Docking, synthesis, and anticancer assessment of novel quinoline-amidrazone hybrids

Ahmad H. Abdullah; Ahmad K. Alarareh; Mahmoud A. Al-Sha’er; Almeqdad Y. Habashneh; Firas F. Awwadi; Sanaa K. Bardaweel

doi:10.3897/pharmacia.71.e117192

Abstract

A group of new amidrazone compounds that include a quinoline component was produced through the reaction of hydrazonyl chloride, derived from 6-aminoquinoline, with appropriate secondary cyclic amines. The new compounds were confirmed through ¹H-NMR, ¹³C-NMR, FTIR, and HRMS, and further verified by single-crystal X-ray diffraction. The antitumor potential of the synthesized compounds was tested against lung cancer (A549) and breast cancer (MCF-7) cell lines. Among the compounds, the ethyl carboxylate and o-hydroxy phenyl piperazine derivatives (10d and 10g) exhibited the strongest activity against both cell lines, with IC₅₀ values of 43.1 and 59.1 μM for the lung and breast cancer cell lines, respectively. Moreover, the most potent compounds were subsequently docked into the c-Abl kinase binding site (PDB code: 1IEP) as a possible anticancer mechanism. In-silico ADMET study shows acceptable pharmacokinetic properties, and the toxicity profile for the most potent compounds is non-carcinogenic.

Keywords

Amidrazones, anti-tumor, c-Abl kinase, Japp-Klingmann reaction, (ADME)

Introduction

Quinoline derivatives have exhibited great potential as effective anticancer agents by selectively targeting and inhibiting the growth and proliferation of cancer cells (Ilakiyalakshmi and Napoleon 2022). Moreover, compounds containing a quinoline nucleus have demonstrated diverse biological activities, including antibacterial (Ranjbar-Karimi et al. 2018), antimalarial (Kalaria et al. 2018), and antiviral properties (Guardia et al. 2018). Naturally occurring quinoline alkaloids such as Cinchona (Sang-sup et al. 2009), and Dictamnine (Jain et al. 2019) have already been used to treat various types of cancer (Fig. 1). Additionally, several synthetic quinolines, such as Neratinin, Acridinecarboxamide, and Cabozantinib, have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of different types of cancer (Fig. 2). On the other hand, numerous piperazine-incorporating amidrazones, including compounds 1–5 (Fig. 3), have been identified as potential anticancer scaffolds due to their ability to target specific enzymes and receptors involved in tumor growth (Paprocka et al. 2022). As such, the development of new anticancer drugs based on these scaffolds (piperazine, amidrazone, and quinoline) is an active area of research, with their capacity to target multiple pathways involved in cancer development making them attractive candidates for drug discovery. This paper provides a comprehensive account of the synthesis, spectroscopic characterization, and in-silico ADMET analysis aimed at assessing the pharmacokinetic properties and toxicity profile of novel piperazinyl amidrazones that incorporate quinoline components. Additionally, it delves into their evaluation of antitumor activity. The proposed mechanism of action involves the inhibition of c-Abl kinase, as elucidated through docking techniques. Nevertheless, it is worth noting that further in vitro enzyme assays are planned for the future to validate this proposed mechanism (Paprocka et al. 2022). The synthetic compounds have been designed and synthesized with the intent of being selective and potential agents against cancer, with a primary focus on their role as c-Abl kinase inhibitors (Paprocka et al. 2022).

Figure 1.

Structure representation of quinoline-based natural alkaloids.

Figure 2.

Anticancer drugs with their structures.

Figure 3.

The Amidrazones structures of antitumor compounds 1–5.

Experimental part

Materials and method

The open capillary method on a Melting Point Meter M3000 (KRÜSS Optronic, Germany) was used to determine the melting points, which are uncorrected. The PerkinElmer Spectrum Two FT-IR Spectrometer (Diamond ATR FTIR) (Perkin-Elmer, USA) was employed to record the IR spectra, with a spectral resolution of 4 cm^-1 and a range of 4000 – 400 cm^-1. Bruker Avance Spectrometer AV500 (Bruker, Germany) was used to record ¹H, ¹³C NMR, and ²D NMR spectra, with DMSO d₆ as the solvent and TMS as an internal standard; chemical shifts were expressed in δ units, and the J value was given in Hertz. HRMS measurements were conducted using the electrospray ion trap (ESI) technique by collision-induced dissociation on a Bruker APEX-4 (7 Tesla) instrument in positive or negative ion mode. The samples were dissolved in chloroform and infused using a syringe pump with a flow rate of 2 µL/min, and external calibration was carried out using an arginine cluster in a mass range of m/z 175–871, with a mass error of 0.00–0.50 ppm. CrysAlisPro was utilized to determine and refine cell properties with multiscan absorption collection and transmission factors of 1.00000 and 0.00000 as maximum and minimum. The structure was solved using Direct Methods and refined using full-matrix least-squares on F2, with non-hydrogen atoms anisotropically refined, and hydrogen atoms placed in estimated locations and refined using a riding model. All reactions were monitored by thin layer chromatography, performed on silica gel 60 WF254S aluminum sheets (Merck, Germany), and visualized using UV light. Chemical reagents in high purity were purchased from Acros Organics (in Belgium). Software: Licensed Biovia 4.5 installed on the USER-THINK server with the following properties; CPU 3.1 GH, RAM 8.00 GB, System type 64 bit, Windows 7.

Chemistry

General procedure for the synthesis of N-(quinolin-6-yl)propanehydrazonoyl chloride (8)

The given compound was synthesized using the following steps: In step (i), a solution of Compound 6-aminoquinoline 6 (2.6 g, 0.01 mol) in 6N aqueous hydrochloric acid (16 mL) was prepared. Sodium nitrite (0.76 g, 0.011 mol) dissolved in water (1.5 mL) was added drop-wise to this solution with efficient stirring at 0–5 °C. The mixture was stirred for 20–30 min. In step (ii), the resulting quinolin-6-diazonium chloride 6A solution, obtained from step (i), was added to a cold solution (0 to -10 °C, ice-salt bath) of 3-chloropentan-2,4-dione (1.35 g, 0.01 mol) in ethanol/water (16 mL, 1:1 v/v) containing 30.0 g of sodium acetate, with vigorous stirring. The mixture was stirred until a solid precipitate formed (5–10 min). The reaction mixture was then diluted with cold water (250 mL). The solid product was collected by suction filtration, washed several times with cold water, and dried. The resulting product was solid with a brownish color. Yield: 94%, brownish powder, mp 197 °C dec; R_f = 0.71: dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 1026, 1171, 1215, 1542, 1689, 2938, 3105 cm^-1; ¹H NMR (500 MHz, DMSO-d₆) d 2.58 (s, 3H, -COCH₃), 7.49 (dd, J = 8.1, 8.2 Hz, 1H, H-3), 7.86 (s, 1, H – 5), 7.97 (d, J = 9.0 Hz, 1H, H-7), 8.00 (d, J = 9.0 Hz, 1-H, H-8), 8.30 (d, J = 8.2 Hz, 1H, H-4), 8.76 (d, J = 8. ,1H, H-2), 10.98 (s, 1H, -NH), ¹³C NMR (125 MHz, DMSO-d₆) d 25.9 (-COCH₃), 110.2 (C-5), 120.0 (C-7), 122.4 (C-3), 124.4 (C=N), 129.1 (C-4a), 130.7 (C-8), 135.7 (C-4), 141.0 (C-6), 145.1 (C-8a), 149.0 (C-2), 188.5 (-COCH₃), HRMS (ESI) calcd for C₁₂H₁₁ClN₃O [M+H]⁺ m/z: 248.05852, found 248.05789.

General procedure for the synthesis of Amidrazone (10a–l)

Compound 8 (0.65 g, 1.8 mmol) was suspended in ethanol (15 mL) at a temperature of 0 to -10 °C. A solution containing the appropriate secondary amine (2.2 mmol) and triethylamine (2 mL) in ethanol (5 mL) was added to the suspension with stirring. The stirring was continued at 0–5 °C for 2–4 h and then at room temperature overnight. The solvent was then removed under reduced pressure, and the resulting residue was treated with water (15 mL). The crude solid product was collected by suction filtration, washed with water, dried, and recrystallized using CHCl₃.

1-(Piperazin-1-yl)-1-(2-(quinolin-6-yl)hydrazineylidene)propan-2-one (10a)

Yield : 40.1%, brownish powder, mp 212 °C dec; R_f = 0.69 dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 1029, 1125, 1215, 1232, 1375, 1515, 1624, 1667, 2853 cm^-1; ¹H NMR (500 MHz, DMSO-d₆) d 2.41 (br.s, 1-H, H-4’), 2.46 (br.s, 3H, Z/E, -COCH₃), 2.98 (br.s, 4H, (H-3’,H-5’)), 3.21 (br.s, 4H, (H-2’,H6’)), 7.44 (br.s, 1H, H-3), 7.78 (s, 1H, H-5), 7.96 (br.s, 2H, (H-7, H-8)), 8.24 (br.s, 1H, H-4), 8.70 (br.s, 1H, H-2), 9.98, 10.07 (Z/E, 1H, -NH), ¹³C NMR (125 MHz, DMSO-d₆) d 26.7 (-COCH₃), 47.7 (C-3’,C-5’), 48.1 (C-2’,C-6’), 109.0 (C-5), 120.3 (C-7), 122.3, 122.1 (Z/E, C-3), 129.4 (C-4a), 130.4, 130.5 (Z/E, C-8), 135.2 (C-4), 141.7, 141.9 (Z/E, C-6), 144.1 (C-8a), 144.7 (-C=N), 148.3 (C-2), 195.1, 195.3 (-COCH₃), HRMS (ESI) calcd for C₁₆H₁₉N₅NaO [M+Na]⁺ m/z : 320.14818, found 320.14509.

1-Morpholino-1-(2-(quinolin-6-yl)hydrazineylidene)propan-2-one (10b)

Yield: 91.3%, yellowish powder, mp 104 °C dec; R_f = 0.78 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 957, 974, 1033, 1066, 1111, 1206, 1234, 1279, 1334,1360, 1496, 1510, 1538, 1598, 1623, 1643, 2860, 3209, 3438 cm^-1; ¹H NMR (500 MHz, DMSO- d₆) d 2.40 (s, 3H, -COCH₃), 2.97 (br.s, 4H, (H-2’, H-6’)), 3.77 (br.s, 4H, (H-3’, H-5’)), 7.44 (dd, J = 8.3 , 8.3 Hz, 1H, H-3), 7.76 (s, 1H, H-5), 7.93 (d, J = 9.2 Hz, 1H, H-7), 7.95 (pst, 1H, H-8), 8.22 (d, J = 8.2 Hz, 1H, H-4), 8.69 (d, J = 4.00 Hz, 1H, H-2), 10.14 (s, 1H, -NH); ¹³C NMR (125 MHz, DMSO-d₆) d 26.7 (-COCH₃), 47.7 (C-3’,C-5’), 48.1 (C-2’,C-6’), 109.0 (C-5), 120.3 (C-7), 122.3, 122.1 (Z/E, C-3), 129.4 (C-4a), 130.4, 130.5 (Z/E, C-8), 135.2 (C-4), 141.7, 141.9 (Z/E, C-6), 144.1 (C-8a), 144.7 (-C=N), 148.3 (C-2), 195.1, 195.3 (-COCH₃), HRMS (ESI) calcd for C₁₆H₁₉N₄O₂ [M+H]⁺ m/z : 299.15025, found 299.14985.

1-(2-(Quinolin-6-yl)hydrazineylidene)-1-thiomorpholinopropan-2-one (10c)

Yield: 85.0%, Reddish powder, mp 160 – 162 °C; R_f = 0.78 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 947, 969, 1117, 1166, 1211, 1279, 1347, 1376, 1515, 1622, 1657, 2851, 2902, 3248 cm^-1; ¹H NMR (500 MHz, DMSO d₆) d 2.39 (s, 3H, -COCH₃), 2.81 (br.s, 4H, (H-3’,H-5’)), 3.16 (br.s, 4H, (H-2’,H6’)), 7.43 (dd, J = 8.3, 8.3 Hz, 1H, H-3), 7.76 (s, 1H, H-5), 7.94 (d, J = 1.8 Hz, 1H, H-7), 7.95 (d, J = 9.1 Hz, 1H, H-8), 8.20 (d, J = 8.2 Hz, 1H, H-4), 8.68 (d, J = 4.0 Hz, 1H, H-2), 10.06 (s, 1H, – NH); ¹³C NMR (125 MHz, DMSO d₆) d 26.4 (-COCH₃), 27.5 (C-3’,C-5’), 50.6 (C-2’,C-6’), 109.2 (C-5), 120.5 (C-7), 122.5 (C-3), 129.3 (C-4a), 130.6 (C-8), 135.3 (C-4), 141.7 (C-6), 144.6 (C-8a), 144.7 (-C=N), 148.5 (C-2), 195.1 (-COCH₃); HRMS (ESI) calcd for C₁₆H₁₉N₄OS [M + H]⁺ m/z : 315.12741, found: 315.12670.

Ethyl-4-(2-oxo-1-(2-(quinolin-6-yl)hydrazineylidene)propyl)piperazine-1- carboxylate (10d)

Yield: 85.7% , brownish powder, mp 125 °C dec; R_f = 0.88 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 967, 992, 1027, 1093, 1118, 1159, 1178, 1208, 1248, 1280, 1338, 1357, 1372, 1423, 1510, 1622, 1663, 1684 , 2854, 2923, 3247 cm^-1; ¹H NMR (500 MHz, DMSO d₆) d 1.19 (t, J = 7.1 Hz, 3H, -CH₂CH₃), 2.39 (s, 3H, -COCH₃), 2.92 (br.s, 2H , (H-2’, H-6’)), 3.56 (br.s , 2H, (H-3’, H-5’)), 4.07 (q, J = 7.1 Hz, 2H, -CH₂CH₃), 7.44 (dd, J = 8.3, 8.3 Hz, 1H, H-3), 7.75 (s, 1H, H-5), 7.92 (d, J = 9.2 Hz, 1H, H-7), 7.95 (d, J = 9.1 , 1H, H-8), 8.21 (d, J = 3 Hz, 1H, H-4), 8.69 (ps-t, 1H, H-2), 10.17 (s, 1H, -NH); ¹³C NMR (125 MHz, DMSO d₆) d 15.0 (-CH₂CH₃), 26.3 (-COCH₃), 44.0 (C-3’, C-5’), 47.8 (C-2’, C-6’), 61.3 (-CH₂CH₃), 109.1 (C-5), 120.3 (C-7), 122.4 (C-3), 129.3 (C-4a), 130.4 (C-8), 135.3 (C-4), 141.7 (C-6), 143.6 (-C=N), 144.7 (C-8a), 148.4 (C-2), 155.3 (-CO₂Et), 195.1 (-COCH₃), HRMS (ESI) calcd for C₁₉H₂₄N₅O₃ [M + H]⁺ m/z : 370.18737, found 370.18886.

1-(4’-(3’’-Hydroxyphenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10e)

Yield = 89.2%, Yellowish powder, mp 157–159 °C; R_f = 0.50 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 977, 996, 1034, 1188, 1231, 1264, 1332, 1372, 1452, 1509, 1545, 1579, 1625, 1670, 2856, 2936, 3271 cm^-1; ¹H NMR (500 MHz, DMSO-d₆) d 3.23 (s, 3H, -COCH₃), 3.85 (br.s, 4H, (H-2’, H-6’)), 4.03 (br.s , 4H, (H-3’, H-5’)), 6.96 (d , J = 7.9 Hz, 1H, H-6’’), 7.10 (s, 1H, H-2’’), 7.16 (d, J = 8.2 Hz, 1H, H-4’’), 7.76 (ps-t, 1H, H-5’’), 8.17 (dd, J = 8.3 , 8.3 Hz , 1H, H-3), 8.51 (s, 1H, H-5), 8.68 (br.s, 1H, H-7), 8.68 (br.s, 1H,H-8), 8.95 (d, J = 8.2 Hz, 1H, H-4), 9.43 (d, J = 2.75 Hz, 1H, H-2), 9.90 (br.s, 1H, OH), 10.84 (s , 1H, -NH), ¹³C NMR (125 MHz, DMSO-d₆) d 26.4 (-COCH₃), 47.8 (C-2’,C-4’), 48.8 (C-3’, C-5’), 103.1 (C-2’’), 106.6 (C-6’’), 107.2 (C-4’’), 109.0 (C-5), 120.3 (C-7), 122.3 (C3), 129.4 (C-4a), 130.0 (C-5’’), 130.4 (C-8), 135.2 (C-4), 141.8 (C-6), 143.9 (C-8a), 144.8 (-C=N), 148.3 (C-2), 153.1 (C-1’’), 195.1 (-COCH₃), HRMS (ESI) calcd for C₁₉H₂₄N₅O₃ [M + H]⁺ m/z: 390.19245, found: 390.19316.

1-(4’-(4’’-Nitrosophenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10f)

Yield: 95.3%, yellowish powder, mp 177 °C dec; R_f = 0.88 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 965, 998, 1027, 1096, 1114, 1127, 1158, 1180, 1209, 1248, 1289, 1324, 1360, 1466, 1488, 1511, 1543, 1598, 1624, 1667, 2852, 3272 cm^-1; ¹H NMR (500 MHz, DMSO-d₆) d 2.40 (s, 3H, -COCH₃), 3.11 (br.s, 4H, (H-2’, H-6’), 3.71 (br.s, 4H, (H-3’, H-5’)), 7.08 (d, J = 9.3 Hz, 2H, (H-2’’, H-6’’)), 7.45 (dd, J = 8.3, 8.3 Hz, 1H, H-3), 7.78 (s , 1H, H-5), 7.95 (d, J = 9.2 Hz, 1H, H-7), 7.99 (d, J = 9.1 Hz, 1H, H-8), 8.09 (d, J = 9.1, 2H, (H-3’’, H-5’’)), 8.23 (d, J = 8.3 Hz, 1H, H-4), 8.70 (d, J = 3.8 Hz, 1H, H-2), 10.23 (s, 1H, – NH), ¹³C NMR (125 MHz, DMSO-d₆) d (ppm): 26.3 (-COCH₃), 47.1 (C-2’, C6’), 47.5 (C-3’, C-5’), 109.1 (C-5), 113.1 (C-2’’, C-6’’), 120.3 (C-7), 122.4 (C-3), 126.3 (C-3’’, C-5’’), 129.3 (C-4a), 130.5 (C-8), 135.2 (C-4), 137.2 (C-4’’), 141.8 (C-6), 143.4 (C=N), 144.8 (C-8a), 148.4 (C-2), 155.3 (C-1’’), 195.1 (-COCH₃), HRMS (ESI) calcd for C₁₉H₂₄N₅O₃ [M + H]⁺ m/z : 419.18262 , found 419.18230.

1-(4’-(2’’-Hydroxyphenyl)piperazin-1-yl)-1-(2-(quinolin-6-yl) hydrazineylidene) propan-2-one (10g)

Yield: 89.4%, Yellowish powder, mp 160 °C dec; R_f = 0.81 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr). IR (KBr) n 1033, 1132, 1216, 1233, 1373, 1354, 1493, 1513, 1625, 1696, 2903, 2972, 3262 cm^-1; ¹H NMR (500 MHz, DMSO-d₆) d 2.43 (s, 3H, -COCH₃), 3.14 (br.s, 8H, (H-2’, H-3’, H-5’, H6’)), 6.81 (m, 2H, (H-4’’, H-5’’)), 6.82 (d, J = 7.2 Hz, 1H, H-6’’), 6.94 (d, J = 7.2 Hz, 1H, H-3’’), 7.44 (m, 1-H, H-3), 7.77 (s, 1H, H-5), 7.95 (br.s, 2H, (H-7, H-8)), 8.23 (d, J = 8.2 Hz, 1H, H-4), 8.70 (br.s, 1H, H-2), 9.02 (s, 1H, -OH), 10.10 (s, 1H, -NH), ¹³C NMR (125 MHz, DMSO-d₆) d 26.4 (-COCH₃), 48.1 (C-2’, C-6’), 50.6 (C-3’, C-5’), 109.0 (C-5), 116.1 , 119.1 (C-5’’, C-6’’), 119.8 (C-3’’), 120.3 (C-7), 122.4 (C-3), 123.4 (C-4’’), 129.3 (C-4a), 130.4 (C-8), 135.2 (C-4), 140.7 (C-2’’), 141.8 (C-6), 144.2 (C-8a), 144.5 (-C=N), 148.3 (C-2), 150.6 (C-1’’), 195.2 (-COCH₃), HRMS (ESI) calcd for C₂₂H₂₄N₅O₂ [M + H]⁺ m/z : 390.19245, found 390.19326.

1-(4’-(4’’-Chlorophenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10h)

Yield: 91.1%, Brownish powder, mp 151–153 °C; R_f = 0.88 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 964, 1005, 1228, 1117, 1156, 1215, 1234, 1317, 1358, 1457, 1496, 1510, 1669, 2850, 2922, 3271 cm^-1; ¹H NMR (500 MHz, DMSO-d₆) d 2.42 (s, 3H, -COCH₃) , 3.11 (br.s, 4H, (H-2’ , H-6’)), 3.33 (br.s , 4H , (H-3’ , H-5’)), 7.00 (d, J = 8.4 Hz, 2H, (H-2’’, H-6’’)), 7.26 (d, J = 8.6 Hz, 2H, (H-3’’, H-5’’)), 7.45 (dd, J = 8.2, 8.3 Hz, 1H, H-3), 7.77 (s, 1H, H-3), 7.94 (d, J = 9.3 Hz, 1H, H-7), 7.95 (d, J = 9.0 Hz, 1H, H-8), 8.21 (d, J = 8.1, 1H, H-4), 8.70 (br.s, 1H, H-2), 10.12 (s, 1H, -NH), ¹³C-NMR (125 MHz, DMSO-d₆) d (ppm): 26.4 (-COCH₃), 47.7 (C-2’, C-6’), 48.6 (C-3’, C-5’), 109.0 (C-5), 117.4 (C-2’’,C-6’’), 120.3 (C-7), 122.3 (C-4’’), 122.7 (C-3), 129.1 (C-3’’, C-5’’, C4a), 130.4 (C-8), 135.2 (C-4), 141.8 (C-6), 143.8 (C-8a), 144.8 (-C=N), 148.4 (C-2), 150.5 (C-1’’), 195.2 (-COCH₃), HRMS (ESI) calcd for C₂₂H₂₃³⁵ClN₅O [M+H]⁺ m/z : 408.15856, found 408.15764.

1-(4’-Phenylpiperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10i)

Yield = 88.0%, Brownish powder, m.p. 135–137 °C; R_f = 0.88 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 991, 1027, 1131, 1159, 1231, 1259, 1328, 1378, 1449, 1491, 1504, 1534, 1596, 1624, 1666, 2826, 2921, 3268 cm^-1; ¹H NMR (500 MHz, DMSO d₆) d 2.49 (s, 3H, -COCH₃), 3.13 (br.s, 4H, (H-2’, H-6’)), 3.35 (br.s, 4H, (H-3’, H-5’)), 6.79 (br.s, 1H, H-4’’), 6.96 (d, J = 6.8 Hz, 2H, (H-2’’, H-6’’)), 7.23 (br.s, 2H, (H-3’’, H-5’’), 7.44 (br.s, 1H, H-3), 7.79 (s, 1H, H-5), 7.96 (s, 1H, H-7), 7.97 (s, 1H, H-8), 8.22 (d, J = 7.35 Hz, 1H, H-4), 8.70 (br.s, 1H, H-2), 10.12 (s, 1H, -NH), ¹³C NMR (125 MHz, DMSO d₆) d 26.4 (-COCH₃), 47.8 (C-2’, C-6’), 48.8 (C-3’, C-5’), 109.0 (C-5), 116.0 (C-2’’, C-6’’), 119.2 (C-4’’), 120.3 (C-7), 122.3 (C-3), 129.4 (C-4a, C-3’’, C-5’’), 130.5 (C-8), 135.2 (C-4), 141.8 (C-6), 143.9 (C-8a), 144.8 (-C=N), 148.3 (C-2), 151.8 (C-1’’), 195.1 (-COCH₃), HRMS (ESI) calcd for C₂₂H₂₄N₅O [M + H]⁺ m/z : 374.19754, found 374.19660.

1-(4’-(4’’-Hydroxyphenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazono)propan-2-one (10j)

Yield: 92.6%, brownish powder, mp 161–163 °C; R_f = 0.46 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n (cm^-1): 955, 1034, 1134, 1230, 1375, 1451, 1512, 1620, 1675, 2947, 3257 cm^-1; ¹H NMR (500 MHz, DMSO d₆) d 2.49 (s, 3H, -COCH₃), 3.07 (br.s, 4H, (H-3’, H-5’)), 3.12 (br.s, 4H, (H-2’, H-6’)), 6.67 (d, J = 8.7 Hz, 2H, (H-2’’, H-6’’)), 6.82 (d, J = 8.2 Hz, 1H, (H-3’’, H-5’’)), 7.44 (dd, J = 8.3, 8.2 Hz , 1H, H-3), 7.77 (s, 1H, H-5), 7.95 (ps.t, 2H, (H-7, H-8)), 8.21 (d, J = 8.2 Hz, 1H, H-4), 8.69 (d, J = 2.75 Hz, 1H, H-2), 8.82 (s,1H,OH), 10.05 (s, 1H, NH): ¹³C NMR (125 MHz, DMSO d₆) d 26.5 (-COCH₃), 48.0 (C-2’), 50,6 (C-3’), 109.0 (C-5), 115.9 (C-2’’, C-6’’), 118.5 (C-3’’, C-5’’), 120.3 (C-7), 122.3 (C-3), 129.4 (C-4a), 130.4 (C-8), 135.2 (C-4), 141.8 (-C=N), 144.0 (C-8a), 144.7 (C-4’’), 145.0 (C-6), 148.3 (C-2), 151.4 (C-1’’), 195.1 (-COCH₃); HRMS (ESI) calcd for C₂₂H₂₄N₅O₂ [M + H]⁺ m/z : 390.19245, found 390.19429.

1-(4’-Phenylpiperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10k)

Yield: 89.1%, yellowish powder, mp 135–137 °C; R_f = 0.73 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 935, 1027, 1130, 1206, 1232, 1259, 1314, 1326, 1355, 1389, 1454, 1512, 1554, 1591, 1645, 1627, 2865, 3211, 3408 cm^-1; ¹H NMR (500 MHz, DMSO-d₆) d 2.41 (s, 3H, -COCH₃), 3.02 (br.s, 4H, (H-3’,H-5’)), 3.96 (br.s, 4H, (H-2’,H6’)), 6.63 (br.s, 1H, H-5’’), 7.44 (d, J = 3.9 Hz , 1H, H-3), 7.78 (s, 1H, H-5), 7.95 (br.s, 1H, H-7), 7.97 (br.s, 1H, H-8), 8.22 (d, J = 7.9 Hz, 1H, H-4),8.37 (d, J = 7.9 Hz, 2H, (H-4’’, H-6’’)), 8.70 (br.s, 1H, H-2), 10.22 (s, 1H, -NH), ¹³C NMR (125 MHz, DMSO-d₆) d (ppm): 26.7 (-COCH₃), 44.0 (C-2’,C-6’), 47.7 (C-3’,C-5’), 109.1 (C-5), 110.5 (C-5’’), 120.3 (C-7), 122.3 (C-3), 129.4 (C-4a), 130.4 (C-8), 135.2 (C-4), 141.8 (C-6), 143.8 (C-8a), 144.8 (-C=N), 148.4 (C-2),158.4 (C4’’, C-6’’), 161.8 (C-2’’), 195.1 (-COCH₃), HRMS (ESI) calcd for C₂₀H₂₂N₇O [M + H]⁺ m/z : 376.18803, found 376.18988.

1-(4’-(pyridin-2-yl)piperazin-1-yl)-1-(2-(quinolin-6-yl)hydrazineylidene)propan-2-one (10l)

Yield: 92.0%, yellowish powder, mp 125–127 °C; R_f = 0.79 (dichloromethane/methanol = 9.75:0.25 by volume). IR (KBr) n 957, 977, 1026, 1124, 1179, 1227, 1255, 1329, 1489, 1528, 1602, 1656, 2855, 3266 cm^-1; ¹H NMR (500 MHz, DMSO- d₆) d 2.42 (s, 3H, -COCH₃), 3.06 (s, 2H, (H-2’, H-6’)), 3.71 (s, 2H, (H-3’, H-5’)), 6.64 (br.s, 1H, H-5’’), 6.85 (d, J = 8.4 Hz, 1H, H-3’’), 7.43 (br.s, 1H, H-3), 7.53 (t, J = 8.2 Hz, 1H, H-4’’), 7.78 (s, 1H, H-5), 7.95 (d, J = 9.1 Hz, 1H, H-7), 7.97 (d, J = 9.0 Hz, 1H, H-8), 8.13 (br.s, 1H, H-6’’), 8.22 (d, J = 8 Hz, 1H, H-4), 8.70 (br.s, 1H, H-2), 10.17 (s, 1H, – NH), ¹³C NMR (125 MHz, DMSO-d₆) d 26.4 (-COCH₃), 45.3 (C-2’, C6’), 47.6 (C-3’, C-5’), 107.6 (C-3’’), 109.0 (C-5), 113.3 (C-5’’), 120.3 (C-7), 122.3 (C-3), 129.4 (C-4a), 130.5 (C-8), 135.2 (C-4), 138.0 (C-4’’), 141.8 (C-6), 143.9 (C=N), 144.8 (C-8a), 148.1 (C-6’’), 148.3 (C-2), 159.6 (C-2’’), 195.1 (-COCH₃), HRMS (ESI) calcd for C₂₁H₂₃N₆O [M + H]⁺ m/z :375.19279, found 375.19116.

Molecular modeling

Computational docking

The synthesized compounds (10a–l) were docked into the active site of c-Abl kinase. The 3D coordinates of the c-Abl kinase with known co-crystallized pyrimidine inhibitor (STI-571), were retrieved from Protein Data Bank (c-Abl, PDB code: 1IEP, resolution: 2.10 Å). First, the protein was prepared by adding hydrogen atoms using Biovia Discovery Studio software 4.5. The protein was cleaned, prepared, and repaired by adding missing atoms, correcting connectivity and names, and inserting missing loops. Secondly, the active site was defined around the co-crystallized ligand (STI-571) using the (From Current Selection) option of the (Define and Edit Binding Site) tool in Biovia Discovery Studio 4.5, shown in (Fig. 4). The co-crystallized ligand (STI-571) was removed from the binding site for docking validation. The ligand was redocked using the LibDock algorithm and the Root Mean Square Deviation (RMSD) was calculated to validate and assess pose similarity between the ligand poses concerning the original pose of the ligand. The RMSD value for the pose with the highest LibDock scores in comparison to the co-crystallized pose was 2.1Å (around 2Å) which is acceptable. The final amidrazone-quinoline compounds bearing 6-aminoquinoline moiety in their structures were docked into the binding site of the selected c-Abl kinase using the default LibDock algorithm.

Figure 4.

A. The co-crystallized pyrimidine ligand (1IEP); B. The co-crystallized pose and the docked pose of the co-crystallized ligand with RMSD = 2.10 Å; C. The binding site of the c-Abl-kinase protein (PDB code: 1IEP, resolution: 2.10 Å). Blue is for the co-crystal compounds, and red is for the highest Libdock score compound (Libdock score = 169.76).

Ligand preparation for LibDock

The site-feature docking algorithm (LibDock) docks ligands, after removing their hydrogen atoms, into an existing active site as guided by binding hotspots. The ligands’ conformations are aligned to polar and apolar receptor interaction sites (i.e., hotspots). Conformations can be either pre-calculated or generated on the fly. Optionally, a CHARMm minimization step can be enabled to further optimize docked poses. Docking with LibDock has several steps which can be summarized in: (i) removal of hydrogen atoms. (ii) Ranking ligand conformations and pruning by solvent-accessible surface area (SASA). (iii) Finding hotspots using a grid that is placed into the binding site and using polar and apolar probes. (iv) The number of hotspots is trimmed by clustering to a user-defined value. (v) Docking of ligand poses by aligning the binding site hotspots, performed by using triplets (three ligand atoms are aligned to three receptor hotspots). (vi) a final BFGS pose optimization stage is performed using a simple pair-wise score (similar to Piecewise Linear Potential). (vii) The top-scoring ligand poses are retained. (viii) Hydrogen atoms are added back to the docked ligands. (ix) Optionally CHARMm minimization can be carried out to reduce steric clashes caused by added hydrogen atoms. The following LibDock parameters were applied in the current study: Before docking, the Biovia 4.5 module CAT-CONFIRM was used to generate a maximum of 250 conformers (not exceeding an energy threshold of 20 kcal/mol from the most stable conformer) for each ligand employing “Fast” conformation generation option. A binding site sphere of 12.77 Å radius surrounding the center of the co-crystallized ligand (STI-571) was retrieved from Protein Data Bank (c-Abl, PDB code: 1IEP, resolution: 2.10 Å) and was used to define the binding site. The number of binding site hotspots (polar and apolar) was set to 100. The ligand-to-hotspots matching RMSD tolerance value was set to 0.25 Å. The maximum number of poses saved for each ligand during hotspots matching before final pose minimization = 100. Maximum number of poses to be saved for each ligand in the binding pocket = 100. Minimum LibDock score (poses below this score are not reported) = 100. Maximum number of rigid body minimization steps during the final pose optimization (using BFGS method) = 50. The maximum number of steric clashes allowed before the pose-hotspot alignment is terminated (specified as a fraction of the heavy atom count) = 0.1. Maximum value for nonpolar solvent accessible surface area for a particular pose to be reported as successful = 15.0 Å2. Maximum value for polar solvent accessible solvent area for a particular pose to be reported as successful = 5.0 Å2. No final ligand minimization was implemented (i.e., in the binding pocket).

Toxicity prediction using EC₅₀ Daphnia calculations

Toxicity prediction studies were performed using software suites implemented in Discovery Studio 4.5 from Biovia Inc. (San Diego, California, Structures were drawn by ChemDraw Ultra 7.0 (Cambridge Soft Corp. (http://www.cambridgesoft.com), USA).

Data set

The synthesized compounds 10a–l were analyzed using the default parameters in Biovia 4.5 using the TOPKAT toxicity function after the addition of all parameters.

In vitro anticancer screening

Cells were seeded in 96-well plates at a density of 8 × 10³ and 5 × 10³, cells per well in the appropriate medium for A549 and MCF-7 cell lines, respectively. For screening anti-MCF7 anti-A549, the desired concentrations of the tested compounds were applied to the cells. For IC₅₀ determination, the cells were treated with increasing concentrations of the tested compound, ranging from 1.00 to 1000 µM. The drugs were dissolved in DMSO before being added to cell cultures, and equal amounts of the solvent were added to control wells. After 48 h of treatment, 10 µL of MTT dye (working concentration of 5 mg/mL) was added to each well, and the plates were further incubated for 4 hours. Afterward, the media was discarded and 100 µL of DMSO was added to the wells. Optical density was measured at 570 nm and 630 nm with a microplate reader (µ Quant Plate Reader, Biotek, USA). All experiments were repeated in triplicate wells and on at least their independent occasions. Dose-response curves were used to obtain IC₅₀ concentrations based on the following Equation:

Equation 1. Cell viability calculation.

$Cell viability (%) = \frac{(Optical density of treated cells)}{optical density of untreated cells} \times 100$

Data were analyzed using Graph Pad Prism Software 9 from San Diego, California, USA (www.graphpad.com).

Collection of X-ray diffraction data and structure analysis of compound (10b)

The slow growth of orange block crystals from a dilute 10b Methanol solution took place over one week. Using epoxy glue, a suitable crystal with approximate dimensions of 0.3 × 0.1 × 0.1 mm³ was mounted onto a glass fiber and then data were collected at room temperature (293 K) via the Oxford Xcalibur diffractometer. The CrysAlis Pro software (CrysAlisPro, Oxford Diffraction Ltd., Version 1.171.35.19 (release 27-10-2011 CrysAlis171.NET) was employed to acquire and process the data. The crystal was kept at 293(2) K during data collection. Using Olex2, the structure was solved with the SHELXT structure solution program using Intrinsic Phasing and refined with the SHELXL (Sheldrick 1996; Sheldrick 2015a, 2015b) refinement package using Least Squares minimization. No hydrogen atoms were refined anisotropically with hydrogen atoms positioned using a riding model. A summary of the crystallographic data can be found in (Table 1). The supplementary crystallographic data for this paper can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif, with the CCDC 2257301 code.

Table 1.

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Crystal data and structure refinements for compound 10b.

Empirical formula	C₁₆ H₂₂ N₄ O₄
Formula weight, g mol^-1	334.37
Temperature, K	293(2)
Wavelengthλ, Å	0.71073
Crystal system	Triclinic
Space group	P1
a, Å	5.2960(3)
b, Å	9.3134(6)
c, Å	9.4794(7)
α/°	106.359(6)
β/°	102.219(5)
γ/°	94.535(5)
Volume, Å³	433.65(5)
Z	1
Density (calcd.), g cm^-3	1.28
Absorption coefficient μ, mm^-1	0.094
F (000), e	178
2θrange for data collection, deg	7.46–58.564
Index rangeshkl	-6 ≤ h ≤ 7, -11 ≤ k ≤ 12, -12 ≤ l ≤ 11
Reflections collected	6705
Independent reflections	3912
R (int)	0.0231
Absorption correction	Semi-empirical from equivalents
Refinement method	Full-matrix least-squares on F²
Data / restraints / parameters	3912 / 3 / 232
R1^a / wR2^b [I > 2 sigma > (I)]	0.0499 / 0.1005
R1^a / wR2^b(all data)	0.0892 /0.1224
Goodness-of-fit on F²	1.026
Largest diff. peak/hole, eÅ^-3	0.12 / -0.17

Results and discussion

Chemistry

In this study, the hydrazonoyl chloride 8 was synthesized by directly coupling the respective quinoline-6-diazonium chloride with 3-chloroethane-2,4-dione in an aqueous alcoholic sodium acetate solution using the Japp-Klingemann reaction (Scheme 1) as per previously documented methods (Yao et al. 1962). To prepare the quinoline-6-diazonium chloride, freshly diazotized the respective 6-aminoquinoline 6 (suspended in 6 N aq. HCl). The resulting hydrazonoyl chloride precursor 8 was expected to undergo nucleophilic addition reactions with piperazines and the related sec-cyclic amine congeners 9a–l, acting as nitrogen nucleophiles, resulting in the formation of the respective amidrazone adducts 10a–l (Scheme 2). This reaction mechanism has been extensively documented (Ulrich 1968; Butler et al. 1970; Benincori and Sannicoló 1988; Habashneh et al. 2014; Abdullah et al. 2016). The newly synthesized compounds were identified and characterized using MS and NMR spectral data, as detailed in the experimental section. The data revealed consistent results supporting the proposed structures. Specifically, the mass spectra displayed the correct molecular ion peaks, and the high-resolution mass spectral data agreed well with calculated values. DEPT and 2D (COSY, HMQC, and HMBC) experiments also helped with signal assignments for the different carbons and their attached and neighboring hydrogens. We confirmed the structures by single crystal X-ray structure determination for 10b (Fig. 4), representing the series.

Scheme 1.

Synthetic route to compound 8.

Scheme 2.

Synthetic route for compounds 10a–l.

X-ray structure determination of (10b)

X-ray crystal structure determination was performed to confirm the structure of 10b (Scheme 2) as a representative example of the new synthetic N-(quinolin-6-yl) amidrazones 10a–l. A summary of data collection and refinement parameters is given in Table 1. The molecular structure of 10b in the crystal is shown in (Fig. 5). 10b crystallizes as dihydrate. The mean plane of the quinoline is nearly perpendicular to the plane of the rest of the molecule. Water molecules are linked via O-H∙∙∙O hydrogen bonding interactions to form a chain structure that runs parallel to the crystallographic a-axis (Fig. 6-top). Subsequently, these layers are linked via C-H∙∙∙O hydrogen bonding interactions to form tunneled framework structures; these tunnels are filled with water molecules (Fig. 6-bottom).

Figure 5.

X-ray structure of 10b.

Figure 6.

Layer structure of 10b (top) and the three-dimensional structure of 10b (bottom).

Computational docking

According to computational docking, a small chemical attaching to a larger receptor should form a stable complex (Khamis et al. 2015). Molecular docking is one of the best in silico methods for predicting chemical-biological target interactions (Kitchen et al. 2004). Diller and Merz’s LibDock algorithm directs docking using protein binding sites (Diller et al. 2001). The LibDock technique involves constructing the ligand’s conformations, finding polar and apolar hot spots, matching the binding site picture with the ligand, and optimizing and scoring (Rao et al. 2007). Docking’s ability to identify active molecules from decoys depends on the protein and the co-crystallized ligand’s similarity to the screened ligands (Al-Sha’er et al. 2015; Al-Sha’er et al. 2016; Al-Sha’er et al. 2019; Al-Sha’er et al. 2022). We selected the protein data bank file (1IEP, resolution: 2.10 Å) based on the provided information. Pyrimidine ligand and c-Abl kinase co-crystallized (STI-571) are included. By calculating the RMSD, the difference between the best-docked posture and the initial co-crystallized pose, the LibDock score (169.76) was used to choose the best stance conformation to confirm docking. An RMSD of 2.10Å was observed. As shown in (Fig. 6), the co-crystallized ligand (STI-571) forms four hydrogen bonds with the c-Abl kinase enzyme’s binding site amino acids: Met318 with the heteroatom N in the pyridinyl group, Thr315 with the NH₂, Asp381 with the carbonyl (C=O) of the amide bond, and Met290 with the NH-. All resulting synthetic compounds have acceptable LibDock scores compared to the co-crystallized ligand, which had 1–5 hydrogen bonds. The two-dimensional study (Fig. 4) shows that the selected chemicals may bind to the c-Abl enzyme via hydrogen bonding, dipole-dipole interactions, charge transfer, and Van der Waal interactions with hydrophobic amino acids.

(Fig. 7) shows the predicted interaction of the most active substance (10d; libDock score: 123.46) with the c-Abl kinase binding site via three hydrogen bonds: Glu316 with phenolic OH, Met318 with phenolic OH group, Glu286 with NH-amidrazone, and ASP381 with quinoline ring via π-π aromatic stacking. The suggested work will be screening synthetic compounds (10d and 10g) for anti-c-Abl kinase activity at 100 µM using Invitrogen Thermo Fisher Scientific Enzyme assay service (Kashem et al. 2007). Most compounds had lower LibDock scores than the co-crystallized ligand (STI-571). The site feature technique (LibDock) has numerous shortcomings because it is mostly used to rapidly dock combinatorial libraries of compounds to prioritize library selection above compound rank sorting. The lack of concordance between docking data and in vitro enzymatic activity is one. Another issue in computational chemistry is protein-ligand affinity prediction accuracy (Meng et al. 2011). However, protein systems score differently, and projections often don’t match experimental evidence (Warren et al. 2006; Rao et al. 2007; Verdonk et al. 2008; Cheng et al. 2009). The targeted chemicals 10a–l may fight cancer without inhibiting c-Abl kinase. After numerous research studies introduced amidrazone compounds as anti-cancer agents, further chemical modification to improve activity and safety and exploration of various suggested mechanisms of anticancer activity are essential. Additionally, the toxicity profile suggests that amidrazone-quinoline derivatives may be toxic to Daphnia with low EC50 values, emphasizing the need for in vivo evaluation.

Figure 7.

A. Diagram of receptor-ligand interaction between compound (10d) and c-Abl kinase (PDB code: 1IEP); B. 3D diagram of receptor-ligand interaction between compound (10d) c-Abl kinase enzyme (PDB code: 1IEP).

Figure 8.

ADME analysis of synthetic amidrazone structures (blue dot).

Table 2.

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Toxicity and Carcinogenic predicted properties of amidrazone derivatives.

Compound No.	Daphnia EC50mg/L^*	Carcinogenicity#
10a.mol	0.54	Carcinogen
10b.mol	0.1	Non-Carcinogen
10c.mol	0.03	Non-Carcinogen
10d.mol	0.11	Non-Carcinogen
10e.mol	0.02	Non-Carcinogen
10f.mol	0.04	Non-Carcinogen
10g.mol	0.12	Non-Carcinogen
10h.mol	0.04	Non-Carcinogen
10i.mol	0.12	Non-Carcinogen
10j.mol	0.11	Non-Carcinogen
10k.mol	0.07	Carcinogen
10l.mol	0.42	Carcinogen

Table 3.

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MTT assay for the synthetic compounds 10 a–l.

Compound	IC₅₀ µM(A549)^#	IC₅₀ µM(MCF-7)^#
10a	482.6	317
10b	320.2	539
10c	96	95.2
10d	43.1	59.1
10e	150.3	191.7
10f	862.9	1127
10g	59.23	63.5
10h	370.6	350
10i	127	140.9
10j	499.1	496.2
10k	280.5	254
10l	529.3	697
Cisplatin*	22	-
Doxorubicin**	-	5

Conclusions

The study reports synthesizing and testing a new series of compounds derived from 6-aminoquinoline and piperazine for their potential antitumor activity against breast and lung cancer cell lines (MCF-7 and A549). The compounds were synthesized by reacting the hydrazonoyl chloride derived from 6-aminoquinoline with the appropriate piperazine. The results of the in vitro tests showed that all of the compounds had weak antitumor activity against the tested cell lines, with compounds 10d and 10g exhibiting the most promising activity with IC₅₀ values of 43.1 µM and 59.1 µM against A549 and MCF-7 cell lines, respectively.

Docking on the binding site of the c-Abl kinase enzyme suggests that the mechanism of antitumor effect may be due to the enzyme inhibition, further, ADMET in silico studies showed acceptable pharmacokinetic properties while the most active hits as possibly highly toxic with Daphnia EC₅₀ 0.11 and 0.12 mg/L so further in vivo evaluation of the safety profile is necessary for the development of the new safe, non-carcinogenic lead compounds.

Acknowledgments

The authors would like to express their gratitude to the Deanship of Scientific Research at Zarqa University and the University of Jordan for their generous funding.

Zarqa University’s Scientific Research Department provided funding for Ahmad K. Alarareh’s master’s project under fund code 5-2(3/2021).

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Supplementary materials

Supplementary material 1

Docking, synthesis, and anticancer assessment of novel quinoline-amidrazone hybrids

Ahmad H. Abdullah, Ahmad K. Alarareh, Mahmoud A. Al-Sha’er, Almeqdad Y. Habashneh, Firas F. Awwadi, Sanaa K. Bardaweel

Data type: docx

This dataset is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0). The Open Database License (ODbL) is a license agreement intended to allow users to freely share, modify, and use this Dataset while maintaining this same freedom for others, provided that the original source and author(s) are credited.

Download file (12.58 MB)

Supplementary material 2

Scanned IR, 1H NMR and 13C NMR spectra of all new compounds

Ahmad H. Abdullah, Ahmad K. Alarareh, Mahmoud A. Al-Sha’er, Almeqdad Y. Habashneh, Firas F. Awwadi, Sanaa K. Bardaweel

Data type: docx

This dataset is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0). The Open Database License (ODbL) is a license agreement intended to allow users to freely share, modify, and use this Dataset while maintaining this same freedom for others, provided that the original source and author(s) are credited.

Download file (12.58 MB)

Abstract

Keywords

Introduction

Experimental part

Materials and method

Chemistry

General procedure for the synthesis of N-(quinolin-6-yl)propanehydrazonoyl chloride (8)

General procedure for the synthesis of Amidrazone (10a–l)

1-(Piperazin-1-yl)-1-(2-(quinolin-6-yl)hydrazineylidene)propan-2-one (10a)

1-Morpholino-1-(2-(quinolin-6-yl)hydrazineylidene)propan-2-one (10b)

1-(2-(Quinolin-6-yl)hydrazineylidene)-1-thiomorpholinopropan-2-one (10c)

Ethyl-4-(2-oxo-1-(2-(quinolin-6-yl)hydrazineylidene)propyl)piperazine-1- carboxylate (10d)

1-(4’-(3’’-Hydroxyphenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10e)

1-(4’-(4’’-Nitrosophenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10f)

1-(4’-(2’’-Hydroxyphenyl)piperazin-1-yl)-1-(2-(quinolin-6-yl) hydrazineylidene) propan-2-one (10g)

1-(4’-(4’’-Chlorophenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10h)

1-(4’-Phenylpiperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10i)

1-(4’-(4’’-Hydroxyphenyl)piperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazono)propan-2-one (10j)

1-(4’-Phenylpiperazin-1-yl)-1-(2-(quinolin-6- yl)hydrazineylidene)propan-2-one (10k)

1-(4’-(pyridin-2-yl)piperazin-1-yl)-1-(2-(quinolin-6-yl)hydrazineylidene)propan-2-one (10l)

Molecular modeling

Computational docking

Ligand preparation for LibDock

Toxicity prediction using EC50 Daphnia calculations

Data set

In vitro anticancer screening

Collection of X-ray diffraction data and structure analysis of compound (10b)

Results and discussion

Chemistry

X-ray structure determination of (10b)

Computational docking

Conclusions

Acknowledgments

References

Supplementary materials

Toxicity prediction using EC₅₀ Daphnia calculations