Synthesis, antimicrobial, antioxidant, and ADMET studies of quinoline derivatives European Journal of Chemistry 12 (1) (2021) 37-44 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2021 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.12.1.37-44.2038 European Journal of Chemistry View Journal Online View Article Online Synthesis, antimicrobial, antioxidant, and ADMET studies of quinoline derivatives Santhosha Sangapurada Mahantheshappa , Harishkumar Shivanna and Nayak Devappa Satyanarayan * Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur-577548, Chikkamagaluru Dt. Karnataka State, India santhosh.1507@rediffmail.com (S.S.M.), harianubupp@gmail.com (H.S.), satya1782005@gmail.com (N.D.S.) * Corresponding author at: Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur-577548, Chikkamagaluru Dt. Karnataka State, India. e-mail: satya1782005@gmail.com (N.D. Satyanarayan). 10.5155/eurjchem.12.1.37-44.2038 Received: 31 August 2020 Received in revised form: 10 January 2021 Accepted: 15 January 2021 Published online: 31 March 2021 Printed: 31 March 2021 The synthesis, antimicrobial, and antioxidant activities of new quinoline analogs were carried out with the aim to find possible hits/leads that can be taken up for future drug development. A series of 2-amino-N’-((2-chloroquinolin-3-yl)methylene)acetohydrazide derivatives (6a-h) have been synthesized by reacting 2-chloro-N’-((2-chloroquinolin-3- yl)methylene)acetohydrazide (5a) and N’-((6-bromo-2-chloroquinolin-3-yl)methylene)-2- chloroacetohydrazide (5b) with secondary amines (Morpholine, diethylamine, piperidine and 1-methylpiperazine). The characterization was achieved by FT-IR, 1H NMR, 13C NMR, and mass spectral analysis. The in silico ADMET studies of the synthesized molecules were analyzed for their drug likeliness and toxic properties. The ADMET study indicates that the synthesized compounds were found to be possessing reliable ADME properties and are nontoxic. The antimicrobial properties were tested against bacterial and fungal species with amoxicillin and fluconazole as standard drugs. The compounds 6a, 6c, 6e, and 6g exhibited good antibacterial potency against P. aeruginosa, and the compounds 6a, 6f, and 6h have shown good activity against E. coli with 1000 µg/mL. The compounds 6b, 6c, and 6e have moderate activity against fungal species C. oxysporum and the compounds 6c, 6e, 6f, 6g, and 6h have good activity against P. chrysogenum. Synthesized compounds were also tested for the DPPH· free radical scavenging activity to check the antioxidant potential, and the results revealed that the compounds 6a, 6b, 6c, and 6e have exhibited antioxidant potency than the remaining synthesized derivatives. The possible hits generated from biological activity could be taken for the generation of lead molecules for the drug discovery of antimicrobial and antioxidant entities from quinoline. DPPH ADMET Acetohydrazide Antioxidant activity Antimicrobial activity 2-Chloroquinoline-3-carbaldehyde Cite this: Eur. J. Chem. 2021, 12(1), 37-44 Journal website: www.eurjchem.com 1. Introduction The reports from the World Health Organization (WHO) indicate that public health has a major concern due to population explosion and an increase in widespread epidemic diseases. Genomic studies on various microorganisms have shown that prolonged use of antibiotics makes these micro- organisms more resistant against them [1]. The literature investigation reveals that a number of quinoline derivatives possess antileishmanial [2], cytotoxicity [3,4], antibacterial, anti-tuberculosis [5], antimalarial [6,7], anti-inflammatory [8] and HIV-1 integrase activities [9]. Quinoline derivatives have been developed for the treatment of many diseases like malaria [10], HIV [11], tumor [12], and antibacterial infections [13]. The hydrazide analogs with azomethine (-CONHN=CH-) functionality were found to exhibit prominent pharmacological and biological activities [14,15] and antagonistic to inflame- matory [16]. The in vitro metabolic studies suggested that the hydrazide hydrazone functionality can easily undergo hydrolytic reactions, which is a benefit to treat various life- threatening diseases [17,18]. Hydrazide hydrazone’s are the most essential intermediates to build various heterocyclic rings utilizing the hydrogen segment of -CONHN=CH azomethine group [19]. The fast-growing microbial immunity to conven- tional anti-infectious agents has necessitated the continuing search for new classes of compounds with novel methods of antimicrobial activity [20-22]. The study depicts that the compound 2-(7-fluoro-2-methoxyquinolin-8-yl)acetohydrazide hydrazone derivatives exhibit good antibacterial activity [23]. Eswaran et. al. have reported the synthesis and investigation of antibacterial properties of 1-(2,8-bis(trifluoromethyl)quinolin- 4-yl)-4-methylsemicarbazide derivatives which showed promising antibacterial activity [24]. The substance 2-chloroquinoline-3-carbaldehyde was prepared by the Vilsmeier-Haack formylation method, the advanced part of this 2-chloro-3-[hydrazinylidenemethyl] quinoline was obtained by treating hydrazine hydrate [25]. In view of the above literature study, the hydrazide hydrazones were found to be having more potential to exhibit good biological activity. Hence, an attempt is made in designing molecules by retaining the pharmacophore hydrazide hydra- ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.12.1.37-44.2038 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.12.1.37-44.2038 mailto:santhosh.1507@rediffmail.com mailto:harianubupp@gmail.com mailto:satya1782005@gmail.com mailto:satya1782005@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.12.1.37-44.2038&domain=pdf&date_stamp=2021-03-31 38 Mahantheshappa et al. / European Journal of Chemistry 12 (1) (2021) 37-44 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.37-44.2038 N Cl N NH2 N O HR1 O ClN 3(a-b)1(a-b) 4(a-b) N H O N Cl N H N 5(a-b) 2 Step-1 Step-2 Step-3 O Cl N Cl N H N O NR2 2 R1 R1 R1 R1 Cl O Cl 6(a-h) Step-4 R2: HN O HN HN HN N 6a,e 6b,f 6c,g 6d,h H N Cl N NH2 4(a-b) R1 N Cl N H N 5(a-b) O ClR1 R1: H (1a, 3a, 4a, 5a, 6a, 6b, 6c, 6d) R1: Br (1b, 3b, 4b, 5b, 6e, 6f, 6g, 6h) Scheme 1. Synthesis of compounds 6a-h. zone functionality at the 3rd position of the quinoline to exhibit maximum biological response. The idea behind the research is to generate molecules with profound biological activities against infectious organisms along with their antioxidant potential. 2. Experimental 2.1. Materials and methods The reagents and chemicals were obtained from Hi-Media, India, Sigma-Aldrich, India and SD-Fine chemical, India. The monitoring of reactions on precoated silica gel aluminum TLC plates (Merck). An open capillary method was adopted to check the melting point using the raga melting point apparatus. The synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR and mass spectrometry. The IR spectra were recorded in KBr on a Perkin-Elmer model 1620 FT-IR spectrophoto- meter. 1H and 13C NMR spectra were recorded on Bruker Spectrospin DPX400 (400 MHz) spectrometer in CDCl3 solvent. The following abbreviations were used to designate the peak multiplicity s-singlet, d-doublet and t-triplet and m-multiplet and the values are expressed in δ (ppm). The mass spectrum has been recorded on FAB mass spectrometer (JEOL SX 102/DA-6,000). 2.2. Synthesis 2.2.1. Synthesis of compounds 3a and 3b 2.2.1.1. Synthesis of 2-chloroquinoline-3-carbaldehyde (3a) Dimethylformamide (22.2 mmol) was taken in a 100 mL round bottom flask. To this, phosphorus oxychloride (44.4 mmol) was added dropwise maintaining a temperature of 0-5 °C, and allowed the reaction to attain room temperature with constant stirring. Acetanilide (7.4 mmol) was added to the reaction mixture and the stirring was continued at 55-60 °C for 8 h on an oil bath. After completion of the reaction, the mixture was poured into ice-cold water; the precipitate thus formed was filtered under suction and dried [25] (Scheme 1). 2.2.1.2. Synthesis of 6-bromo-2-chloroquinoline-3- carbaldehyde (3b) Dimethylformamide (22.2 mmol) was taken in a 100 mL round bottom flask. To this, phosphorus oxychloride (44.4 mmol) was added dropwise maintaining a temperature of 0-5 °C, and allowed the reaction to attain room temperature with constant stirring. N-(3-bromophenyl)acetamide (7.4 mmol) was added to the reaction mixture and the stirring was continued at 55-60 °C for 8 h on an oil bath. After completion of the reaction, the mixture was poured into ice-cold water; the precipitate thus formed was filtered under suction and dried [25] (Scheme 1). 2.2.2. Synthesis of compounds 4a and 4b 2.2.2.1. Synthesis of 2-chloro-3-(hydrazonomethyl) quinoline (4a) The compound 2-chloroquinoline-3-carbaldehyde (3a) (4.8 mmol) was taken in a round bottom flask (100 mL), to this, methanol (10 mL) was added and cooled to 0-5 °C by keeping in an ice bath followed by the addition of hydrazine hydrate (19.4 mmol) dropwise. The reaction mixture is allowed to warm to room temperature with constant stirring and is stirred an additional 2-3 h with occasionally monitoring by TLC. After completion of the reaction, the solid formed was filtered under suction and dried [25,26] (Scheme 1). 2.2.2.2. Synthesis of 6-bromo-2-chloro-3-(hydrazonomethyl) quinoline(4b) The compound 6-bromo-2-chloroquinoline-3-carbaldehyde (3b) (4.8 mmol) was taken in a round bottom flask (100 mL), to this methanol (10v) was added and cooled to 0-5°C by keeping in an ice bath followed by the addition of hydrazine hydrate (19.4 mmol) dropwise. The reaction mixture is allowed to warm to room temperature with constant stirring and is stirred an additional 2-3 h with occasionally monitoring by TLC. After completion of the reaction, the solid formed was filtered under suction and dried [25,26] (Scheme 1). Mahantheshappa et al. / European Journal of Chemistry 12 (1) (2021) 37-44 39 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.37-44.2038 2.2.3. Synthesis of compounds 5a and 5b 2.2.3.1. Synthesis of 2-chloro-N’-((2-chloroquinolin-3-yl) methylene)acetohydrazide (5a) The compound 2-chloro-3-(hydrazonomethyl)quinoline (4a) (4.8 mmol) was taken in a 50 mL round bottom flask. To this, DCM (10 mL) and 2-chloroacetyl chloride (7.2 mmol) was added dropwise maintaining a temperature of 0-5 °C. The reaction mixture was stirred at ambient temperature for 2-3 h on a magnetic stirrer with occasionally monitored by the TLC. After completion of the reaction, the reaction mixture was quenched with NaHCO3 solution, extracted with DCM, and dried over Na2SO4. The organic layer was concentrated under reduced pressure to get a solid product [25,27,28] (Scheme 1). 2.2.3.2. Synthesis of N’-((6-bromo-2-chloroquinolin-3-yl) methylene)-2-chloroacetohydrazide (5b) The compound 6-bromo-2-chloro-3-(hydrazonomethyl) quinoline (4b) (4.8 mmol) was taken in a 50 mL round bottom flask. To this, DCM (10 mL) and 2-chloroacetyl chloride (7.2 mmol) was added dropwise maintaining a temperature of 0-5 °C. The reaction mixture was stirred at ambient temperature for 2-3 h. on a magnetic stirrer with occasionally monitored by the TLC. After completion of the reaction, the reaction mixture was quenched with NaHCO3 solution, extracted with DCM, and dried over Na2SO4. The organic layer was concentrated under reduced pressure to get solid [25,27,28] (Scheme 1). 2.2.4. Synthesis of compounds 6a-d 2-Chloro-N’-((2-chloroquinolin-3-yl)methylene) acetohydra- zide (5a) (3.5 mmol)and DMF (20 mL) was taken in a 50 mL round bottom flask. To this, dry K2CO3 (7.0 mmol) was added followed by secondary amines (Morpholine, diethylamine, piperidine and 1-methylpiperazine) at 0-5 °C. The reaction was stirred at 25-30 °C for 3-4 h on a magnetic stirrer with occasionally monitoring by TLC. After completion of the reaction, the reaction mixture was quenched with cold water and extracted with ethyl acetate, dried over Na2SO4, and filtered. The organic layer was concentrated under reduced pressure and controlled temperature to get a solid product (68- 70%) (Scheme 1). N’-((2-Chloroquinolin-3-yl) methylene)-2-morpholinoaceto hydrazide (6a): Color: Light brown. Yield: 68%. M.p.: 156-159 °C. FT-IR (KBr, ν, cm-1): 3459 (N-H), 2933 (C-H), 1694 (C=O). 1H NMR (400 MHz, CDCl3,δ, ppm): 10.39 (s, 1H, NH), 8.97 (s, 1H, CH=N), 8.60 (s, 1H, Ar-H), 8.019-7.997 (d, J = 8.8 Hz, 1H, Ar-H), 7.918-7.898 (d, J = 7.6Hz, 1H, Ar-H), 7.762-7.749 (t, J = 7.6 Hz, 1H, Ar-H), 7.603-7.588 (t, J = 7.2 Hz, 1H, Ar-H), 3.573-3.561 (t, J = 2 Hz, 4H, CH2OCH2), 3.10 (s, 2H, CH2C=O), 2.486-2.482 (t, J = 2 Hz, 4H, CH2NCH2). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.6, 158.9, 148.0, 143.1, 136.7, 131.7, 128.5, 128.3, 127.7, 127.0, 125.2 (Ar-C), 66.0 (COC), 60.9 (CC=O), 53.6 (CNC). MS (EI, m/z (%)): 333.6 (M+1). N’-((2-Chloroquinolin-3-yl) methylene)-2-(diethylamino)ace tohydrazide (6b): Color: Brown. Yield: 78%. M.p.: 164-167 °C. FT-IR (KBr, ν, cm-1): 3428 (N-H), 2930 (C-H), 1696 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.47 (s, 1H, NH), 8.99 (s, 1H, CH=N), 8.60 (s, 1H, Ar-H), 8.019-7.997 (d, J = 8.8 Hz, 1H, Ar-H), 7.918-7.898 (d, J = 7.6Hz, 1H, Ar-H), 7.784-7.770 (t, J = 7.6 Hz, 1H, Ar-H), 7.583-7.568 (t, J = 7.2 Hz, 1H, Ar-H), 3.19 (s,2H, CH2C=O), 2.574-2.542 (q, J= 4.8 Hz, 4H, CH2NCH2), 1.131-1.111 (t, J= 7.2 Hz, 6H, CH3,CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.6, 158.9, 148.0, 143.1, 136.7, 131.7, 128.5, 128.3, 127.7, 127.0, 125.2, 61.9 (CC=O), 47.0 (CNC), 11.7 (CH3). MS (EI, m/z (%)): 319.7 (M+1). N’-((2-Chloroquinolin-3-yl) methylene)-2-(piperidin-1-yl)ace tohydrazide (6c): Color: Pale white. Yield: 75%. M.p.: 178-180 °C. FT-IR (KBr, ν, cm-1): 3553 (N-H), 2993 (C-H), 1693 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.47 (s, 1H, NH), 8.99 (s, 1H, CH=N), 8.60 (s, 1H, Ar-H), 8.019-7.997 (d, J = 8.8 Hz, 1H, Ar-H), 7.918-7.898 (d, J = 7.6Hz, 1H, Ar-H), 7.784-7.770 (t, J = 7.6 Hz, 1H, Ar-H), 7.603-7.588 (t, J = 7.2 Hz, 1H, Ar-H), 3.19 (s,2H, CH2C=O), 2.57-2.54 (t, J = 4.8 Hz, 4H, CH2NCH2), 1.70-1.61 (m, 4H, CH2,CH2), 1.538-1.522 (m, 2H, CH2). 13C NMR (100 MHz, CDCl3, δ, ppm): 167.4, 149.0, 148.1, 143.0, 136.8, 131.7, 128.6, 128.4, 127.8, 127.1, 125.4 (Ar-C), 61.9 (CC=O), 55.2 (CNC), 26.2 (CH2), 23.6 (CH2). MS (EI, m/z (%)): 331.8 (M+1). N’-((2-Chloroquinolin-3-yl) methylene)-2-(4-methylpipera zin-1-yl)acetohydrazide (6d): Color: Light brown. Yield: 74%. M.p.: 195-197 °C. FT-IR (KBr, ν, cm-1): 3459 (N-H), 2933 (C-H), 1694 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.34 (s, 1H, NH), 8.98 (s, 1H, CH=N), 8.62 (s, 1H, Ar-H), 8.076-8.055 (d, J = 8.8 Hz, 1H, Ar-H), 7.998-7.967 (d, J = 8 Hz, 1H, Ar-H), 7.788- 7.774 (t, J = 7.2 Hz, 1H, Ar-H), 7.589-7.571 (t, J = 7.6 Hz, 1H, Ar- H), 3.25 (s, 2H, CH2C=O), 2.67-2.54 (m, 8H, CH2NCH2 ), 2.31 (s, 3H, CH3-N). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.6, 158.9, 148.0, 143.1, 136.79, 131.7, 128.5, 128.3, 127.7, 127.0, 125.2 (Ar-C), 60.9 (CC=O), 55.0 (CNC), 53.6 (CNC), 45.9 (C-N). MS (EI, m/z (%)): 346.6 (M+1). 2.2.5. Synthesis of compounds 6e-f N’-((6-Bromo-2-chloroquinolin-3-yl) methylene)-2-chloro acetohydrazide (5b) (3.5 mmol) and DMF (20 mL) was taken in a 50 mL round bottom flask. To this, dry K2CO3 (7.0 mmol) was added followed by secondary amines (Morpholine, diethyl amine, piperidine and 1-methylpiperazine) at 0-5 °C. The reaction was stirred at 25-30 °C for 3-4 h on a magnetic stirrer with occasionally monitoring by TLC. After completion of the reaction, the reaction mixture was quenched with cold water and extracted with ethyl acetate, dried over Na2SO4, and filtered. The organic layer was concentrated under reduced pressure and controlled temperature to get a solid product (68- 70%) (Scheme 1). N’-((6-Bromo-2-chloroquinolin-3-yl) methylene)-2-morpholi noacetohydrazide (6e): Color: Pale brown. Yield: 68%. M.p.: 147-149 °C. FT-IR (KBr, ν, cm-1): 3487 (N-H), 2928 (C-H), 1699 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.39 (s, 1H, NH), 8.97 (s, 1H, CH=N), 8.51 (s, 1H, Ar-H), 8.019-7.997 (d, J = 8.8 Hz, 1H, Ar-H), 7.918-7.898 (d, J = 7.6Hz, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 3.10 (s,2H, CH2C=O), 3.584-3.573 (t, J= 7.2 Hz, 4H, CH2OCH2), 2.486-2.482 (t, J= 1.6 Hz, 4H, CH2NCH2). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.7, 158.9, 148.1, 143.1, 136.8, 131.7, 128.6, 128.3, 127.7, 127.1, 125.3 (Ar-C), 66.0 (COC), 60.9 (CC=O), 53.6 (CNC). MS (EI, m/z (%)): 412.4 (M+1). N’-((6-Bromo-2-chloroquinolin-3-yl) methylene)-2-(diethyl amino)acetohydrazide (6f): Color: Light brown. Yield: 58%. M.p.: 197-199 °C. FT-IR (KBr, ν, cm-1): 3490 (N-H), 2924 (C-H), 1699 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.47 (s, 1H, NH), 8.99 (s, 1H, CH=N), 8.60 (s, 1H, Ar-H), 8.019-7.997 (d, J = 8.8 Hz, 1H, Ar-H), 7.766-7.762 (d, J = 1.6 Hz, 1H, Ar-H), 7.60-7.56 (m, 1H, Ar-H), 3.19 (s,2H, CH2C=O), 2.574-2.562 (q, J= 2.0 Hz, 4H, CH2NCH2), 1.707-1.698 (t, J= 3.6 Hz, 6H, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.6, 159.0, 148.0, 143.1, 136.7, 131.7, 128.5, 128.3, 127.7, 127.0, 125.2 (Ar-c), 60.9 (CC=O), 46.0 (CNC), 11.7 (CH3). MS (EI, m/z (%)): 398.5 (M+1). N’-((6-Bromo-2-chloroquinolin-3-yl) methylene)-2-(piperi din-1-yl)acetohydrazide (6g): Color: Light brown. Yield: 65%. M.p.: 215-218 °C. FT-IR (KBr, ν, cm-1): 3488 (N-H), 2924 (C-H), 1657 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.42 (s, 1H, NH), 8.96 (s, 1H, CH=N), 8.62 (s, 1H, Ar-H), 8.02-7.99 (d, J = 8.8 Hz, 1H, Ar-H), 7.918-7.898 (d, J = 8.0 Hz, 1H, Ar-H), 7.59 (s, 1H, Ar-H), 3.19 (s, 2H, CH2C=O), 2.57-2.56 (t, J = 4.8 Hz, 4H, CH2NCH2), 1.70-1.61 (m, 4H, CH2,CH2), 1.61-1.50 (m, 2H, CH2). 13C NMR (100 MHz, CDCl3, δ, ppm): 167.1, 157.0, 148.5, 143.1, 136.7, 131.5, 128.6, 128.3, 127.9, 127.1, 125.2 (Ar-C), 61.9 40 Mahantheshappa et al. / European Journal of Chemistry 12 (1) (2021) 37-44 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.37-44.2038 (CC=O), 55.2 (CNC), 26.2 (CH2), 23.6 (CH2). MS (EI, m/z (%)): 410.6 (M+1). N’-((6-Bromo-2-chloroquinolin-3-yl)methylene)-2-(4-methyl piperazin-1-yl)acetohydrazide (6h): Color: White. Yield: 59%. M.p.: 223-226 °C. FT-IR (KBr, ν, cm-1): 3387 (N-H), 2924 (C-H), 1657 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.34 (s, 1H, NH), 9.22 (s, 1H, CH=N), 8.98 (s, 1H, Ar-H), 8.644-8.622 (d, J = 8.8 Hz, 1H, Ar-H), 7.91-7.89 (t, J = 8 Hz, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 3.25 (s, 2H, CH2C=O), 2.67-2.54 (m, 8H, CH2NCH2), 2.31 (s, 3H, CH3N). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.5, 158.7, 148.0, 143.2, 136.71, 131.5, 128.3, 128.1, 127.9, 127.1, 125.5 (Ar-C), 60.9 (CC=O), 55.0 (CNC), 53.6 (CNC), 45.9 (CN). MS (EI, m/z (%)): 425.3 (M+1). 2.3. Biological activity 2.3.1. In silico ADME(T) studies The QSAR parameters are employed to optimize the molecular descriptors. The properties help to understand physicochemical and pharmacokinetics of their potentiality for ADME (Absorption, Distribution, Metabolism, Excretion) Toxicity [29-35]. The study enables the evaluation of biologi- cally active and inactiveness of molecules, undesirable functi- onal groups. The Plog BB, log HIA, Caco-2 cell permeability (PCaco), Log pGI, Log Papp, and aqueous solubility (Plog S) help to know to understand the metabolism of active compounds [29-35]. The study also helps to envisage the toxic effect of different routes of drug administration. 2.3.2. Pharmacokinetics properties: ADMET screening in silico profile The compound required to elicit a biological response depends upon bioavailability. Poor bioavailability leads to infectiveness. To overcome such a problem, predicting such parameters before drug development is to optimize and important to reduce the cost. Hence, molecular parameters study utilizing pharmacokinetic parameters is essential [29- 32]. 2.3.3. Antimicrobial activity The in vitro antimicrobial screening of the synthesized compounds 6a-h was carried out by using a cup plate method using nutrient agar (NA) medium A, with different bacterial strains viz. Staphylococcus aureus (ATCC-25923), Vibrio cholera (ATCC-39315), Pseudomonas aeruginosa (ATCC-27853), and Escherichia coli (ATCC-25922). The antifungal activities were evaluated by using potato dextrose agar medium B (peptone 1%, distilled water 1000 mL, agar 2%, and glucose 4%) with a pH = 5.6 with different fungal strains Aspergillus niger (ATCC- 13497), Candida albicans (ATCC-10231), Penicillin chryso genum (ATCC-10106) and Cladosporium oxysporum (ATTC- 76499). These microorganisms obtained from Microbiology Department, Kuvempu University, Jnana Sahyadri, Shankar- ghatta, Shimoga, India. The test solutions were prepared with DMSO solvent and diluted with double distilled water to obtain concentrations of 1000, 500, and 250 μg/mL. The test micro- organisms have been maintained in slant tubes as solid culture. The solid slant was prepared and inoculated from the original stock culture and then finally the liquid medium was inoculated from the above solid slants. The inoculated bacterial micro- organisms were allowed to incubate at 37 °C for 24 h and fungal species at 28 °C for 24 h, respectively. The liquid agar media of 20 mL was taken in the McCartney bottle and that was sterilized in an autoclave for 15 min at 121 °C and 15 psi [36,37]. The sterilized media was poured into the sterilized Petri plates aseptically in a horizontal laminar airflow chamber. The layers of media were uniformly distributed and were allowed to solidify in the aseptic chamber, followed by inoculating the bacterial strains separately in the petri plates. The suspension was adjusted with sterile saline to make a concentration of approximately 1.0×107 CFU/mL. For the establishment of activity, the inoculated Petri plates were divided into three quarters parts and to each quarter a well was made in the media with the help of a sterilized cork borer (9 mm). The known concentrations of the standard drug amoxicillin, fluconazole, and test compounds were added to the particular labeled wells. Then, the applied plates were kept in the refrigerator for 10 min, followed by incubation at 37 °C for 24 h for bacterial species and 28 °C for 72 h for fungal species, respectively [36- 40]. 2.3.4. Antioxidant activity 2,2’-Diphenyl-1-picrylhydrazyl (DPPH) is a stable free radical, it can accept an electron or hydrogen radical to become a steady diamagnetic molecule. Due to its odd number of electrons, the methanol solution of DPPH shows a strong absorption band at 517 nm. DPPH free radical reacts with assorted electron donating molecules (reducing agents or antioxidants), when electrons become paired off, it leads to bleaching of the DPPH solution. This consequences in the formation of the colorless 2,2’-diphenyl-1-picryl hydrazine. Reduction of the DPPH radicals can be projected quantitatively by measuring the decrease in absorbance at 517 nm. Equal volume of 100 μM 2,2’-diphenyl-1-picrylhydrazyl (DPPH) in methanol was added to different concentrations of test compounds (100 μM/mL) in methanol, assorted well and kept in the dark for 20 min. The absorbance at 517 nm was measured by using the spectrophotometer UV-1650, Shimadzu [41-43]. By plotting the percentage of DPPH· scavenging against concentration, it gives the standard curve. The percentage of scavenging was calculated according to Equation (1). % Inhibition = ×100 Absorbance of blank - Absorbance of test Absorbance of blank (1) 3. Results and discussion 3.1. Chemistry The 2-chloroquinoline-3-carbaldehyde (3a) was synthe- sized by Vilsmeier Haack reaction [44]. Upon reacting acetanilide (1) with dimethyl formamide (2) in the presence of phosphorousoxy chloride at 50 °C for 8 h. The obtained quinoline aldehyde 3a was further reacted with hydrazine hydrate in the presence of methanol to yield 2-chloro-3- (hydrazonomethyl)quinoline (4a). The 2-chloro-3-(hydrazono methyl)quinoline (4a) was reacted with 2-chloroacetyl chloride to yield 2-chloro-N’-((2-chloroquinolin-3-yl)methylene)aceto hydrazide (5a) which upon reaction with secondary amines (Morpholine, diethylamine, piperidine and 1-methylpipera zine) yield the target compounds 6a-d (Scheme 1). The purification of the compounds 6a-h was achieved by column chromatography using n-hexane: ethyl acetate gradient as the mobile phase. The structures of the compounds were confirmed by FT-IR, 1H NMR, 13C NMR and mass spectral analysis. Similar experimental methods were applied for 6-bromo-2-chloro quinoline-3-carbaldehyde (3b) and we obtained the compounds 6e-h. The 1H NMR spectrum of the prepared compounds revealed a singlet signal corresponding to the methylene protons at δ 3.25-3.10 ppm. CH=N singlet signal resonates at δ 9.22-8.96 ppm and singlet signal corresponds to NH proton at δ 10.47- 10.34 ppm. The 13C NMR spectrum of the synthesized compounds revealed a signal corresponds to methylene carbon at δ 61.9-60.9 ppm. Mahantheshappa et al. / European Journal of Chemistry 12 (1) (2021) 37-44 41 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.37-44.2038 Table 1. ADME and pharmacological parameters prediction for the compounds6a-h using ADME SAR toolbox. Compound Plog BB a Log HIA b PCaco c Log pGI (substrate) d Log pGI (non-inhibitor) e Plog S f Log Papp g 6a 0.8814 0.9957 0.5353 0.6850 0.6924 -2.9531 1.0229 6b 0.8242 0.9947 0.5293 0.7943 0.8627 -3.0447 0.9365 6c 0.8798 0.9795 0.5999 0.7101 0.6695 -3.2752 0.4522 6d 0.8754 0.9884 0.5465 0.8332 0.5257 -3.1011 0.5510 6e 0.9155 0.9923 0.5903 0.6474 0.5924 -3.4830 0.7029 6f 0.9074 0.9947 0.5895 0.6389 0.6521 -3.5299 0.6933 6g 0.8643 0.9920 0.5499 0.8274 0.5867 -3.1759 0.5444 6h 0.8686 0.9859 0.5981 0.7019 0.7232 -3.3413 0.4480 Amoxicillin 0.9967 0.9008 0.8722 0.5741 0.9665 -3.0180 -0.0502 Fluconazole 0.9382 0.9894 0.8867 0.6008 0.8782 1.8626 1.3598 Ascorbic acid 0.8532 0.7710 0.6559 0.8696 0.9347 0.1081 -0.3148 a Predicted blood/brain barrier partition coefficient (1-high penetration, 2- medium penetration and 3- Low penetration). b Predicted Human intestinal absorption in nm/s (acceptable range: 0 poor, > 1 great). c Predicted Caco-2 cell permeability in nm/s (acceptable range: -1 is poor, 1 is great). d Predicted P-glycoprotein substrate in nm/s (acceptable range of -5 is poor, 1 is great). e Predicted P-glycoprotein inhibitor in nm/s (accepted range: 0 to 1). f Predicted aqueous solubility (concerned value is 0-2 highly soluble). g Predicted probability of Caco-2 cell permeability in cm/s (Concern value is -1 to 1). Table 2. LD50 and probability of health effects of compounds 6a-h using ACD/ I-Lab 2.0. ADME-TOX parameters Intraperitoneal a Oral a Intravenous a Subcutaneous a 6a 910(0.5) 610(0.2) 57(0.31) 210(0.11) 6b 940(0.5) 630(0.2) 52(0.49) 220(0.16) 6c 930(0.5) 490(0.3) 61(0.41) 190(0.28) 6d 920(0.5) 480(0.3) 58(0.30) 250(0.12) 6e 1220(0.2) 510(0.3) 50(0.39) 160(0.20) 6f 1140(0.4) 470(0.3) 51(0.47) 200(0.19) 6g 1100(0.5) 490(0.2) 58(0.40) 180(0.28) 6h 1220(0.3) 480(0.3) 62(0.41) 240(0.11) Amoxicillin 310 (0.8) 880(0.5) 110 (0.67) 400(0.52) Fluconazole 1200(0.7) 1000(0.5) 580(0.47) 2700(0.23) Ascorbic acid 1100(0.7) 4500(0.6) 820(0.58) 2700(0.50) a Estimated LD50-mouse value in mg/kg after intraperitoneal, oral, intravenous, and subcutaneous administration. The FTIR spectrum of prepared compounds revealed a peak corresponds to N-H at 3387-3553 cm-1, C-H signal resonates at 2924-2993 cm-1 and the signal corresponds to C=O at 1657- 1699 cm-1. 3.2. ADME Prediction The in silico predicted pharmacokinetic (ADME) properties of all prepared compounds include blood/brain partition coefficient (Plog BB), human intestinal absorption (log HIA), Caco-2 cell permeability (PCaco), P glycoprotein substrate and noninhibitor (log pGI), aqueous solubility (Plog S), probability of Caco-2 cell permeability (log Papp) and are given in Table 1. The transport of drug metabolites is permeable if log HIA (Human intestinal absorption) and PCaco-2 (cell permeability) are in the positive range. Maximum absorption of compounds enhances the maximum response to protein. The functional groups of compounds such as Br, Cl, F, or methoxy had high partition co-efficient values [45]. This leads to the accumulation of compounds in the human intestine and less involved in metabolism. The human intestinal range of absorption was between -5 to +1, considered within the acceptable range for compounds 6a-h. The solubility of compounds 6a-h in aqua lies in the range of 0 (poor) to 2 (good). The log Papp stated that the compounds had good permeability on lipid absorption and metabolism. While the reference compound and compounds 6a-h were within the acceptable range (Table 1). The overall results predicted that the tested compounds have good drug- like, lead-like, and fragment-like properties. 3.3. Toxicity-LD50 prediction The toxicities of the compounds 6a-h were analyzed upon lethal dosages on different organs. The LD50 and health effects were also predicted using software (ACD/I-Lab 2.0). LD50 of the hits notice the increasing potential of acute toxicity when administered through oral, intraperitoneal, intravenous, and subcutaneous on mouse models. The comparative study of reference compounds with tested compounds on oral, subcutaneous, intraperitoneal, and intravenous is low. The results suggest that no contradictions for compounds 6a-h were observed with the tested dosages. The possibility of a negative effect of compounds 6a-h has found to be less on various organs (Table 2). 3.4. Antibacterial activity The antibacterial studies were conducted against viz. P. aeruginosa, S. aureus, V. cholera, and E. coli with standard Amoxicillin. The compounds 6a, 6c, 6e, and 6g showed promising activity profile against P. aeruginosa with a zone of inhibition of 28±0.2, 26±0.1, 27±0.2 and 25±0.2, respectively, at 1000 µg/mL. The compounds 6a, 6f, and 6h have shown promising activity against E. coli with zone of inhibition of 29±0.2, 28±0.3 and 27±0.3, respectively, at 1000 µg/mL. The compounds 6a-h have exhibited moderate activity against S. aureus and V. cholera (Table 3). 3.5. Antifungal activity The antifungal studies were conducted against fungal species C. oxysporum, P. chrysogenum, C. albicans, and A. niger, along with standard fluconazole. The compounds 6b,6c, and 6e showed a promising activity profile on C. oxysporum with zone of inhibition of 21±0.4, 22±0.2 and 21±0.2, respectively, with 1000 µg/mL. The compounds 6c, 6e, 6f, 6g, and 6hshowed promising activity against P. chrysogenum with zone of inhibition of 25±0.20, 22±0.2, 24±0.2, 23±0.2 and 22±0.2, respectively, at 1000 µg/mL. The synthesized target molecules 6a-h have exhibited moderate activity against C. albicans and A. niger (Table 4). 3.6. Structure activity relation The structure activity relation (SAR) study revealed that the activity is mainly due to substitution on quinoline ring, the 42 Mahantheshappa et al. / European Journal of Chemistry 12 (1) (2021) 37-44 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.37-44.2038 Table 3. The in vitro antibacterial potential of compounds 6a-h. Compound Conc. of test sample (µg/mL) Zone of inhibition in mm (mean±SD) n=3 P. aeruginosa S. aureus V. cholera E. coli 6a 1000 500 250 28±0.2 26±0.1 21±0.1 21±0.1 17±0.3 11±0.1 18±0.1 15±0.1 11±0.1 29±0.2 22±0.1 14±0.2 6b 1000 500 250 21±0.2 18±0.1 14±0.1 16±0.1 13±0.1 9±0.2 17±0.2 13±0.1 12±0.1 18±0.1 16±0.2 12±0.1 6c 1000 500 250 26±0.1 21±0.2 18±0.1 22±0.2 17±0.1 15±0.2 21±0.2 18±0.1 14±0.2 22±0.2 17±0.2 13±0.1 6d 1000 500 250 19±0.3 17±0.2 14±0.2 23±0.1 17±0.2 13±0.2 17±0.2 14±0.1 11±0.1 19±0.2 16±0.3 11±0.1 6e 1000 500 250 27±0.2 21±0.3 19±0.1 22±0.1 19±0.3 13±0.2 19±0.1 16±0.3 9±0.2 23±0.3 19±0.2 12±0.2 6f 1000 500 250 19±0.2 16±0.3 11±0.1 21±0.1 19±0.3 12±0.2 17±0.1 15±0.3 11±0.2 28±0.3 21±0.1 19±0.2 6g 1000 500 250 25±0.2 21±0.3 19±0.1 19±0.1 16±0.3 13±0.2 19±0.1 15±0.3 13±0.2 19±0.3 18±0.2 11±0.1 6h 1000 500 250 21±0.2 18±0.3 15±0.1 19±0.1 17±0.3 13±0.2 19±0.1 17±0.1 12±0.2 27±0.3 21±0.2 19±0.2 Standard (Amoxicillin) 1 mg/mL 32±0.2 26±0.2 28±0.1 34±0.2 Table 4. The in vitro antifungal potential of compounds 6a-h. Compound Conc. of the test sample (µg/mL) Zone of inhibition in mm (mean±SD) n=3 C. oxysporum P. chrysogenum C. albicans A. niger 6a 1000 500 250 18±0.2 11±0.3 - 8±0.3 - - 16±0.3 10±0.2 - - - - 6b 1000 500 250 21±0.4 09±0.3 - 11±0.3 - - 17±0.3 12±0.3 07±0.2 14±0.4 09±0.3 - 6c 1000 500 250 22±0.2 18±0.3 16±0.3 25±0.2 21±0.3 17±0.4 19±0.2 11±0.2 - 15±0.3 - - 6d 1000 500 250 14±0.2 10±0.3 9±0.2 11±0.3 - - 13±0.4 09±0.5 - 16±0.4 11±0.3 - 6e 1000 500 250 21±0.2 17±0.2 10±0.2 22±0.2 9±0.2 - 17±0.4 11±0.3 10±0.3 17±0.4 11±0.3 - 6f 1000 500 250 19±0.2 16±0.2 10±0.2 24±0.2 16±0.2 09±0.4 17±0.4 12±0.3 - 11±0.4 - - 6g 1000 500 250 21±0.2 17±0.2 - 23±0.2 9±0.2 - 14±0.4 11±0.3 - - - - 6h 1000 500 250 19±0.2 17±0.2 10±0.2 22±0.2 9±0.2 - 19±0.4 15±0.3 10±0.3 - - - Standard (Fluconazole) 1 mg/mL 28±0.3 32±0.2 24±0.2 20±0.4 Table 5. Antioxidant activity of compounds 6a-h. Compound % Inhibition (mean±SD) 50 µM 75 µM 100 µM 6a 20±0.25 35±0.26 41±0.26 6b 18±0.14 31±0.15 35±0.14 6c 15±0.32 28±0.31 36±0.34 6d 14±0.21 26±0.22 31±0.23 6e 19±0.30 32±0.28 40±0.29 6f 16±0.27 24±0.29 30±0.29 6g 17±0.37 25±0.36 34±0.35 6h 15±0.31 27±0.32 32±0.32 Ascorbic acid 72±0.33 84±0.35 98±0.34 * SD: Standard deviation. compounds having Cl substitution at 2nd position, and imine bond substitution present at the 3rd position of quinoline. The hydrazide analogs with azomethine (-CONHN=CH-) function- nality are found to establish prominent pharmacological and biological activities. The hydrazide hydrazone functionalities can easily endure hydrolytic reactions, which is an advantage to increase the activity [17,45]. The compounds 6a, 6c, 6e, and 6g having morpholine, piperidine rings, respectively, as side chain substitution at 3rd position, exhibited promising activity. The substitution of a metabolically stable heterocyclic ring (pyrrolidine and morpholine) in the short chain analogs leads to an increase in activity [18]. The basic nature of the side chain is essential for the accumulation of the drug within the acidic food vacuole of the parasite [46]. Mahantheshappa et al. / European Journal of Chemistry 12 (1) (2021) 37-44 43 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.37-44.2038 3.7. Antioxidant activity The antioxidant properties of the novel synthesized compounds 6a-h were found that the DPPH· method gave good antioxidant profile for the synthesized compounds. The antioxidant properties of the compounds exhibited by both electron withdrawing (Cl, Br) groups and electron donating (methoxy, methyl) functionalities. The in vitro antioxidant evaluation of the synthesized compounds revealed that among these compounds 6a, 6b, 6c, and 6e exhibited the maximum antioxidant potential and the rest of them were moderate to poor (Table 5). 4. Conclusion A series of quinoline derivatives (6a-h) were synthesized and screened for in vitro antimicrobial activity. The in silico ADMET studies of the prepared molecules were analyzed and found to be obeying the ADME properties and they were nontoxic. The compounds 6a, 6c, 6e, and 6g showed promising activity profiles against P. aeruginosa. The compounds 6a, 6f and 6h were shown promising activity against E. coli. The antioxidant evaluation of the synthesized compounds revealed that among these compounds, compounds 6a, 6b, 6c and 6e were shown antioxidant potency and the rest of them were moderate to poor. The overall data represent that the molecules are found to be active but not near to the results of that of the standard. Hence, they can be taken as possible hits. Upon which, further modification can reveal compounds with good activity which may be taken up for further development. Acknowledgments The authors are grateful to the authorities of Kuvempu University for providing the necessary facilities to carry out the present work. The author thanks The Indian Institute of Science, Bangalore, for their kind of support in providing spectral analysis. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Santhosha Sangapurada Mahantheshappa https://orcid.org/0000-0001-8734-2991 Harishkumar Shivanna https://orcid.org/0000-0002-3752-3919 Nayak Devappa Satyanarayan https://orcid.org/0000-0003-4511-3749 References [1]. 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This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Materials and methods 2.2. Synthesis 2.2.1. Synthesis of compounds 3a and 3b 2.2.1.1. Synthesis of 2-chloroquinoline-3-carbaldehyde (3a) 2.2.1.2. Synthesis of 6-bromo-2-chloroquinoline-3-carbaldehyde (3b) 2.2.2. Synthesis of compounds 4a and 4b 2.2.2.1. Synthesis of 2-chloro-3-(hydrazonomethyl) quinoline (4a) 2.2.2.2. Synthesis of 6-bromo-2-chloro-3-(hydrazonomethyl) quinoline(4b) 2.2.3. Synthesis of compounds 5a and 5b 2.2.3.1. Synthesis of 2-chloro-N’-((2-chloroquinolin-3-yl) methylene)acetohydrazide (5a) 2.2.3.2. Synthesis of N’-((6-bromo-2-chloroquinolin-3-yl) methylene)-2-chloroacetohydrazide (5b) 2.2.4. Synthesis of compounds 6a-d 2.2.5. Synthesis of compounds 6e-f 2.3. Biological activity 2.3.1. In silico ADME(T) studies 2.3.2. Pharmacokinetics properties: ADMET screening in silico profile 2.3.3. Antimicrobial activity 2.3.4. Antioxidant activity 3. Results and discussion 3.1. Chemistry 3.2. ADME Prediction 3.3. Toxicity-LD50 prediction 3.4. Antibacterial activity 3.5. Antifungal activity 3.6. Structure activity relation 3.7. Antioxidant activity 4. Conclusion Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: