Organic & Biomolecular Chemistry
Paper
benzooxazepine derivatives against MtbLigA. Overall, the studies (50 MHz, CDCl3) δ150.9, 149.4, 136.1, 132.0, 129.3, 128.7,
revealed that tetracyclic and tricyclic indole derivatives could dis- 123.0, 122.4, 121.1, 120.6, 119.8, 119.5, 69.8, 67.1, 65.8, 64.7,
tinguish between the two classes of ligases. The in vivo studies 53.7, 50.3, 34.4, 29.8, 27.7, 23.2. IR (neat, cm−1): 3400, 3019,
support that the possible mode of action of the compounds are 2928, 2399, 1602, 1489, 1384, 1215, 1084, 928, 757, 669.
due to inhibition of the essential LigA in bacteria. The com- ESI-MS: (m/z) = 396 [M + H]+. HRMS (ESI) exact mass calcd for
pounds also did not display general interactions with DNA and [C24H34N3O2 + H]+ 396.2651, found 396.2573.
act by competing with the cofactor NAD+. The ongoing focus is
1-(6-(Dibenzo[b,e][1,4]oxazepin-5(11H)-yl)-2-hydroxyhexyl)-
the development of next generation derivatives that exhibit piperidine-4-carboxamide (39). Light yellow viscous liquid
improved potency and specificity for LigA. Being smaller in size, (160 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 7.31–7.28
these molecules are suitable for further optimisation.
(m, 2H), 7.11–6.99 (m, 3H), 6.80–6.78 (m, 3H), 5.79 (s, 1H),
5.57 (s, 1H), 5.31 (s, 2H), 3.77–3.73 (t, J = 6.6 Hz, 2H), 3.61–360
(m, 1H), 3.02–2.99 (m, 1H), 2.79–2.15 (m, 4H), 1.91–1.83 (m,
4H), 1.79–1.74 (m, 4H), 1.70–1.66 (m, 4H). 13C NMR (50 MHz,
CDCl3) δ 177.7, 150.8, 149.3, 136.0, 131.9, 129.2, 128.6, 122.8,
122.3, 121.0, 120.5, 119.7, 119.3, 114.1, 69.7, 66.1, 64.2, 54.8,
Experimental section
General procedure for the synthesis of target molecules
The respective epoxy compounds and dry secondary amines 51.5, 50.2, 42.5, 34.4, 33.8, 31.9, 31.6, 29.7, 29.5, 28.9, 27.6,
(1.2 eq.) were dissolved in absolute ethanol (5–10 ml) and the 23.1, 22.7. IR (neat, cm−1): 3408, 3020, 2930, 2401, 1675, 1599,
solutions were refluxed under continuous stirring for 10–12 h. 1489, 1262, 1076, 928, 760, 670. ESI-MS: (m/z) = 424 [M + H]+.
After completion of the reaction, ethanol was removed under HRMS (ESI) exact mass calcd for [C25H34N3O3 + H]+ 424.2600,
vacuum to give the crude products as coloured oily liquids. found 424.2618.
The crude compounds were purified by column chromato-
graphy using neutral alumina as adsorbent and MeOH/CHCl3 hexan-2-ol (40). Colourless viscous liquid (130 mg, 69%). H
as eluent to afford the pure products. NMR (300 MHz, CDCl3) δ 7.12–7.02 (m, 2H), 6.80–6.59 (m, 3H),
6-(Dibenzo[b,e][1,4]oxazepin-5(11H)-yl)-1-(piperazin-1-yl)-
1
6-(6,7-Dihydro-12H-benzo[2,3]oxepino[4,5-b]indol-12-yl)- 6.54–6.50 (m, 3H), 5.32 (s, 2H), 3.76–3.72 (t, J = 6.5 Hz, 2H),
1-(piperidin-1-yl)hexan-2-ol (17). Colourless viscous liquid 3.62 (s, 1H), 3.13–2.61 (m, 4H), 2.59–2.50 (m, 2H), 2.30–2.18
1
(150 mg, 72%). H NMR (300 MHz, CDCl3) δ 7.61–7.58 (d, J = (m, 5H), 1.69–1.38 (m, 5H). 13C NMR (50 MHz, CDCl3) δ 150.8,
7.6 Hz, 1H), 7.48–7.42 (m, 2H), 7.30–7.19 (m, 5H), 4.63–4.59 (t, 149.2, 135.9, 131.9, 129.2, 128.6, 122.8, 122.2, 120.9, 120.5,
J = 6.4 Hz, 2H), 4.33–4.28 (t, J = 7.3 Hz, 2H), 3.65–3.62 (m, 1H), 119.6, 119.3, 69.6, 65.7, 64.7, 54.3, 50.23, 46.1, 34.4, 27.6, 23.1.
3.39 (brs, 2H), 3.08–3.04 (t, J = 6.4 Hz, 2H), 2.67–2.66 (m, 2H), IR (neat, cm−1): 3401, 3019, 2399, 1602, 1384, 1215, 1084, 928,
2.27–2.25 (d, J = 6.5 Hz, 2H), 2.08–203 (m, 3H), 1.83–1.80 (m, 758, 669. ESI-MS: (m/z) = 382 [M + H]+. HRMS (ESI) exact mass
5H), 1.78–1.65 (m, 4H). 13C NMR (50 MHz, CDCl3) δ 142.3, calcd for [C23H32N3O2 + H]+ 382.2495, found 382.2497.
139.4, 137.3, 136.3, 133.0, 130.1, 127.9, 127.7, 127.3, 126.3,
6-(Dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-1-(piperidin-1-yl)-
1
121.6, 119.4, 118.3, 114.8, 114.3, 110.3, 67.7, 62.1, 54.4, 43.9, hexan-2-ol (45). Light yellow viscous liquid (130 mg, 68%). H
34.6, 34.0, 33.0, 32.1, 29.6, 29.4, 29.2, 23.6, 22.9, 22.8. IR (neat, NMR (300 MHz, CDCl3) δ 7.18–7.15 (m, 1H), 7.12–7.05 (m, 4H),
cm−1): 3401, 3019, 2941, 2399, 1606, 1384, 1215, 1083, 757, 6.95–6.83 (m, 1H), 6.81–6.76 (m, 2H), 4.41 (s, 2H), 3.69 (s, 1H),
669. ESI-MS: (m/z) = 419 [M + H]+. HRMS (ESI) exact mass 3.22–3.17 (t, J = 7.2 Hz, 2H), 2.64–2.63 (m, 2H), 2.35–2.25 (m,
calcd for [C27H34N2O2 + H]+ 419.2620, found 419.2704.
3H), 2.21–1.72 (m, 5H), 1.65–1.43 (m, 8H). 13C NMR (50 MHz,
1-(4-Aminopiperidin-1-yl)-6-(6,7-dihydro-12H-benzo[2,3]- CDCl3) δ 157.8, 148.1, 141.5, 130.4, 128.7, 128.3, 124.4, 123.6,
oxepino[4,5-b]indol-12-yl)hexan-2-ol
(21). Light
yellow 120.1, 65.6, 64.6, 54.8, 53.1, 34.8, 29.6, 27.9, 25.0, 23.6, 23.1.
1
viscous liquid (152 mg, 70% yield). H NMR (300 MHz, CDCl3) IR (neat, cm−1): 3401, 3019, 2928, 2399, 1601, 1384, 1215, 1084,
δ 7.60–7.58 (d, J = 7.8 Hz, 1H), 7.47–41 (m, 2H), 7.31–7.14 (m, 928, 758, 627. ESI-MS: (m/z) = 381 [M + H]+. HRMS (ESI) exact
5H), 4.62–4.58 (t, J = 6.4 Hz, 2H), 4.31–4.26 (t, J = 7.5 Hz, 2H), mass calcd for [C24H33N2O2 + H]+ 381.2542, found 381.2543.
3.08–3.03 (t, J = 7.2 Hz, 2H), 2.93–2.89 (m, 4H), 2.73.2.69 (m,
6-(Dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-1-(pyrrolidin-1-yl)-
1
3H), 2.39–2.27 (m, 4H), 2.18–1.98 (m, 3H), 1.43–1.39 (m, 4H). hexan-2-ol (46). Light yellow viscous liquid (130 mg, 71%). H
13C NMR (50 MHz, CDCl3) δ 157.2, 138.0, 128.3, 127.4, 126.9, NMR (300 MHz, CDCl3) δ 7.25–7.10 (m, 5H), 7.08–7.05 (m, 1H),
123.8, 123.1, 121.9, 119.5, 118.1, 114.0, 112.9, 110.3, 66.1, 63.9, 6.96–6.76 (m, 2H), 4.41 (s, 2H), 3.2 (s, 1H), 3.20–3.17 (m, 4H),
54.0, 51.0, 48.5, 44.5, 35.8, 34.3, 29.9, 29.7, 24.4, 22.8. IR (neat, 2.92–2.89 (m, 2H), 2.74–2.71 (m, 4H), 2.49–2.45 (m, 1H),
cm−1): 3401, 3019, 2929, 1644, 1384, 1215, 1084, 758, 669. 2.07–2.05 (m, 3H), 1.89–1.66 (m, 5H).13C NMR (50 MHz,
ESI-MS: (m/z) = 434 [M + H]+. HRMS (ESI) exact mass calcd for CDCl3) δ 157.7, 148.1, 141.5, 139.2, 130.3, 128.7, 128.3, 124.4,
[C27H35N3O2 + H]+ 435.2841, found 435.2645.
123.6, 121.8, 120.2, 120.1, 114.0, 67.5, 62.1, 54.8, 54.3, 53.2,
1-(4-Aminopiperidin-1-yl)-6-(dibenzo[b,e][1,4]oxazepin-5- 34.8, 33.8, 31.9, 29.5, 29.1, 28.9, 27.8, 23.4, 22.6. IR (neat,
(11H)-yl)hexan-2-ol (36). Colourless viscous liquid (135 mg, cm−1): 3400, 3018, 2927, 2399, 1602, 1384, 1215, 1084, 928,
68%). 1H NMR (300 MHz, CDCl3) δ 7.31–7.28 (m, 2H), 758, 669. ESI-MS: (m/z) = 367 [M + H]+. HRMS (ESI) exact mass
7.11–6.69 (m, 3H), 6.84–6.79 (m, 3H), 5.31(s, 2H), 3.77–3.73 (t, calcd for [C23H31N2O2 + H]+ 367. 2386, found 367.2378.
J = 6.6 Hz, 2H), 3.59–3.56 (m, 1H), 2.93–2.68 (m, 3H), 2.22–2.18
1-(6-(Dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-2-hydroxyhexyl)-
(m, 5H), 1.81–1.66 (m, 4H), 1.40–1.27 (m, 5H). 13C NMR piperidin-4-ol (48). Colourless viscous liquid (142 mg, 72%).
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 5475–5487 | 5485