Novel synthesis of 3-(Phenyl) (ethylamino) methyl)-4-hydroxy-2H-chromen-2-one derivatives using biogenic ZnO nanoparticles and their applications Chimica Techno Acta ARTICLE published by Ural Federal University 2022, vol. 9(1), No. 20229104 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.1.04 1 of 16 Novel synthesis of 3-(Phenyl) (ethylamino) methyl)-4- hydroxy-2H-chromen-2-one derivatives using biogenic ZnO nanoparticles and their applications G.C. Anjan Kumar a, Yadav D. Bodke a*, B. Manjunatha a, N.D. Satyanarayan b, B.N. Nippu b, Muthipeedika Nibin Joy c a: Department of PG Studies and Research in Chemistry, School of Chemical Sciences, Kuvempu Uni- versity, 577451 Jnana Sahyadri, Shankaraghatta, Karnataka, India b: Department of Pharmaceutical Chemistry, P.G. Centre, Kuvempu University, 577548 Kadur, Karnataka, India c: Innovation Centre for Chemical and Pharmaceutical Technologies, Institute of Chemical Technology, Ural Federal University, 620002 Mira st., 19, Yekaterinburg, Russia * Corresponding author: ydbodke@gmail.com This article belongs to the Regular Issue. © 2021, The Authors. This article is published in open access form under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract The present work describes the novel synthesis of 3, 3-((phenyl) (ethylamino) methyl)-4-hydroxy-2H-chromen-2-one derivatives cata- lyzed by biogenic ZnO nanoparticles. The synthesized heterocyclic compounds were characterized by fourier-transform infrared spec- troscopy (FT-IR), nuclear magnetic resonance (NMR) and mass spec- trometric techniques. Absorption, distribution, metabolism and ex- cretion properties and various toxicities (ADMET) studies and in sili- co molecular docking studies were carried out for the synthesized compounds. The synthesized compounds were screened for their effi- cacy towards the antioxidant activity and were subjected to corro- sion inhibition study towards the mild steel in acidic medium by weight loss method. Additionally, the recyclability of the employed catalyst was studied. Keywords MCRs biogenic ZnO benzylamino coumarins antioxidant corrosion inhibition Received: 29.11.2021 Revised: 15.01.2022 Accepted: 15.01.2022 Available online: 21.01.2022 1. Introduction In the past decades, the aqueous environment has elicited much consideration in organic synthesis. Water demon- strated unique reactivity and selectivity, which cannot be attained in conventional organic solvents [1]. Multicompo- nent reactions (MCRs) provide the most effective advance in the field of green chemistry and are vital tools in mate- rial, medical and modern synthetic organic chemistry; in particular, for the building of heterocyclic scaffolds. The last two decades were exclusively devoted to MCRs involv- ing three or more precursors to synthesize structurally diverse bioactive heterocyclic compounds [2, 3]. The su- premacy of MCRs are high atom-economy, convergence and structural diversity, operational simplicity of the re- sulting products makes this sustainable approach a potent tool for the synthesis of biologically active molecules and optimization processes in the medicinal industry [4–6]. Coumarin heterocyclic moiety is well regarded as a privi- leged structural motif in abundant natural products and synthetic organic compounds of various pharmacological properties. The 4H-pyran core is a rich source of biologi- cally vital molecules possessing a broad spectrum of bio- logical and pharmacological activities [7]. Pharmacological activities includes neuroprotective agents [8], antimicro- bial agents [9, 10], cardio preventive agents [11], antioxi- dant [12–14], anti-inflammatory agents [15] and an- tituberculating agents [16]. Further, the presence of N and O made them good corrosive inhibitors [17, 18]. Therefore, we tried to synthesize benzyl substituted coumarins via the Mannich type reaction. The Mannich reaction is one of the most powerful synthetic methods for carbon-carbon bond forming reactions for the synthesis of novel nitro- gen-containing organic molecules. Currently, mild steel (MS) finds extensive applications in the industrial handling of alkali, acids, and salt solu- tions. The aggressiveness of these solutions causes brutal corrosion to engineered structures made of MS, which leads to immense economical and material losses. Hence, the study of MS corrosion and its inhibition has attracted http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.1.04 http://creativecommons.org/licenses/by/4.0/ Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 2 of 16 the attention of scientists and authorities to think up ways of overcoming the corrosion. Among the variety of corro- sion control measures, utilization of corrosion inhibitors is a known method. It is identified that corrosion inhibitors act by adsorbing on the metal surface. Compounds having aromatic systems incorporated with N, S, and O heteroa- toms have been found to possess exceptionally potent an- ticorrosion properties. In recent years, due to environ- mental issues, researchers have been functioning on the concept of diminished destructive effects to the environ- ment to avoid the toxic effect of synthetic corrosion inhibi- tors [19–21]. In this regard, several methods have been employed for the synthesis of different corrosion inhibitors for the MS. Earlier methods employed for these types of synthesis suf- fered from many drawbacks such as poor yield, longer reaction time, use of expensive reagents, etc. One of the methods of overcoming these drawbacks is using the metal oxide nanoparticles as catalysts due to their higher sur- face-to-volume ratio of nanoparticles (NPs) which is pre- dominantly responsible for their catalytic properties. In addition, they actas paramount adsorbents for the multi- tude of organic compounds, amplifying the reactivity of the reacting molecules [22, 23]. Synthesis of metal and oxide nanoparticles using plants and their parts is a sustainable method because of its en- vironmental compatibility for pharmaceutical and other biomedical applications. Plants and their parts have emerged as a substitute to chemical synthetic procedures because no complex processes such as intracellular syn- thesis, no several purification steps are involved and no toxic chemicals are used in the synthesis. From the litera- ture survey, among others, ZnO NPs have gained more attention because of their versatile characters like low toxicity, large surface area, high pore volume, low cost, Lewis acidic nature, ecofriendliness, heterogeneous nano- catalytic properties and reusability [24–26]. In the present study, we discussed the synthesis of 3- ((phenyl) (ethylamino) methyl)-4-hydroxy-2H-chromen-2- one derivatives catalyzed by biogenic ZnO NPs by the reac- tion of 4-hydroxy coumarin with aromatic aldehydes and especially with ethylamine as an amine source. The sche- matic pathway is given in Scheme 1. 2. Experimental 2.1. Materials and methods All the chemicals were purchased from Sigma Aldrich, Merck and used as received with no further purifications. Areca nuts were collected from local suppliers near Chan- nagiri, Davanagere and used after washing with double distilled water. UV-Visible spectra were recorded using HR 4000 UV-Vis Spectrophotometer and FT-IR spectra by Al- pha T Brucker instrument. The NMR spectra were record- ed in DMSO with TMS as an internal standard on a Bruck- er Avance DRX 400 MHz spectrometer and chemical shift (δ) values were expressed in parts per million (ppm) units. High-resolution liquid chromatography-Mass Spec- tra (HRMS) were recorded using Water’s SYNAPT G2 QTOF LCMS instrument, and the crystalline structure of ZnO was obtained by X-ray diffractometer (XRD) (Rigaku). The surface morphology and crystallinity were obtained by scanning electron microscopy (SEM), (CIIRC) and the ele- mental analysis of ZnO nanoparticles was conducted by energy dispersive analyzer using X-rays (EDX) (Thermo Scientific Noran 7). Molinspiration Cheminformatics web- based server [27] was used to evaluate drug likeliness; Absorption, distribution, metabolism and excretion prop- erties and various toxicities (ADMET) prediction for all the designed compounds was evaluated using the ADMET de- scriptor module of the ADMET lab Web-based server [28]. Protein Used: Cyclooxygenase cox-2, Classification: Oxi- doreductase and Organism(s): Mus musculus, PDB ID: 1PXX. In silico molecular docking study was also carried out by (ChemBioOffice Ultra 14.0 suite). 2.2. Preparation 2.2.1. Preparation of Areca nut extract mediated ZnO NPs Freshly collected Areca nuts were stripped off their outer layer, washed with double distilled water, dried, and ground well to get a fine powder. To prepare the Areca nut extract, 5 g of Areca nut powder was boiled in water for about 30 min at 80 °C to get the reddish colour solution. Then the extract was filtered and dried under vacuum us- ing a rotary evaporator. O OH O O H O NHOH O + + NH2 1 2(a-h) 3 4(a-h) Where : R = 4-Cl, 4-NO 2 , 3-NO 2 , H, 4-OH, 3-OH, 4-OH 3-OCH 3 , 4-OH 3-OCH 2 CH 3 . R R biogenic Nano ZnO R T, 10 -15 Min Scheme 1 The schematic pathway of synthesis of 3-((phenyl) (ethylamino) methyl)-4-hydroxy-2H-chromen-2-one derivatives Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 3 of 16 The ZnO NPs were prepared by solution combustion method. In brief, 10 mL of Areca nut extract and 0.5 g of zinc nitrate hexahydrate Zn(NO3)26H2O were weighed in a silica crucible and placed in a preheated muffle furnace maintained at 500 °C. An exothermic vigorous reaction leads to the formation of fine, white ZnO NPs. The ob- tained product was kept in a sealed container for further analysis [29]. 2.3. Characterization of prepared nanomaterials 2.3.1. UV-Vis Spectroscopy The UV-Vis absorption spectrum of ZnO nanoparticles was recorded between the wavelength of 200 and 800 nm and is presented in Fig. 1. The spectrum showed the absorb- ance peak at 293 nm corresponding to the characteristic band of zinc oxide nanoparticles. The bandgap energy (E) is calculated using the following equation: 𝐸 = ℎ𝐶  , (1) where ℎ is the Planks constant, 6.62610−34 Js, C is the velocity of light, 3.0108 m/s, and 𝜆 is the wavelength (nm). The bandgap of ZnO NPs was found to be 3.15 eV. Fig. 1 UV-Vis Spectrum of ZnO NPs 2.3.2. FT-IR spectroscopy The FT-IR spectrum of ZnO was recorded in the range of 400–4000 cm−1 and is presented in Fig. 2. The peaks at 3450.46 cm−1 and 1636.48 cm−1 are due to the stretching and bending vibration of the OH functionality. The peak at 1382.97 cm−1 is due to stretching vibrations of Zn–O–ZnO, and the peak between 700–400 cm−1 is due to stretching vibration of Zn–O. 2.3.3. X-Ray diffraction studies The powder X-Ray Diffraction (P-XRD) pattern of pre- pared ZnO NPs is presented in Fig. 3. It indicates the phase purity and structural parameters of ZnO. The XRD peaks are observed in the wide-angle range of 2θ (10°<2θ<80°). Fig. 2 FT-IR Spectrum of ZnO NPs The reflections from (100), (002), (101) and (110) planes suggested that the synthesized nanoparticle s pos- sess hexagonal symmetry, which was further confirmed from the JCPDS No.: 01-089-0510. The crystallite size (D) can be determined by Scherrer’s formula: 𝐷 = 𝐾 c𝑜𝑠 (2) where 𝜆 is the wavelength of X-ray radiation (Cu K𝛼 = 0.15406 nm), K is a constant taken as 0.90, β is the line width at half-maximum height (FWHM) of the peak and θ is the diffracting angle. The (100) plane is cho- sen to calculate the crystallite size. The average crystallite size for the synthesized ZnO NPs was found approximately 12 nm from this Debye-Sherrer equation 2. Fig. 3 XRD pattern of synthesized ZnO 2.3.4. SEM and EDX The surface morphology of the prepared ZnO NPs was studied using scanning electron microscopic (SEM) tech- nique; it showed that the particles were in spherical shape, as shown in Fig. 4. The Energy-dispersive X-ray spectroscopic (EDX) study was carried out for the pre- pared ZnO NPs to identify the elemental composition. EDX confirms the existence of zinc and oxygen signals of ZnO NPs as shown in Fig. 5. Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 4 of 16 Fig. 4 SEM image of synthesized ZnO Fig. 5 EDX analysis of synthesized ZnO The elemental analysis of the nanoparticle yielded 50.54% of zinc and 49.46% of oxygen, as shownin Table 1. Table 1 The elemental analysis of synthesized nanoparticle Element line Weight % Weight % error Atom % Atom % error O 20.00 ±1.43 50.54 ±3.61 Zn – – – – Zn 80.00 ±3.36 49.46 ±2.08 Total 100.00 100.00 2.4. Synthetic procedure for 3-((phenyl) (ethyla- mino) methyl)-4-hydroxy-2H-chromen-2-one derivatives A mixture of 4-hydroxy coumarin (1 mmol) 1, aromatic aldehydes (1 mmol) 2, ethylamine (1 mmol) 3, and bio- genic ZnO nanoparticles (5 mol.%) was taken in a round-bottom flask containing 10 mL water and stirred at room temperature. After the completion of the reac- tion (checked by thin-layer chromatography (TLC)), the reaction mixture was quenched in water, the solid com- pound obtained was filtered off, and the crude product was purified by recrystallization from EtOH. 2.4.1. 3-[(4-Chlorophenyl) (ethylamino) methyl]-4- hydroxy-2H-chromen-2-one: 4a White solid, Yield: 98%. m.p. 189–191 °C; FT-IR (KBr) in cm–1: 3431 (O–H), 3137 (N–H), 2983 (Ar–H), 2708 (Ali- phatic C–H) 1706 (C=O), 1604, 1518 (C–N), 756 (C–Cl). 1H NMR (400 MHz, DMSO-d6): δ: 10.20 (s, 1H, OH), 9.30 (s, 1H, NH), 8.54 (s, 1H, Ar–H), 8.22–8.20 (d, 1H, J = 8.0 Hz, Ar–H), 8.15–8.13 (d, 1H, J = 8.0 Hz, Ar–H) 8.01–7.99 (t, 1H, J = 8.0 Hz, Ar–H) 7.87–7.79 (m, 3H, Ar–H), 7.65–7.61 (t, 1H, J = 8.0 Hz, Ar–H),7.55 (s, 1H, Ar–H), 7.51–7.40 (m, 1H, Ar–H), 5.52 (s, 1H, Aliphatic H), 2.95–2.65 (q, 2H, J = 12.0 Hz, CH2), 1.19 (t, 3H, J = 8.0 Hz, CH3) ppm. 13C NMR (100 MHz, DMSO-d6): 173.92 (C=O), 163.79, 154.23, 148.07, 147.33, 146.58, 141.39, 134.69, 131.44, 130.32, 128.83, 124.84, 123.25, 122.96, 116.37, 91.56, 58.35, 11.52 ppm. HRMS (ESI) m/z = 330.06 [M]+; Mol. Formula: C18H16ClNO3. Calcd: for C 65.56, H 4.89 and N 4.25. Found: C 65.60, H 4.90 and 4.20. 2.4.2. 3-[(Ethylamino) (4-nitrophenyl) methyl]-4- hydroxy-2H-chromen-2-one: 4b Yellow solid, 95%. m.p. 315–317 °C; FT-IR (KBr) in cm–1: 3418 (O–H), 3063 (N–H), 2986 (Ar–H), 2803 (Aliphatic C–H) 1634 (C=O), 1602, 1519 (C–N), 1348 (N–O). 1H NMR (400 MHz, DMSO-d6): δ: 10.06 (s, 1H, OH), 9.98 (s, 1H, NH), 8.90 (s, 1H, Ar–H),7.84 (d, 1H, 8.0 Hz, Ar–H), 7.62 (d, 2H, J = 8.0 Hz, Ar–H), 7.43–7.39 (t, 3H, Ar–H), 7.17–7.12 (q, 2H, J = 8.0 Hz, Ar–H), 5.34 (s, 1H, Aliphatic H) 2.92 (q, 2H, J = 8.0 Hz), 1.12 (t, 3H, J = 7.9 Hz, CH3), ppm. 13C NMR (100 MHz, DMSO-d6): 173.83 (C=O), 163.75, 154.19, 138.29, 132.99, 131.31, 129.91, 128.70, 124.78, 123.93, 122.84, 122.57, 116.37, 91.96, 58.70, 11.53 ppm. HRMS (ESI) m/z = 342.16 [M+1]; Mol. Formula: C18H16N2O5. Calcd: for C 63.52, H 4.74 and N 8.23. Found: C 63.90, H 4.67 and 8.20. 2.4.3. 3-[(Ethylamino) (3-nitrophenyl) methyl]-4- hydroxy-2H-chromen-2-one: 4c Light yellow solid, Yield: 94%. m.p. 310–312 °C; FT-IR (KBr) in cm–1: 3421 (O–H), 3067 (N–H), 2985, (Ar–H), 2808 (Aliphatic C–H) 1630 (C=O), 1606, 1524 (C–N), 1348 (N–O). 1H NMR (400 MHz, DMSO-d6):): δ: 9.91 (s, 1H, OH), 9.06 (s, 1H, NH), 8.53 (s, 1H, Ar–H), 8.12 (d, 1H, J = 12.0 Hz, Ar–H), 7.99 (d, 1H, J = 8.0 Hz, Ar–H), 7.83–7.81 (t, 1H, J = 7.9 Hz, Ar–H), 7.62 (s, 1H, Ar–H), 7.40 (s, 1H, Ar–H), 7.13 (t, 2H, J = 8.0 Hz, Ar–H), 5.52 (s, 1H, Aliphatic CH), 2.95 (q, 2H, J = 8.0 Hz, CH2), 1.19 (t, 3H, J = 8.0 Hz, CH3) ppm. 13C NMR (100 MHz, DMSO-d6): 173.99 (C=O), 163.87, 154.32 148.15 141.49 134.80, 131.56, 130.44, 124.94, 123.37, 123.07, 122.66, 122.58, 116.49, 91.65, 58.38, 11.62, 1.70 ppm. HRMS (ESI) m/z =341.16 [M]+; Mol. Formula: C18H16N2O5. Calcd: for C 63.49, H 4.70, and N 8.23. Found: C 63.90, H 4.64 and 8.12. 2.4.4. 3-[(Ethylamino) (phenyl) methyl]-4-hydroxy-2H- chromen-2-one: 4d White solid, 93%. m.p. 274–276 °C; FT-IR (KBr) in cm–1: 3419 (O–H), 3158, (N–H), 2981 (Ar–CH), 1634 (C=O), 1608, 1497 (C–N). 1H NMR(400 MHz, DMSO-d6): δ: 10.59 (s, 1H, OH), 9.42 (s, 1H, NH), 7.82–7.79 (q, 1H, J = 8.0 Hz, Ar–H), 7.59–7.56 (t, 2H, Ar–H), 7.31–7.25(q, 3H, J = 8.0 Hz, Ar–H), 7.13–7.09 (m, 2H, J = 8.0 Hz, Ar– H), 5.28 (s, 1H, Aliphatic CH), 2.90 (q, 2H, J = 7.2 Hz, CH2), 1.15 (t, 3H, J = 8.0 Hz, CH3) ppm. 13C NMR (100 MHz, Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 5 of 16 DMSO-d6): 173.88 (C=O), 163.84, 154.26, 139.53, 131.36, 128.88, 128.48, 128.11, 124.84, 122.97, 122.68, 116.39, 92.28, 59.49, 11.63 ppm. HRMS (ESI) m/z = 296.11 [M]+; Mol. Formula: C18H17NO3. C 73.20, H 5.80 and N 4.74. Found: C 75.40, H 5.90 and 4.70. 2.4.5. 3-[(Ethylamino) (4-hydroxyphenyl) methyl]-4- hydroxy-2H-chromen-2-one: 4e White solid, 90% m.p. 245–247 °C; FT-IR (KBr) in cm–1: 3409 (O–H), 3081 (N–H), 2987 (Ar–CH), 1638 (C=O), 1602, 1510 (C–N), 756. 1H NMR (400 MHz, DMSO-d6): δ: 9.74 (s, 1H, OH), 9.46 (s, 1H, NH), 8.92 (s, 1H, Ar–H), 7.82 (m, 1H, J = 12.0 Hz, Ar–H), 7.37–7.35 (d, 3H, J = 8.0 Hz, Ar–H), 7.12–7.10 (d, 2H, Ar–H), 6.69 (d, 2H, J = 8.4 Hz) 5.15 (s, 1H, Aliphatic CH), 2.88 (q, 2H, J = 8.0 Hz, CH2), 1.14 (t, 3H, J = 12.0 Hz, CH3) ppm. 13C NMR (100 MHz, DMSO-d6): 173.89 (C=O), 163.84, 157.85, 154.24, 140.75, 131.36, 129.87, 124.83, 122.98, 118.73, 116.39, 115.46, 115.04, 92.21, 59.58, 11.64 ppm. HRMS (ESI) m/z = 311.09 [M]+; Mol. Formula: C18H17NO4. Calcd. for C 69.44, H 5.50 and N 4.50. Found: C 69.49, H 5.44 and 4.46. 2.4.6. 3-[(Ethylamino)(3-hydroxyphenyl) methyl]-4- hydroxy-2H-chromen-2-one: 4f White solid, 91%. m.p. 237–239 °C; FT-IR (KBr) in cm–1: 3452 (O–H), 3108 (N–H), 2875 (Ar–CH), 1649 (C=O), 1616, 1516 (C–N). 1H NMR (400 MHz, DMSO-d6): δ: 10.31 (s, 1H, OH), 9.47 (s, 1H, NH), 8.83 (s, 1H, J = 7.6 Hz, Ar–H), 7.88 (d, 1H, J = 8.0 Hz, Ar–H),7.48 (m, 1H, Ar–H), 7.22–7.14 (m, 3H, J = 8.0 Hz, Ar–H), 7.07 (q, 2H, J = 7.9 Hz), 6.72–6.70 (t, 1H, Ar–H), 5.25 (s, 1H, Aliphatic H), 2.96–2.91 (q, 2H, J = 7.2 Hz, CH2), 1.22 (t, 3H, J = 7.2 Hz, CH3) ppm. 13C NMR (100 MHz, DMSO-d6): 173.34 (C=O) 163.27 157.30, 153.69, 140.18, 130.77, 129.29, 124.26, 122.39, 118.19, 115.82, 115.41, 114.92, 114.50, 91.64, 59.12, 11.09 ppm. HRMS (ESI) m/z = 311.97 [M]+; Mol. Formula: C18H17NO4. Calcd. for C 69.44, H 5.50, and N 4.50. Found: C 69.40, H 5.54 and 4.43. 2.4.7. 3-[(Ethylamino) (4-hydroxy-3-methoxyphenyl) methyl]-4-hydroxy-2H-chromen-2-one: 4g White solid, 90%. m.p. 235–237 °C; FT-IR (KBr) in cm–1: 3435 (O–H), 3098 (N–H), 2856 (Ar–CH),1649 (C=O), 1606, 1539 (C–N). 1H NMR (400 MHz, DMSO-d6): δ: 10.07 (s, 1H, OH), 9.05 (s, 1H, NH), 8.72 (s, 1H, Ar–H), 7.88 (d, 1H, J = 8.0 Hz, Ar–H), 7.48–7.44 (m, 1H, Ar–H), 7.27 (d, 1H, J = 2.0 Hz, Ar–H), 7.21–7.15 (m, 2H, J = 7.8 Hz, Ar–H), 7.00 (d, 1H, J = 8.0 Hz, Ar–H), 6.71 (d, 1H, Ar–H), 5.22 (s, 1H, Aliphatic CH), 3.76 (s, 3H, CH3), 2.92–2.87 (q, 2H, J = 7.8 Hz, CH2), 1.21 (t, 3H, J = 12.0 Hz, CH3) ppm. 13C NMR (100 MHz, DMSO-d6): 173.29 (C=O), 163.31, 153.67, 152.84, 147.25, 146.55, 130.68, 129.63, 124.28, 122.34, 120.57, 115.78, 115.08, 112.40, 92.00, 59.13, 55.69, 11.10 ppm. HRMS (ESI) m/z = 341.09 [M]+; Mol. Formula: C19H19NO5. Calcd: for C 66.85, H 5.61 and N 4.10. Found: C 66.80, H 5.56 and 4.06. 2.4.8. 3-[(3-Ethoxy-4-hydroxyphenyl) (ethylamino) methyl]-4-hydroxy-2H-chromen-2-one: 4h White solid, 90%. m.p. 288–290 °C; FT-IR (KBr) in cm–1: 3452 (O–H), 3111 (N–H), 2856 (Ar–CH), 1649 (C=O), 1632, 1513 (C–N). 1H NMR (400 MHz, DMSO-d6): δ: 10.04 (s, 1H, OH), 8.99 (s, 1H, NH), 8.77 (s, 1H, Ar–H), 7.89 (d, 1H, J = 8.0 Hz, Ar–H), 7.48 (t, 1H, J = 7.90 Hz, Ar– H), 7.27 (s, 1H, Ar–H), 7.21–7.15 (q, 2H, J = 8.0 Hz, Ar–H), 7.00 (d, 1H, J = 8.0 Hz, Ar–H), 6.76 (s, 1H, J = 8.0 Hz, Ar– H), 5.22 (s, 1H, Aliphatic CH), 4.03–3.97 (q, 2H, J = 8.0 Hz, CH2),2.93–2.87 (q, 2H, J = 8.0 Hz, CH2), 1.35–1.31 (t, 3H, J = 8.0 Hz, CH3), 1.22 (t, 3H, J = 8.0 Hz, CH3), ppm. 13C NMR (100 MHz, DMSO-d6): 173.28 (C=O), 163.33, 153.67, 152.45, 146.89, 146.38, 130.69, 129.63, 124.29, 122.36, 120.65, 115.79, 115.18, 113.81, 92.07, 64.08, 59.06, 14.76, 11.10 ppm. HRMS (ESI) m/z = 340.09 [M]+; Mol. Formula: C20H21NO5. Calcd: for C 67.59, H 5.96 and N 3.94. Found: C 67.53, H 5.90 and 3.92. 3. Results and discussion 3.1. Chemistry The structure of synthesized compounds was characterized by using different spectroscopic techniques such as UV-Vis, FT-IR, 1H NMR, 13C NMR and HRMS. The FT-IR spectrum of the compound 4a showed strong absorption bands at 756 cm–1 due to the chlorine atom attached to the benzene ring, 1529 cm–1 and 1518 cm–1 due to C–N, 1706 cm–1 due to C=O functionality of coumarin ring, 2708 cm–1 due to aliphatic –CH, 2983 cm–1 due to aromatic CH, 3137 cm–1 due to N–H and 3431 cm–1 due to –OH functionality. The 1H NMR spectrum of the compound 4a showed a singlet at δ 10.20 due to the OH proton and another singlet at δ 9.30 ppm due to the NH pro- ton. The multiplet appeared between δ 7.12–8.50 ppm is due to the presence of aromatic protons. It also displayed a sin- glet at δ 5.50 ppm due to the –CH proton. In the HRMS spec- trum of the compound 4a, it showed a molecular ion peak M+ at m/z 330.0664, which is close to its molecular weight. The reaction of 4-hydroxy coumarin (1), aromatic alde- hyde (2(a–h)), and ethylamine (3) achieved the desired product 3-((phenyl) (ethylamino) methyl)-4-hydroxy-2H- chromen-2-one (4(a–h)) by using biogenic ZnO NPs in green solvent (Scheme 1). Initially, to come across the finest conditions, screen- ing was performed with solvent-free and a variety of polar and nonpolar solvents like DMSO, DMF, ethanol, methanol, toluene, tetrahydrofuran, acetonitrile, ethanol, methanol, polyethylene glycol and water, as shown in Table 2. We observed that the polar protic solvents afforded better yield than other solvents, and in water (Table 2, Entry 11) the supreme catalytic activity of biogenic nano ZnO was observed. Further, we were concentrated on the efficient assess- ment of various catalysts for the model reaction in an aqueous medium at room temperature. Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 6 of 16 Table 2 Effect of solvents on the three-component synthesis of benzylamino coumarin derivative 4a Entry Solvents Yield a (%) 1 No solvent – 2 Toluene 43 3 Tetrahydrofuran 46 4 Acetonitrile 54 5 DMSO 63 6 DCM 61 7 DMF 56 8 Ethanol 79 9 Methanol 75 10 Polyethylene glycol (PEG) 80 11 H2O 98 a Isolated yield A wide variety of catalysts, including L-proline, alum, tetrabutylammonium bromide, nano aluminum oxide (Al2O3), zeolites, bulk ZnO and biogenic ZnO NPs, were employed to study their efficacy for the synthesis of ben- zyl amino coumarins. 68% yield of product was obtained in 4 h by using bulk ZnO and the results are presented in Table 3 which illustrats that the presence of biogenic nano ZnO has given the products with 98% yield within 10–15 min. Therefore, this catalyst appeared to be of bet- ter quality than any of the other catalysts. Table 3 Influence of different catalysts on the synthesis of ben- zylamino coumarin derivative 4a Entry Catalysts Time (h) Yield a (%) 1 L-proline 6.0 45 2 Alum 8.0 30 3 Acetic acid 4.5 60 4 Bi(NO3)35H2O 1.45 94 5 Tetrabutylammonium bromide 6.0 25 6 Nano aluminium oxide (Al2O3) 8.0 26 7 Zeolites 7.0 35 8 Bulk ZnO 4.0 68 9 Biogenic ZnO NPs 10–15 min 98 a Isolated yield After the selection of catalyst, we have concentrated on the amount of the catalyst to be used by varying the mole ratio of the biogenic ZnO NPs.Table 4 displays the differ- ent mole ratios of catalyst employed on the model reac- tion. It shows unambiguously that the enhancement of catalyst load from 3 to 15 mol.%, amplified the yield of the desired product to a large extent (38–98%). Table 4 Optimization of catalyst loading on model reaction Entry Catalysts Yield a (%) 1 Nano-ZnO (3 mol.%) 38 2 Nano-ZnO (5 mol.%) 98 3 Nano-ZnO (7 mol.%) 92 4 Nano-ZnO (10 mol.%) 90 5 Nano-ZnO (15 mol.%) 85 6 Nano-ZnO (5 mol.%) + L-Proline 65 7 Nano-ZnO (5 mol.%) + p-toluenesulphonic acid (5 mol.%) 15 8 Nano-ZnO (5 mol.%) + Methanesulphonic acid (5 mol.%) 29 9 Nano-ZnO (5 mol.%) + boric acid (5mol.%) 25 10 Nano-ZnO (5 mol.%) + Tetrabu- tylammonium bromide (5 mol.%) 30 a Isolated yield of the pure product Again, it also observed that no other additive combina- tions like protic or lewis acids are at all beneficial in this method. These groundwork results encouraged us to advance the applicability of the catalyst for the synthesis of couma- rin derivatives. To study the possibility and limitations of this protocol, we engaged a series of aromatic aldehydes with ethylamine to get the resultant BAC. In view of these results, we propose a mechanistic interpretation for the high catalytic activity of biogenic nanocrystalline ZnO, especially in aqueous media. The nano ZnO catalyst-water colloidal combination plays vital accountability for the swift formation and stabilization of the imine intermedi- ate. The catalyst may encourage 4-hydroxy coumarin to act as the Mannich donor for the rapid formation of ben- zylamino coumarin derivatives. The swift imine genera- tion and subsequent C–C bond development within a very little instant catalyzed by amphoteric nano ZnO (colloidal composite) are the striking features of this protocol. To generalize this method, the reaction was studied us- ing different aromatic aldehydes and the results are ap- pended in Table 5. Aromatic aldehydes with different sub- stitutions underwent smooth reactions with ethylamine and 4-hydroxycoumarin, furnishing the respective prod- ucts in good yields and considerably shortened reaction time in comparison with the previously reported methods. However, under the same conditions, when the aliphatic aldehydes were used as starting materials, for up to 12 h we could not observe any products, but after 14 h, traces of biscoumarin were observed. Table 5 Optimization of the model reaction Entry Aldhyde Amine Product Time (min) Yield a % M.P. (°C) 1 4Cl CH3CH2NH2 4a 15 98 189–191 2 4–NO2 CH3CH2NH2 4b 10 95 315–317 3 3–NO2 CH3CH2NH2 4c 10 94 310–312 4 H CH3CH2NH2 4d 15 93 274-276 5 4–OH CH3CH2NH2 4e 15 90 245–247 6 3–OH CH3CH2NH2 4f 10 91 237–239 7 4–OCH3 CH3CH2NH2 4g 10 90 235–237 8 4–OH, 3–OCH3 CH3CH2NH2 4h 15 90 288–290 Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 7 of 16 Fig. 6 Electronic spectra of synthesized compounds in different solvents Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 8 of 16 Further, the same reaction was performed using aro- matic amines, but no detectable products were obtained and this may be due to the low solubility of aromatic amines in water. 3.2. Absorption studies The UV–Vis absorption spectra of compounds 4(a–h) were recorded in various solvents and the effect of solvent polarity and the electronic substitution were studied at a concentration of 10–5 M at room temperature. The typical absorption spectra are displayed in Fig. 6. The absorption maxima (λmax) and its corresponding logarithmic molar extinction coefficient (intensity of the absorption) for all the compounds in studied solvents were obtained from the plot and summarized in Table 6 and Table 7, respectively. The electronic spectra of the synthesized compounds 4(a–h) showed broad peaks in the region 300–325 nm due to π→π* transitions respectively and additional peaks from 420–510 nm appeared in these compounds were owing to the interaction of attached electron-donating groups (4–OH, 3–OH, OCH3, and 4–OH OCH3) with polar solvent due to n→π*. From the close examination of the spectral data (Ta- ble 6), it can be noted that as the solvent polarity increases, the absorption maxima shift towards a longer wavelength so that the bathochromic shift is observed in all the com- pounds. This may be due to the effective interaction be- tween the solvent molecules and the lone pair of electrons present on the electron-donating sites of synthesized com- pounds. The presence of electron-donating substituents on the aromatic ring group also contributes to the batho- chromic shift. This study concludes that solvent polarity and electronic substitution played a very important role in the shift of λmax for all the studied compounds. Table 6 The electronic spectral data of the compounds (4(a–h)) in different solvents Compounds max (nm) CHCl3 DCM DMF DMSO ACN MeOH 4a 312 317 306 310 312 314 4b 309 317 314 321 312 316 4c 308 315 316 316 311 315 4d 306 317 311 314 311 316 4e 310 311 311 311 308 315 4f 308 310 311 319 308 315 4g 308 314 312 320 312 315 4h 306 315 314 312 312 317 3.3. In silico molecular docking studies 3.3.1. Drug Likeness (Molinspiration Physicochemical Parameters) Molinspiration software was used to predict the physico- chemical parameters of synthesized compounds 4(a–h) like drug-likeliness activities and it is used to make sure whether the synthesized compounds are alike to existing drugs. Drug-likeliness measurements were governed by the famous rule called Lipinski’s rule of five and drug- likeliness data were useful to study the pharmacokinetic parameters like absorption, distribution, metabolism, and excretion from the living body [30, 31]. The computed val- ues are tabulated in Table 8. All the compounds exhibited fine physicochemical parameters: enough number of rota- tional bonds, which would illustrate good flexibility. Fur- ther, the ample number of H-donors and H-bond acceptors of the synthesized compounds exhibited strong binding with target molecules. The good absorption values from computed data uncovered by all the synthesized com- pounds and so can easily be absorbed by the living sys- tems. The % ABS was calculated by using the formula % ABS = 109–(0.345 x TPSA). All the synthesized compounds showed good absorption, i.e., % ABS = 60.5482–76.3561 which ranges from considerable to good range. Also, we calculated the hydrophilicity values of the octanol-water partition coefficient (milogP), which indicates toxicity, absorption, and drug-receptor interactions. The data range of milogP for the synthesized compounds is from 1.05 to 2.19. This range is less than 5.0 and showed good concur- rence as per Lipinski’s rule. Also, the number of H-bond acceptors ranges from 2–5 for synthesized compounds that are less than 10, and the number of H-bond donors for all synthesized compounds is 2 and thus, less than 5 as per the rule. According to the Lipinski (Pfizer's rule) of five for any chemical compound, as an oral drug would be bio- logically active if it does not violate more than one rule out of the proposed rules wherein, the first rule said, the octanol-water partition coefficient (milogP) must be ≤5; the second rule said, the molecular weight of the probable drug must be <500 Daltons; the third rule said, taking into consideration of the number of H-bond acceptors in the molecule under consideration must be ≤10 and the last rule said, the number of H-bond donors must be ≤5 [32, 33]. Table 9 disclosed bioactivity results, showing that the parameters of all the synthesized compounds were within limits of Lipinski’s rule of five with no viola- tion of rules. Thus, all the synthesized molecules 4(a–h) possessed good drug-like properties. 3.3.1.1. ADMET Studies ADMET prediction for all the designed compounds was evaluated using the ADMET descriptor module of the ADMET lab Web-based server [34]. Various ADME de- scriptors like LogS, LogP, intestinal absorption, Caco-2 Permeability, Plasma Protein binding Percentage, CNS Blood-Brain Barrier, cytochrome P450 models, and toxici- ty descriptors like Hepatotoxicity, Mutagenicity, LD50 val- ue, Half-life and Clearance of the drug were used to predict properties related to pharmacokinetics. The synthesized compounds were subjected to study their toxicity before their application. All of them mod- erately toxic, having a lower value of LD50 compared to the standard (LD50  500 mg/kg indicate high toxicity, LD50 500 to 1000 mg/kg indicates reasonable toxicity. LD50 1000 to 2000 mg/kg shows low toxicity). The LD50 values are listed in Table 10. Chimica Techno Acta 2022, vol. 9(1), No. 20229104 ARTICLE 9 of 16 Table 7 logarithmic molar extinction coefficient of studied compounds 4(a–h) Compounds Logarithmic molar extinction coefficient (L M–1 cm) CHCl3 DCM DMF DMSO ACN MeOH 4a 6.1373 6.1781 6.0047 6.1401 6.0955 6.0812 4b 6.1586 6.1522 6.1078 6.2848 6.1251 6.1303 4c 6.1565 6.0820 6.1945 6.2219 6.1115 6.1414 4d 6.0996 6.1473 5.8356 6.2151 6.1878 6.1559 4e 6.1705 5.9934 6.0224 6.1338 5.8509 6.1489 4f 6. 1728 6.1489 5.9925 6.2798 6.1065 6.0989 4g 5.9929 5.9929 5.9661 6.2846 6.1061 6.1075 4h 6.1051 6.1051 6.1287 6.1120 6.1146 6.1146 Table 8 Drug-likeliness results of the synthesized compounds 4(a–h) Compound MW g/mol logP nHA nHD TPSA nViolations 4a 329.080 3.465 4 2 62.470 0 4b 340.110 2.634 7 2 105.610 0 4c 340.110 2.617 7 2 105.610 0 4d 295.120 2.633 4 2 62.470 0 4e 311.120 2.903 5 3 82.364 0 4f 311.337 2.903 5 3 82.723 0 4g 341.363 2.912 6 3 91.931 0 4h 355.391 3.302 6 3 91.931 0 Table 9 ADMET results of the synthesized compounds 4(a–h) Ligands a LogS (Log mol/l) b PCaco (cm/s) c Intetstinal absorp- tion(HIA) in % d logPGI (inhibi- tor) e logPGI Sub- strate f logBB Probability g Plasma protein binding in % h CYP450 2D6 inhib- itor i P450 CYP2D6 substrate 4a –3.469 –4.930 63.1 NI NS 0.896 95.668 NI NS 4b –3.370 –4.953 45.8 NI NS 0.773 95.378 NI NS 4c –3.198 –4.975 45.8 NI NS 0.696 93.374 NI NS 4d –2.881 –4.930 60.0 NI NS 0.888 91.289 I NS 4e –2.781 –5.004 40.5 NI NS 0.735 93.256 NI NS 4f –2.624 –5.079 44.5 NI NS 0.656 85.096 NI NS 4g –2.800 –5.036 34.9 NI NS 0.676 87.738 I NS 4h –3.083 –4.949 29.2 NI NS 0.593 91.268 NI NS Ibuprofen –3.736 –4.379 85.7 NI NS 0.991 87.592 NI NS a Predicted aqueous solubility (Optimal level – higher than – 4 log mol/L); b Predicted Caco-2 cell permeability (cm/s) (Optimal level higher than –5.15); c Predicted Human intestinal absorption in % ( acceptable level ≥30%); d Predicted P-glycoprotein inhibitor (I – Inhibitor, NI – Non Inhibitor); e Predicted P-glycoprotein substrate (S – Substrate, NS – Non-substrate); f Blood/brain barrier prob- ability (acceptable value >=0.1 is acceptable, <0.1 is poor ); g Plasma protein binding (optimal level greater than 90% drugs that are highly protein-bound and have a low therapeutic index); h CYP450 2D6 inhibitor (I-Inhibitor, NI-Non-Inhibitor); I P450 CYP2D6 sub- strate (S – Substrate, NS – Non-substrate). Table 10 Toxicity evaluation designed molecules 4(a–h) Ligands a T ½ half life (h) b Clearance (L/min/kg) c LD50 (mg/kg) d Human Hepatotoxicity e AMES toxicity 4a 1.910 1.690 811.387 Yes No 4b 1.625 1.753 911.815 Yes Yes 4c 1.564 1.754 790.509 Yes Yes 4d 2.070 2.078 708.467 Yes No 4e 1.760 2.348 692.199 Yes No 4f 2.249 2.324 658.007 Yes No 4g 1.578 2.086 616.902 Yes No 4h 1.690 2.140 577.704 Yes No Ibuprofen 0.801 0.536 2555.452 Yes No a Half life in hour (Optimal level >0.5 h, >8 h – high, < 3h – low); b Clearance of drug in mL/min/kg (>15 mL/min/kg – high; 5mL/min/kg