Design and Synthesis of New 2-Aminobenzamide Derivatives Containing Benzothiazole and Phenylamine Moiety and Their Cytotoxicity

Abstract

Twelve new compounds including 2-aminobenzamide derivatives bearing benzothiazole and phenylamine moiety were designed and synthesized. The synthesized compounds were tested their cytotoxic activity against A549 and SW480 tumor cell lines. Compounds 3a and 3c exhibited cytotoxicity toward A549 cell line with IC₅₀ values of 24.59 and 29.59 µM, respectively.

Keywords

benzothiazole phenylamine synthesis 2-aminobenzamide cytotoxic activity

Introduction

Benzothiazole (Figure 1) and its derivatives are heterocyclic compounds with many interesting biological applications.^1‐3 Basic research on benzothiazole is known for many biological properties such as anticancer,^4‐8 antimicrobial,^9‐11 anti-inflammatory,¹² and antiviral.^13,14 Thus, benzothiazole compounds have been attracting the considerable interest of scientists in recent years vested in their different biological applications. This has prompted scientists the search for novel derivatives with high biological activity and development into new drugs.

Figure 1.

General structure of benzothiazole.

On the other hand, 2-aminobenzamide are zinc binding groups in histone deacetylase structure (HDAC).¹⁵ Several typical 2-aminobenzamide derivatives of this class such as chidamide (CS055), entinostat (MS-275), and mocetinostat (MGCD0103) (Figure 2) have been synthesized. Among these, CS055 has been approved by the FDA in 2015 to treat peripheral T-cell lymphoma¹⁶; MGCD0103¹⁷ and MS-275¹⁸ are currently undergoing in human clinical trials for treatment of some types of cancer.^15,19 From their superior biological activity, 2-aminobenzamide derivatives were designed and synthesized, which promise as anti-cancer drugs.^19,20

Figure 2.

Structure of some 2-aminobenzamide derivatives.

After considering the biological activity of benzothiazole and 2-aminobenzamide, 12 novel benzothiazole hybrids were created by the combination of benzothiazole and 1,2-diaminobenzene to form novel 2-aminobenzamide derivatives bearing benzothiazole moiety. All the products were evaluated for their in vitro cytotoxic activities toward A549 and SW480 cell lines.

Results and Discussion

The eight 2-aminobenzamide derivatives containing benzothiazole moiety were synthesized via 2 steps (Figure 3). In the first step, 2-aminobenzothiazole, 2-amino-6-methoxybenzothiazole, 2-amino-6-methylbenzothiazole, and 2-amino-6-ethoxybenzothiazole (1a-d) were reacted with various acid anhydrides in dimethylformamide (DMF) in the presence of pyridine at 65 °C for 24 h to produce the corresponding amide intermediates 2a-d and 4a-d. These compounds were used further to react with 1,2-diaminobenzene in DMF in the presence of 0.6 equiv of benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2 equiv of 4-dimethylaminopyridine (DMAP), and 1.2 equiv of triethylamine (TEA), for 48 h at room temperature to get the corresponding conjugates 3a-d and 5a-d (Figure 3, Supplemental Figures S1-S31). The reaction was best performed using BOP as a carboxylic group activating agent.¹⁵

Figure 3.

Synthesis of compounds 3a-d and 5a-d. (a) 1.4 equiv anhydride, 1.2 equiv pyridine, DMF, 65 °C, 24 h; (b) 1.5 equiv 1,2-diaminobenzene, 0.6 equiv BOP, 2 equiv DMAP, 1.2 equiv TEA, DMF, rt, 48 h.

Analogously, four 2-aminobenzamide derivatives containing phenylamine moiety (8a-b and 10a-b) were also synthesized, starting from compounds 6a-b via the amide intermediate 7a-b and 9a-b (Figure 4). The structures of the products were confirmed by analysis of spectral data such as ¹H NMR, ¹³C NMR, IR, and MS (Supplemental Figures S32-S46).

Figure 4.

Synthesis of compounds 8a-b and 10a-b. (a) 1.4 equiv anhydride, 1.2 equiv pyridine, DMF, 65 °C, 24 h; (b) 1.5 equiv 1,2-diaminobenzene, 0.6 equiv BOP, 2 equiv DMAP, 1.2 equiv TEA, DMF, rt, 48 h.

Using Sulforhodamine B (SRB) assay, the in vitro cytotoxic activity of all the synthesized compounds were evaluated against A549 and SW480 cell lines. As results (Table 1), compounds 3a and 3c show good cytotoxicity against A549 cell line with IC₅₀ values of 29.49 and 27.59 µM, respectively. Comparing to the cytotoxicity of 6-methyl conjugates with the 6-hydro counterpart, the methyl analogs (3c) exhibit more potent cytotoxic effects than the corresponding hydro counterpart (3a). On the other hand, comparing to the bond length of the bridge (3CH₂ and 2CH₂), it can be seen that 3CH₂ bridge compound (3c) exhibits a stronger cytotoxic effect than that of 2CH₂ bridge compound (5c).

Table 1.

Synthesis and Cytotoxicity (IC₅₀) of 3a-d, 5a-d, 8a-b, 10a-b.

Compounds (Yield, %)	IC₅₀ (µM)		Compounds (Yield, %)	IC₅₀ (µM)
Compounds (Yield, %)	A549	SW480	Compounds (Yield, %)	A549	SW480
3a (59.5)	29.49	282.38	5c (53.8)	282.38	281.34
3b (58.3)	79.08	260.33	5d (49.7)	261.01	262.13
3c (60.2)	27.59	271.63	8a (61.2)	307.51	305.68
3d (63.5)	158.93	251.16	8b (52.4)	293.09	291.15
5a (55.3)	282.38	285.36	10a (62.8)	190.28	274.06
5b (51.7)	270.18	273.17	10b (56.7)	264.94	263.20
			Ellipticine^a	1.42	1.75

IC₅₀, half-maximal inhibitory concentration.

Positive control compound.

Material and Method

General

The reactions were carried out in a glass apparatus that was dried in a suitable oven. Solvents and chemicals were purchased from Sigma-Aldrich, TCI, Merck. Flash column chromatography was performed using silica gel (60 Å, particle size 40-60 µm). Thin-layer chromatography, RP-18 F₂₅₄S (0.25 mm, Merck) was used and visualized by either UV irradiation or Ce(SO₄)₂ staining. Melting points were determined by the capillary method. IR spectra were measured on a Spectrum Two Perkin Elmer by Nujol with KBr pellets. ¹H NMR spectra were recorded on a Bruker Avance (600 MHz) using DMSO-d₆ as solvent and TMS as internal standard. ¹³C NMR spectra were measured on a Bruker Avance spectrometer at 150 MHz in frequency. Multiplicities were designated as singlet (s), doublet (d), triplet (t), multiplet (m), or br (broad). Mass spectra were provided by HRESIMS (high resolution-mass spectra) which was carried out by SCIEX X500 QTOF mass spectrometer (AB Sciex LLC.).

General Procedure for the Synthesis of Compounds 3a-d, 5a-d, 8a-b, and 10a-b

To a solution of corresponding acid 2a-d, 4a-d, 7a-b, 9a-b (1.0 mmol) in DMF (5 mL) was added BOP (0.6 mmol), DMAP (2.0 mmol), and TEA (1.2 mmol). The reaction mixture was stirred for 10 to 15 min at room temperature. 1,2-Diaminobenzene (1.5 mmol) was then added, and the resulting mixture was stirred for 48 h at room temperature. The solvent was removed in vacuo, the residue was redissolved in EtOAc (15.0 mL), and washed with water (15.0 mL). The aqueous layer was extracted with EtOAc (3 × 20.0 mL), the combined organic layers were combined, washed with water, and dried Na₂SO₄. Removal of the solvent in vacuo and the residue was purified by column chromatography on silica gel using n-hexane/ethyl acetate (4:1) as eluent to afford targeted conjugates 3a-d, 5a-d, 8a-b, 10a-b, respectively.

N¹-(2-Aminophenyl)-N⁵-(Benzo[d]Thiazol-2-yl)Glutaramide (3a)

White solid. Yield 59.5%. MP: 184-186 °C. IR (KBr) ν (cm⁻¹): 3371, 2995, 2939, 1659, 1648, 1550, 1496, 756. ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.33 (1H, s, NH), 9.10 (1H, s, NH), 7.96 (1H, d, J = 8.0 Hz), 7.72 (1H, d, J = 8.0 Hz)), 7.42 (1H, t, J = 7.5 Hz), 7.29 (1H, t, J = 7.0 Hz), 7.17 (1H, d, J = 8.0 Hz), 6.88 (1H, t, J = 8.0 Hz), 6.71 (1H, d, J = 7.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.82 (2H, s, NH₂), 2.58 (2H, t, J = 7.0 Hz), 2.58 (2H, t, J = 7.0 Hz), 2.40 (2H, t, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ: 171.9 (C = O), 170.0 (C = O), 157.8, 148.5, 141.9, 131.4, 126.0, 125.7, 125.4, 123.3, 121.5, 120.4, 116.0, 115.7, 34.7, 34.4, 20.52. HRESIMS: Found m/z 355.1211 [M + H]⁺, Calcd for C₁₈H₁₈N₄O₂S: 355.1229.

N¹-(2-Aminophenyl)-N⁵-(6-Methoxybenzo[d]Thiazol-2-yl)Glutaramide (3b)

White solid. Yield 58.3%. MP: 183-185 °C. IR (KBr) cm⁻¹: 3362, 2958, 1650, 1611, 1557, 1460, 747.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.19 (1H, s, NH), 9.09 (1H, s, NH), 7.61 (1H, d, J = 9.0 Hz), 7.55 (1H, d, J = 7.0 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.70 (1H, d, J = 8.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.81 (2H, s, NH₂), 3.80 (3H, s), 2.55 (2H, t, J = 7.0 Hz), 2.39 (2H, t, J = 7.0 Hz), 1.94 (2H, t, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ: 171.6 (C = O), 170.5 (C = O), 156.0, 155.8, 142.5, 141.9, 132.6, 125.7, 125.3, 123.3, 121.0, 116.0, 115.7, 114.7, 104.6, 55.5, 34.7, 34.3, 20.5. HRESIMS: Found m/z 385.1318 [M + H]⁺, Calcd for C₁₉H₂₀N₄O₃S: 385.1334.

N¹-(2-Aminophenyl)-N⁵-(6-Methylbenzo[d]Thiazol-2-yl)Glutaramide (3c)

White solid. Yield 60.2%. MP: 188-190 °C. IR (KBr) cm⁻¹: 3365, 2999, 2948, 1653, 1608, 1549, 1458, 752. ¹H NMR (600 MHz, DMSO-d₆) δ: 12.25 (1H, s, NH), 9.09 (1H, s, NH), 7.74 (1H, s), 7.60 (1H, d, J = 8.0 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 8.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.81 (2H, s, NH₂), 2.56 (2H, t, J = 7.0 Hz), 2.40-2.38 (5H, m), 1.98-1.92 (2H, m). ¹³C NMR (150 MHz, DMSO-d₆) δ:) 171.7 (C = O), 170.5 (C = O), 156.9, 146.4, 141.9, 132.8, 131.5, 127.3, 125.7, 125.3, 123.3, 121.1, 120.0, 116.0, 115.7, 34.7, 34.4, 20.9, 20.5. HRESIMS: Found m/z 369.1370 [M + H]⁺, Calcd for C₁₉H₂₀N₄O₂S: 369.1358.

N¹-(2-Aminophenyl)-N⁵-(6-Ethoxybenzo[d]Thiazol-2-yl)Glutaramide (3d)

White solid. Yield 63.5%. MP: 181-183 °C. IR (KBr) cm⁻¹: 3356, 2976, 2948, 1652, 1609, 1556, 1491, 786. ¹H NMR (600 MHz, DMSO-d₆) δ: 12.18 (1H, s, NH), 9.09 (1H, s, NH), 7.60 (1H, d, J = 9.0 Hz), 7.52 (1H, d, J = 7.0 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.00 (1H, d, J = 8.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.70 (1H, d, J = 8.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.81 (2H, s, NH₂), 4.08-4.06 (2H, m), 2.55 (2H, t, J = 7.0 Hz), 2.39 (2H, t, J = 7.0 Hz), 1.98-1.91 (2H, m), 1.34 (3H, t, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ: 171.6 (C = O), 170.5 (C = O), 155.8, 155.2, 142.5, 141.9, 132.6, 125.7, 125.3, 123.3, 120.9, 116.0, 115.7, 115.1, 105.3, 63.5, 34.7, 34.3, 20.5, 14.6. HRESIMS: Found m/z 399.1471 [M + H]⁺, Calcd for C₂₀H₂₂N₄O₃S: 399.1491.

N¹-(2-Aminophenyl)-N⁴-(Benzo[d]Thiazol-2-yl)Succinamide (5a)

White solid. Yield 55.3%. MP: 164-166 °C. IR (KBr) cm⁻¹: 3348, 2972, 2911, 1735, 1696, 1656, 1560, 759. ¹H NMR (600 MHz, DMSO-d₆) δ: 12.34 (1H, s, NH), 9.20 (1H, s, NH), 7.94 (1H, d, J = 8.0 Hz), 7.72 (1H, d, J = 8.0 Hz), 7.42 (1H, t, J = 7.0 Hz), 7.29 (1H, t, J = 7.0 Hz), 7.12 (1H, d, J = 7.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.70 (1H, d, J = 7.0 Hz), 6.51 (1H, t, J = 7.0 Hz), 4.84 (2H, s, NH₂), 2.81 (2H, t, J = 6.0 Hz), 2.71 (2H, t, J = 6.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 171.8 (C = O), 170.0 (C = O), 157.8, 148.5, 142.2, 131.4, 126.0, 125.9, 125.5, 123.6, 123.1, 121.6, 120.4, 116.0, 115.8, 30.5, 30.0. HRESIMS: Found m/z 355.1211 [M + H]⁺, Calcd for C₁₇H₁₆N₄O₂S: 355.1229.

N¹-(2-Aminophenyl)-N⁴-(6-Methoxybenzo[d]Thiazol-2-yl)Succinamide (5b)

White solid. Yield 51.7%. MP: 163-165 °C. IR (KBr) ν (cm⁻¹): 3347, 2995, 1688, 1646, 1555, 1495, 755.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.22 (1H, s, NH), 9.19 (1H, s, NH), 7.62 (1H, d, J = 9.0 Hz), 7.54 (1H, s), 7.13 (1H, d, J = 7.5 Hz), 7.01 (1H, d, J = 7.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 6.51 (1H, t, J = 7.0 Hz), 4.84 (2H, s, NH₂), 3.80 (3H, s), 2.80 (2H, t, J = 6.0 Hz), 2.71 (2H, t, J = 6.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ: 171.4 (C = O), 169.9 (C = O), 156.0, 155.8, 142.6, 142.1, 132.6, 125.8, 125.4, 123.1, 121.0, 115.9, 115.6, 114.7, 104.6, 55.5, 30.4. HRESIMS: Found m/z 371.1167 [M + H]⁺, Calcd for C₁₈H₁₈N₄O₃S: 371.1178.

N¹-(2-Aminophenyl)-N⁴-(6-Methylbenzo[d]Thiazol-2-yl)Succinamide (5c)

White solid. Yield 53.8%. MP: 168-170 °C. IR (KBr) ν (cm⁻¹): 3331, 2990, 2925, 1697, 1646, 1551, 1492, 747. ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.28 (1H, s, NH), 9.16 (1H, s, NH), 7.73 (1H, s), 7.60 (1H, d, J = 8.0 Hz), 7.23 (1H, d, J = 7.0 Hz), 7.13 (1H, d, J = 7.0 Hz), 6.87 (1H, t, J = 7.0 Hz), 6.69 (1H, d, J = 7.0 Hz), 6.51 (1H, t, J = 6.0 Hz), 4.84 (2H, s, NH₂), 2.81 (2H, s), 2.71 (2H, s), 2.40 (3H, s). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 171.5 (C = O), 169.9 (C = O), 156.9, 146.5, 142.1, 132.8, 131.4, 127.3, 125.8, 125.4, 123.1, 121.1, 120.0, 115.9, 115.6, 30.5, 30.0. HRESIMS: Found m/z 355.1214 [M + H]⁺, Calcd for C₁₈H₁₉N₄O₂S: 355.1229.

N¹-(2-Aminophenyl)-N⁴-(6-Ethoxybenzo[d]Thiazol-2-yl)Succinamide (5d)

White solid. Yield 49.7%. MP: 161-163 °C. IR (KBr) ν (cm⁻¹): 3419, 2938, 2868, 1732, 1665, 1453, 743.

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.17 (1H, s, NH), 9.09 (1H, s, NH), 7.59 (1H, d, J = 11.0 Hz), 7.52 (1H, d, J = 7.0 Hz), 7.18 (1H, d, J = 7.0 Hz), 7.00 (1H, d, J = 8.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.81 (2H, s, NH₂), 4.08-4.06 (2H, m), 2.55 (2H, t, J = 7.0 Hz), 2.39 (2H, t, J = 7.0 Hz), 1.34 (3H, t, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 171.7 (C = O), 170.5 (C = O), 155.8, 155.3, 142.5, 141.9, 132.7, 125.7, 125.4, 123.4, 121.1, 116.0, 115.6, 115.1, 105.3, 63.5, 34.6, 34.3, 14.6. HRESIMS: Found m/z 384.1247 [M + H]⁺, Calcd for C₁₉H₂₀N₄O₃S: 384.1256.

N¹-(2-Aminophenyl)-3-Methyl-N⁵-(p-Tolyl)Pentanediamide (8a)

White solid. Yield 61.2%. MP: 161-163 °C. IR (KBr) ν (cm⁻¹): 3285, 2958, 2922, 1649, 1533, 1456, 781.

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.82 (1H, s, NH), 9.16 (1H, s, NH), 7.47 (2H, d, J = 7.0 Hz), 7.14 (1H, d, J = 7.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 6.89 (1H, t, J = 7.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.81 (2H, s, NH₂), 2.88 (0.5H, s, CH), 2.72 (0.5H, s, CH), 2.39 (2H, m), 2.27-2.21 (5H, m), 0.98 (3H, d, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 170.1 (C = O), 170.0 (C = O), 141.9, 136.7, 131.9, 128,9, 125.8, 125.4, 123.4, 119.1, 116.1, 115.9, 43.2, 42.6, 28.0, 20.4, 19.4. HRESIMS: Found m/z 326.1853 [M + H]⁺, Calcd for C₁₉H₂₃N₃O₂: 326.1869.

N¹-(2-Aminophenyl)-N⁵-(4-Methoxyphenyl)-3-Methylpentanediamide (8b)

White solid. Yield 52.4%. MP: 162-164 °C. IR (KBr) ν (cm⁻¹): 3374, 2927, 2868, 1728, 1664, 1501, 1457, 733. ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.81 (1H, s, NH), 9.15 (1H, s, NH), 7.47 (2H, d, J = 7.0 Hz), 7.13 (1H, d, J = 7.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.52 (1H, t, J = 7.0 Hz), 4.80 (2H, s, NH₂), 3.78 (3H, s), 2.87 (0.5H, s, CH), 2.71 (0.5H, s, CH), 2.38 (2H, m), 2.26-2.22 (2H, m), 0.98 (3H, d, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 170.2 (C = O), 170.1 (C = O), 141.9, 136.6, 131.8, 1288 (2xCH), 125.7, 125.3, 123.3, 119.1, 116.0, 115.8, 43.1, 42.5, 28.0, 20.3, 19.3. HRESIMS: Found m/z 342.1815 [M + H]⁺, Calcd for C₁₉H₂₃N₃O₃: 342.1818.

N¹-(2-Aminophenyl)-N⁵-(p-Tolyl)Glutaramide (10a)

White solid. Yield 62.8%. MP: 163-165 °C. IR (KBr) ν (cm⁻¹): 3279, 2962, 2921, 1651, 1597, 1454, 777.

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.79 (1H, s, NH), 9.07 (1H, s, NH), 7.48 (2H, d, J = 7.0 Hz), 7.16 (1H, d, J = 7.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 6.88 (1H, t, J = 7.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.81 (2H, s, NH₂), 2.39-2.34 (4H, m), 2.23 (3H, s), 1.90 (2H, t, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 170.6 (C = O), 170.5 (C = O), 141.8, 136.7, 131.7, 128,9, 125.6, 125.2, 123.4, 119.0, 116.0, 115.7, 35.5, 34.9, 21.1, 20.3. HRESIMS: Found m/z 312.1695 [M + H]⁺, Calcd for C₁₈H₂₁N₃O₂: 312.1634.

N¹-(2-Aminophenyl)-N⁵-(4-Methoxyphenyl)Glutaramide (10b)

White solid. Yield 56.7%. MP: 160-162 °C. IR (KBr) ν (cm⁻¹): 3278, 2958, 2918, 1645, 1538, 1454, 802.

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.76 (1H, s, NH), 9.10 (1H, s, NH), 7.50 (2H, d, J = 9.0 Hz), 7.16 (1H, d, J = 7.0 Hz), 6.90 - 6.85 (3H, m), 6.70 (1H, d, J = 8.0 Hz), 6.53 (1H, t, J = 7.0 Hz), 4.83 (2H, s, NH₂), 3.70 (3H, s), 2.39-2.34 (4H, m), 1.90 (2H, t, J = 7.0 Hz). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 170.7 (C = O), 170.3 (C = O), 154.9, 141.9, 132.5, 125.7, 125.3, 123.4, 120.6, 116.0, 115.8, 113.7, 55.1, 35.5, 35.0, 21.2. HRESIMS: Found m/z 328.1640 [M + H]⁺, Calcd for C₁₈H₂₁N₃O₃: 328.1661.

Cytotoxic Assays

Refer to Supplemental Material.

Conclusions

To sum up, 12 new 2-aminobenzamide derivatives containing benzothiazole and phenylamine moieties were designed and successfully synthesized. All these compounds were evaluated in vitro for their cytotoxicity using the SRB assay against 2 human cancer cell lines including A549 and SW480. Compounds 3a and 3c exhibited cytotoxicity toward A549 cell line with IC₅₀ values of 24.59 and 29.59 µM, respectively. The results also suggested that the bond length may affect cytotoxic activity of the compounds.

Supplemental Material

sj-doc-1-npx-10.1177_1934578X221116188 - Supplemental material for Design and Synthesis of New 2-Aminobenzamide Derivatives Containing Benzothiazole and Phenylamine Moiety and Their Cytotoxicity

Supplemental material, sj-doc-1-npx-10.1177_1934578X221116188 for Design and Synthesis of New 2-Aminobenzamide Derivatives Containing Benzothiazole and Phenylamine Moiety and Their Cytotoxicity by Dinh Thi Cuc, Nguyen Thi Hien, Vu Ngoc Doan, Tran Dang Thuan, Dang Thi Tuyet Anh, Nguyen Ha Thanh, Trinh Thu Ha, Nguyen Thi Nga, Nguyen Thi Kim Tuyet and Phan Van Kiem in Natural Product Communications

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Our institution does not require ethical approval for reporting individual cases or case series.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is funded by Graduate University of Science and Technology under grant number GUST.STS.ĐT2020-HH14.

ORCID iD

Phan Van Kiem

Statement of Human and Animal Rights

This paper does not contain any studies concerning about human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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Design and Synthesis of New 2-Aminobenzamide Derivatives Containing Benzothiazole and Phenylamine Moiety and Their Cytotoxicity

Abstract

Keywords

Introduction

Results and Discussion

Material and Method

General

General Procedure for the Synthesis of Compounds 3a-d, 5a-d, 8a-b, and 10a-b

N1-(2-Aminophenyl)-N5-(Benzo[d]Thiazol-2-yl)Glutaramide (3a)

N1-(2-Aminophenyl)-N5-(6-Methoxybenzo[d]Thiazol-2-yl)Glutaramide (3b)

N1-(2-Aminophenyl)-N5-(6-Methylbenzo[d]Thiazol-2-yl)Glutaramide (3c)

N1-(2-Aminophenyl)-N5-(6-Ethoxybenzo[d]Thiazol-2-yl)Glutaramide (3d)

N1-(2-Aminophenyl)-N4-(Benzo[d]Thiazol-2-yl)Succinamide (5a)

N1-(2-Aminophenyl)-N4-(6-Methoxybenzo[d]Thiazol-2-yl)Succinamide (5b)

N1-(2-Aminophenyl)-N4-(6-Methylbenzo[d]Thiazol-2-yl)Succinamide (5c)

N1-(2-Aminophenyl)-N4-(6-Ethoxybenzo[d]Thiazol-2-yl)Succinamide (5d)

N1-(2-Aminophenyl)-3-Methyl-N5-(p-Tolyl)Pentanediamide (8a)

N1-(2-Aminophenyl)-N5-(4-Methoxyphenyl)-3-Methylpentanediamide (8b)

N1-(2-Aminophenyl)-N5-(p-Tolyl)Glutaramide (10a)

N1-(2-Aminophenyl)-N5-(4-Methoxyphenyl)Glutaramide (10b)

Cytotoxic Assays

Conclusions

Supplemental Material

sj-doc-1-npx-10.1177_1934578X221116188 - Supplemental material for Design and Synthesis of New 2-Aminobenzamide Derivatives Containing Benzothiazole and Phenylamine Moiety and Their Cytotoxicity

Footnotes

Declaration of Conflicting Interests

Ethical Approval

Funding

ORCID iD

Statement of Human and Animal Rights

Statement of Informed Consent

Supplemental Material

References

Supplementary Material

N¹-(2-Aminophenyl)-N⁵-(Benzo[d]Thiazol-2-yl)Glutaramide (3a)

N¹-(2-Aminophenyl)-N⁵-(6-Methoxybenzo[d]Thiazol-2-yl)Glutaramide (3b)

N¹-(2-Aminophenyl)-N⁵-(6-Methylbenzo[d]Thiazol-2-yl)Glutaramide (3c)

N¹-(2-Aminophenyl)-N⁵-(6-Ethoxybenzo[d]Thiazol-2-yl)Glutaramide (3d)

N¹-(2-Aminophenyl)-N⁴-(Benzo[d]Thiazol-2-yl)Succinamide (5a)

N¹-(2-Aminophenyl)-N⁴-(6-Methoxybenzo[d]Thiazol-2-yl)Succinamide (5b)

N¹-(2-Aminophenyl)-N⁴-(6-Methylbenzo[d]Thiazol-2-yl)Succinamide (5c)

N¹-(2-Aminophenyl)-N⁴-(6-Ethoxybenzo[d]Thiazol-2-yl)Succinamide (5d)

N¹-(2-Aminophenyl)-3-Methyl-N⁵-(p-Tolyl)Pentanediamide (8a)

N¹-(2-Aminophenyl)-N⁵-(4-Methoxyphenyl)-3-Methylpentanediamide (8b)

N¹-(2-Aminophenyl)-N⁵-(p-Tolyl)Glutaramide (10a)

N¹-(2-Aminophenyl)-N⁵-(4-Methoxyphenyl)Glutaramide (10b)