-Adl et al.
Bioorganic Chemistry 105 (2020) 104399
4.1.6.1. 2-{4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)benzoyl}-N-
4.1.6.5. 2-{4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)benzoyl}-N-
ethylhydrazine-1-carbothioamide (11a). Yield, 80%; m.p. 250–2 ◦C;
phenylhydrazine-1-carbothioamide (11e). Yield, 80%; m.p. 270–2 ◦C;
IRνmax (cmꢀ 1): 3282, 3173 (4NH), 3067 (C H aromatic), 2977 (C
H
IRν
max
(cmꢀ 1): 3262, 3201 (4NH), 3099 (C H aromatic), 1677 (CO);
–
–
–
aliphatic), 1648 (CO); 1HNMR (400 MHz, DMSO‑d6): 1.08 (t, J = 7.6 Hz,
3H, CH3), 3.50 (q, J = 7.6 Hz, 2H, CH2), 7.48 (dd, J = 6.8, 8 Hz, 1H, H-7
quinox.),7.55 (dd, J = 7.2, 8 Hz, 1H, H-8 quinox.), 7.79 (d, J = 7.2 Hz,
1H, H-9 quinox.), 7.97 (dd, J = 8.8, 9.8 Hz, 2H, H-3 and H-5 phenyl),
8.12 (s, 1H, NH-CH2-CH3) 8.25 (d, J = 8 Hz, 1H, H-6 quinox.), 8.34 (dd,
J = 8.8, 9.8 Hz, 2H, H-2 and H-6 phenyl), 9.25 (s, 1H, NH of
CONHNHCS) (D2O exchangeable), 10.07 (s, 1H, CH triazolo), 10.25 (s,
1H, NH of CONHNHCS) (D2O exchangeable), 10.52 (s, 1H, NH-ph) (D2O
exchangeable); 13CNMR (100 MHz, DMSO‑d6): 26.9, 39.00, 116.67,
119.92 (2), 123.11 (2), 125.64, 126.81, 127.50, 128.13, 128.99 (2),
136.18, 138.79, 143.36, 143.40, 166.02, 181.82; Anal. Calcd. for
1HNMR (400 MHz, DMSO‑d6): 7.14 (t, J = 7.2 Hz, 1H, H-4 C6H5),
7.29–7.33 (m, 2H, H-3 and H-5 C6H5), 7.46 (dd, J = 7.6, 8 Hz, 1H, H-7
quinox.), 7.52 (dd, J = 7.6, 6.5 Hz, 1H, H-8 quinox.), 7.55 (d, J = 7.6 Hz,
1H, H-9 quinox.), 7.79 (dd, J = 7.2 Hz, 2H, H-2 and H-6 C6H5), 7.88 (dd,
J = 8.8, 10 Hz, 2H, H-3 and H-5 of C6H4), 8.25 (d, J = 8 Hz, 1H, H-6
quinox.), 8.33 (dd, J = 8.8, 10 Hz, 2H, H-2 and H-6 C6H4), 9.68 (s, 1H,
NH of CONHNHCS) (D2O exchangeable), 9.79 (s, 1H, NH of
CONHNHCS) (D2O exchangeable), 10.06 (s, 1H, CH triazole), 10.43 (s,
1H, NH-C6H4) (D2O exchangeable), 10.52 (s, 1H, NH-C6H5) (D2O
exchangeable); Anal. Calcd. for C23H18N8OS (454.51): C, 60.78; H, 3.99;
N, 24.65. Found: C, 60.51; H, 4.12; N, 24.87.
C
19H18N8OS (406.47): C, 56.14; H, 4.46; N, 27.57. Found: C, 56.52; H,
4.62; N, 27.41.
4.1.7. General procedure for synthesis of target compounds (12a-c)
A mixture of 4-Chloro-[1,2,4]triazolo[4,3-a]quinoxaline 4 (0.5 g,
0.002 mol) and the appropriate sulfa derivatives namely, sulfanilamide,
sulfathiazole and/or sulfadiazine (0.002 mol) in the presence of few
drops of TEA, was refluxed in MeCN (20 ml) for 10 h. The resulting
precipitate was filtered, washed with n-hexane, air dried to obtain the
target compounds 12a-c respectively.
4.1.6.2. 2-{4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)benzoyl}-N-
propylhydrazine-1-carbothioamide (11b). Yield, 85%; m.p. 255–7 ◦C;
IRνmax (cmꢀ 1): 3279, 3115 (4NH), 3023 (C H aromatic), 2907 (C
–
–
H
aliphatic), 1681 (CO); 1HNMR (400 MHz, DMSO‑d6): 0.85 (t, J = 7.6 Hz,
3H, CH3) 1.54–1.57 (m, 2H, CH2-CH2-CH3), 3.44 (t, J = 7.6 Hz, 2H, CH2-
CH2-CH3), 7.46 (dd, J = 7.2, 8 Hz, 1H, H-7 quinox.), 7.53 (dd, J = 8, 7.4
Hz, 1H, H-8of quinox.), 7.77 (d, J = 7.4 Hz, 1H, H-9 quinox.), 7.97 (dd, J
= 9.2, 10.8 Hz, 2H, H-3 and H-5 phenyl), 8.12 (s, 1H, NH-CH2-CH2-CH3)
8.23 (d, J = 7.4 Hz, 1H, H-6 quinox.), 8.34 (dd, J = 9.2, 10.8 Hz, 2H, H-2
and H-6 phenyl), 9.25 (s, 1H, NH of CONHNHCS) (D2O exchangeable),
10.05 (s, 1H, CH triazole), 10.26 (s, 1H, NH of CONHNHCS) (D2O
exchangeable), 10.51 (s, 1H, NH-ph) (D2O exchangeable); Anal. Calcd.
for C20H20N8OS (420.50): C, 57.13; H, 4.79; N, 26.65. Found: C, 57.46;
H, 4.95; N, 26.82.
4.1.7.1. 4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)benzenesulfona-
mide (12a). Yield, 90%; m.p. 285–7 ◦C; IRνmax (cmꢀ 1): 3345, 3236 (NH,
NH2), 3106 (C H aromatic), 1112, 1209 (SO2); 1HNMR (400 MHz,
–
DMSO‑d6): 7.31 (s, 2H, NH2) (D2O exchangeable), 7.45 (dd, J = 8, 4 Hz,
1H, H-7 quinox.), 7.49 (dd, J = 8, 4 Hz, 1H, H-8 quinox.), 7.77 (d, J = 8
Hz, 1H, H-9 of quinox.), 7.85 (dd, J = 8, 7.2 Hz, 2H, H-3 and H-5
phenyl), 8.22 (d, J = 8 Hz, 1H, H-6 quinox.), 7.38 (dd, J = 8, 7.2 Hz, 2H,
H-2 and H-6 phenyl), 10.04 (s, 1H, CH triazole), 10.59 (s, 1H, NH-ph)
(D2O exchangeable); MS (m/z): 340 (M+, 22.14%), 339 (95.26%), 338
(base beak, 100%), 89 (50.13%), 75 (29.47%); Anal. Calcd. for
C15H12N6O2S (340.36): C, 52.93; H, 3.55; N, 24.69. Found: C, 53.18; H,
3.57; N, 24.87.
4.1.6.3. 2-{4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)benzoyl}-N-
butylhydrazine-1-carbothioamide (11c). Yield, 90%; m.p. 260–2 ◦C;
IRνmax (cmꢀ 1): 3279, 3100 (4NH), 3050 (C H aromatic), 2967 (C
–
–
H
aliphatic), 1657 (CO); 1HNMR (400 MHz, DMSO‑d6): 0.89 (t, J = 7.6 Hz,
3H, CH3), 1.26–1.31 (m, 2H, CH2CH2CH2CH3), 1.50 (m, 2H,
CH2CH2CH2CH3), 3.46 (t, J = 7.6 Hz, 2H, CH2CH2CH2CH3), 7.51 (t, J =
8, 8.2 Hz, 1H, H-7 quinox.),7.58 (t, J = 8, 8.4 Hz, 1H, H-8 quinox.), 7.82
(d, J = 8.2 Hz, 1H, H-9 quinox.), 7.97 (dd, J = 8, 9.8 Hz, 2H, H-3 and H-5
phenyl), 8.08 (s, 1H, NHCH2CH2CH2CH3) 8.28 (d, J = 8.4 Hz, 1H, H-6
quinox.), 8.35 (dd, J = 8, 9.8 Hz, 2H, H-2 and H-6 phenyl), 9.22 (s, 1H,
NH of CONHNHCS) (D2O exchangeable), 10.09 (s, 1H, CH triazolo),
10.23 (s, 1H, NH of CONHNHCS) (D2O exchangeable), 10.54 (s, 1H, NH-
ph) (D2O exchangeable); MS (m/z): 434 (M+, 8.67%), 423 (54.68%),
338 (36.51%), 312 (base beak, 100%), 278 (8.56%); Anal. Calcd. for
4.1.7.2. 4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)-N-(pyrimidin-2-
yl)benzenesulfonamide (12b). Yield, 85%; m.p. 236–7 ◦C; IRνmax (cmꢀ 1):
3335, 3200 (2NH), 3025 (C H aromatic), 1126, 1225 (SO2); 1HNMR
–
(400 MHz, DMSO‑d6): 7.05 (t, J = 13.6 Hz, 1H, H-4 pyrimidine), 7.48
(dd, J = 9.6, 8.4 Hz, 1H, H-7 quinox.), 7.54 (dd, J = 8.4, 7.2 Hz, 1H, H-8
quinox.), 7.90 (d, J = 8.4 Hz, 1H, H-9 of quinox.), 8.00 (dd, J = 9.6, 10.2
Hz, 2H, H-3 and H-5 phenyl), 8.24 (d, J = 8.4 Hz, 1H, H-6 quinox.), 8.42
(dd, J = 9.6, 10.2 Hz, 2H, H-2 and H-6 phenyl), 8.51 (dd, J = 13.6 Hz,
2H, H-3 and H-5 pyrimidine), 10.8 (s, 1H, CH triazole), 10.71 (s, 1H,
NH-ph) (D2O exchangeable), 11.70 (s, 1H, NH of SO2NH) (D2O
exchangeable); 13CNMR (100 MHz, DMSO‑d6): 110.50, 114.5, 116.38
(2), 117.99 (2), 121.05, 123.74, 125.48, 125.98, 126.85 (2), 131.73,
133.81, 136.62, 142.09 (2) 155.57, 156.72; Anal. Calcd. for
C
21H22N8OS (434.52): C, 58.05; H, 5.10; N, 25.79. Found: C, 58.41; H,
5.03; N, 25.92.
C
19H14N8O2S (418.44): C, 54.54; H, 3.37; N, 26.78. Found: C, 54.80; H,
4.1.6.4. 2-{4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)benzoyl}-N-
cyclohexylhydrazine-1-carbothioamide (11d). Yield, 85%; m.p. 265–7 ◦C;
3.54; N, 27.01.
IRνmax (cmꢀ 1): 3182, 3133 (4NH), 3017 (C H aromatic), 2900 (C
–
–
H
aliphatic), 1628 (CO); 1HNMR (400 MHz, DMSO‑d6): 1.23–1.56 (m, 6H,
C-3, C-4, C-5 cyclohexyl), 1.64–1.68 (m, 2H, C-2 cyclohexyl), 1.75–1.78
(m, 2H, C-6 cyclohexyl), 3.39 (m, 1H, C-1 cyclohexyl), 6.27 (s, 1H, NH-
cyclohexyl), 7.47 (dd, J = 10.8, 9.6 Hz, 1H, H-7 quinox.), 7.54 (dd, J =
6.8, 9.6 Hz, 1H, H-8 quinox.), 7.73 (s, 1H, NH of CONHNHCS) (D2O
exchangeable), 7.80 (d, J = 9.6 Hz, 1H, H-9 quinox.), 7.92 (dd, J = 10,
12 Hz, 2H, H-3 and H-5 phenyl), 8.25 (d, J = 10.8 Hz, 1H, H-6 quinox.),
8.32 (dd, J = 10, 12 Hz, 2H, H-2 and H-6 phenyl), 10.02 (s, 1H, CH
triazole), 10.06 (s, 1H, NH of CONHNHCS) (D2O exchangeable), 10.49
(s, 1H, NH-ph) (D2O exchangeable); Anal. Calcd. for C23H24N8OS
(460.56): C, 59.98; H, 5.25; N, 24.33. Found: C, 59.87; H, 5.47; N, 24.50.
4.1.7.3. 4-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylamino)-N-(thiazol-2-yl)
benzenesulfonamide (12c). Yield, 80%; m.p. 273–5 ◦C; IRν
(cmꢀ 1):
max
3300, 3250 (2NH), 3100 (C H aromatic), 1136, 1255 (SO2); 1HNMR
(400 MHz, DMSO‑d6): 6.59 (d, J = 4 Hz, 1H, H-4 of thiazole), 7.12 (d, J
= 4 Hz, 1H, H-5 thiazole.), 7.43 (dd, J = 6.8, 9.6 Hz, 1H, H-7 quinox),
7.64 (dd, J = 8, 9.6 Hz, 1H, H-8 quinox.), 7.69 (d, J = 9.6 Hz, 1H, H-9
quinox.), 7.85 (dd, J = 8, 9.8 Hz, 2H, H-3 and H-5 phenyl), 8.06 (d, J =
6.8 Hz, 1H, H-6 quinox.), 8.43 (dd, J = 8, 9.8 Hz, 2H, H-2 and H-6
phenyl), 10.8 (s, 1H, CH triazole), 10.71 (s, 1H, NH-ph), (D2O
exchangeable), 11.70 (s, 1H, NH of SO2NH) (D2O exchangeable); MS
(m/z): 423 (M+, 10.07%), 342 (41.37%), 339 (base beak, 100%), 115
(27.17%); Anal. Calcd. for C18H13N7O2S2 (423.47): C, 51.05; H, 3.09; N,
23.15. Found: C, 51.32; H, 3.25; N, 23.41.
–
16