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. 2023 Feb 25;77(7):3791–3802. doi: 10.1007/s11696-023-02741-3

Synthesis of 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol as potential antimycobacterial agents

Abhijit Shinde 1, Prashant P Thakare 1, Yogesh Nandurkar 1,2, Abhijit Chavan 1, Abdul Latif N Shaikh 1,3, Pravin C Mhaske 1,✉
PMCID: PMC9961301  PMID: 37252671

Abstract

Resistance to antibiotic drugs has directed global health security to a life-threatening situation due to mycobacterial infections. In search of a new potent antimycobacterial, a series of (±) 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) have been synthesized. The structures of the newly synthesized derivatives were characterized by spectrometric analysis. Derivatives 8a–p were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC 25177), antibacterial activity against Proteus mirabilis (NCIM2388), Escherichia coli (NCIM 2065), Bacillus subtilis (NCIM2063) Staphylococcus albus (NCIM 2178) and antifungal activity against Candida albicans (NCIM 3100), Aspergillus niger (ATCC 504). Thirteen 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–m) derivatives reported moderate to good antitubercular activity against M. tuberculosis H37Rv with MIC 9.2–106.4 μM. Compounds 8a and 8h showed comparable activity with respect to the standard drug pyrazinamide. The active compounds screened for cytotoxicity activity against L929 mouse fibroblast cells showed no significant cytotoxic activity. Compounds 8c, 8d, 8e, 8g, 8k, and 8o displayed good activity against S. albus. Compounds 8c and 8n showed good activity against P. mirabilis and E. coli, respectively. The potential antimycobacterial activities imposed that the 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol derivatives could lead to compounds that could treat tuberculosis.

Graphical abstract

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Supplementary Information

The online version contains supplementary material available at 10.1007/s11696-023-02741-3.

Keywords: Quinoline, Antitubercular activity, Antimicrobial activity

Introduction

After COVID-19, tuberculosis (TB), an infection caused by Mycobacterium tuberculosis (MTB) became grievous to global health security and is now the foremost cause of mortality from a single infectious agent. According to the World Health Organization (WHO) TB report 2021, 10 million people developed TB in 2020 and 1.5 million died (Global tuberculosis report 2021). Over the years, the extensive development of drug resistance in the causative pathogen, MTB, has been an encumbrance of global commitments to end TB (Mabhula and Singh 2019; Sheikh et al. 2021). The current treatment regimens for TB disease rely on a combination of drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) and are associated with suboptimal efficacy, toxicity, and long duration and poor adherence which may ultimately lead to drug-resistant cases (Nguyen 2016; Sharma et al. 2021; Tiberi et al. 2018; Bald et al. 2017). Multidrug-resistant (MDR) or extensively drug-resistant (XDR) TB therapy includes much more toxic and expensive drugs and is tainted by a diminished chance of success (Global tuberculosis report 2020; World Health Organization 2020). There is great demand for developing effective new anti-TB drugs with better efficacy, reduced duration of action, and improved patient compliance.

The quinoline pharmacophore (Fig. 1) fulfilled the medicinal need of society for the last five decades. The modification of quinoline by different functional groups has an immense impact on biological activity (Nayak et al. 2015; Rakesh et al. 2016; Cohen 2013). Many quinoline derivatives have been successfully marketed as antimycobacterial, antimalarial, and anticancer agents. The quinoline compounds are endowed with a wide variety of biological activities such as antituberculosis (Keri and Patil 2014; Gonçalves et al. 2010), antimicrobial (Marella et al. 2013; Hu et al. 2017a, b), anticancer (Bollu et al. 2017), antimalarial (Kalaria et al. 2018; Hu et al. 2017a, b), anti-inflammatory (Gupta and Mishra 2016) and antiviral (Guardia et al. 2018) activities. Quinolines-oxazole was reported for promising antitubercular activity (Lilienkampf et al 2009, 2012).

Fig. 1.

Fig. 1

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Quinoline pharmacophore containing TB drugs and lead molecules A–D

The literature revealed that azolyl-ethanol pharmacophores are reported to be highly beneficial for antimicrobial potency, and have been extensively employed in the design of numerous new drug molecules. Notably, many azolyl ethanol derivatives as antimicrobial agents have been successfully marketed. (Sun et al. 2022; Ni et al. 2022) The azolyl alkoxy derivatives are reported for significant antimicrobial and antitubercular activity and are a part of many antimicrobial drugs. (Peng et al. 2016; Zhang et al. 2018) Implying facts, the intrinsic potent of quinoline which can be extended specifically using the effect of combining with alkoxy ethanol has compelled us to synthesize the 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) derivatives and screen for antimicrobial activity.

Results and discussion

Chemistry

The synthetic route for (±) 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) derivatives is presented in Scheme 1. 6-Substituted quinoline-2,4-dicarboxylic acids (2a–d) were synthesized via Pfitzinger reaction using pyruvic acid and 5-substituted isatin in the aqueous potassium hydroxide at 60 °C. (Shvekhgeimer 2004) The dicarboxylic acid (2a–d) on selective decarboxylation at 210 °C in nitrobenzene gave 6-substituted-4-quinoline carboxylic acid (3a–d). (Thakare et al. 2020) Acids (3a–d) were coupled with N,O-dimethylhydroxyamine hydrochloride (DMHA·HCl) using N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC·HCl) as a coupling reagent and N,N-dimethyl amino pyridine (DMAP) as a base in DCM gave 6-substituted-N-methoxy-N-methylquinoline-4-carboxamide (4a–d). (Thakare et al. 2020) Carboxamide (4a–d) on Grignard reaction with MeMgBr gave 1-(6-substituted quinolin-4-yl)ethenone (5a–d) (Thakare et al. 2021, 2022). The epoxide ring of 6-substituted-4-(2-methyloxiran-2-yl)quinoline (6a–d) was achieved using sodium metal in respective solvent (7a–d) at 70–75 °C gave ( ±) 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p). The physical properties of compounds (8a–p) are presented in Table 1.

Scheme 1.

Scheme 1

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Synthesis of ( ±) 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p)

Table 1.

Physical properties of compounds ( ±) 8a–p

Compound R R1 Physical appearance Yield(%)a MP °C
8a H Methyl White solid 68 84–88
8b H Ethyl Off-white solid 70 82–84
8c H n-Propyl Off-white solid 65 70–72
8d H n-Butyl Off-white solid 70 68–72
8e Br Methyl Off-white solid 74 168–172
8f Br Ethyl Off-white solid 76 126–130
8g Br n-Propyl Off-white solid 68 88–92
8h Br n-Butyl Pale brown solid 65 68–72
8i Cl Methyl Off-white solid 70 165–168
8j Cl Ethyl Off-white solid 68 86–90
8k Cl n-Propyl Off-white solid 73 62–66
8l Cl n-Butyl Thick liquid 70 Liquid
8m F Methyl Off-white solid 68 100–102
8n F Ethyl Off-white solid 65 62–65
8o F n-Propyl Brown solid 68 60–62
8p F n-Butyl Off-white solid 70 56–57
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aIsolated yield

The structure of compounds (8a–p) was confirmed by spectral analysis. As a representative analysis, the 1H NMR spectrum of 2-(6-chloroquinolin-4-yl)-1-ethoxypropan-2-ol, (8j) revealed a singlet in the aliphatic region at δ 1.73 for the methyl group attached at quaternary carbon, a broad singlet at δ 3.50 assigned to –OH proton. A triplet at δ 1.21 and a quartet at δ 3.60 integrated for three and two protons, respectively were assigned to the ethoxy group protons. Two doublets at δ 3.69 and 4.05, each integrated for one proton, correspond to diastereotopic geminal methylene protons of the (HO(CH3)C–CH2–O) group. The C-2 and C-3 protons of quinoline resonated as a doublet at δ 8.82 and δ 7.43, respectively. The C-5, C-7, and C-8 of quinoline appeared as a doublet, double doublet, and triplet at δ 8.75, 7.62, and 8.05, respectively. All the 1H-1H proton interactions were further confirmed by the COSY NMR spectrum. The 13C NMR spectrum of compound 8j showed five signals in the aliphatic region, The methyl group attached to quaternary carbon appeared at δ 26.6, the ethoxy group carbons appeared at δ 15.0 (CH3), 67.2 (CH2), the methylene carbon of C–CH2–O group showed a signal at δ 76.8 and a signal of quaternary carbon appeared at δ 74.8. The aromatic carbons resonated between δ 119.6 and 150.0. The structure of compound (8j) was further confirmed by molecular ion peaks (LC–MS) at m/z = 266.08 (M + H) + , 268.08 (M + 2 + H) +. The structure of all synthesized compounds was confirmed similarly.

Biological activity

Antitubercular activity

All the synthesized (±) 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) derivatives, were evaluated for antitubercular activity using microplate Alamar Blue assay (MABA) (Lourenço et al. 2007; Franzblau et al 1998). The antitubercular drugs isoniazid and pyrazinamide were used as the positive control. The antitubercular activity results in Minimum Inhibitory Concentration (MIC) in µM (µg/mL) have been presented in Table 2.

Table 2.

Antitubercular activity in MIC in μM (μg/mL) of compounds 8a–p

Compound R R1 M. tuberculosis, H37 RV
8a H Methyl 14.4 (3.12)
8b H Ethyl 27.1 (6.25)
8c H n-Propyl 102 (25)
8d H n-Butyl 24.1 (6.25)
8e Br Methyl 21.2 (6.25)
8f Br Ethyl 20.2 (6.25)
8g Br n-Propyl 19.3 (6.25)
8h Br n-Butyl 9.2 (3.12)
8i Cl Methyl 24.9 (6.25)
8j Cl Ethyl 47.2 (12.5)
8k Cl n-Propyl 22.4 (6.25)
8l Cl n-Butyl 42.7 (12.5)
8m F Methyl 106.4 (25)
8n F Ethyl 401.6 (100)
8o F n-Propyl 190.1 (50)
8p F n-Butyl 180.5 (50)
Pyrazinamide 25.34 (3.12)
Isoniazid 11.67 (1.6)
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The antitubercular activity result analysis of 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) presented in Table 2 provided some lead compounds that exhibited good to excellent activity against M. tuberculosis, H37RV. The substituent effect on activity revealed that substitution of the halogen group at the 6-position of quinoline and alkoxy group of ether linkage affect the activity. Among the compounds, 1-alkoxy-2-(quinolin-4-yl)propan-2-ol (8a-d) compound 8a (R = H, R1 = CH3) showed excellent activity with MIC 14.4 µM, which was more potent than the reference drug pyrazinamide. The -CH3 group which was substituted by the –C2H5 group in 8b (R = H, R1 = C2H5), presented good activity with MIC 27.1 µM. The –CH3 group was substituted by the − nC3H7 group in compound 8c (R = H, R1 = C3H7) the activity decreased by four-fold, and it showed MIC 102 µM. The –CH3 group was substituted by the − nC4H9 group in compound 8d (R = H, R1 = C4H9) and showed good activity with MIC 24.1 µM which was comparable with respect to the reference drug pyrazinamide.

Among the compounds 2-(6-bromoquinolin-4-yl)-1-alkoxypropan-2-ol, (8e–h) compound 8e (R = Br, R1 = CH3), good activity with MIC 21.2 µM which was comparable with respect to the drug pyrazinamide and two-fold less than the drug isoniazid. The substitution of –CH3 group by the –C2H5 or − nC3H7 group in compounds 8f (R = Br, R1 = C2H5) and 8g (R = Br, R1 = − nC3H7) the activity retained. Whereas, the -CH3 group was substituted by the − nC4H9 group in compound 8h (R = Br, R1 = − nC4H9) the activity increased by two folds and it showed comparable activity with respect to the standard drug isoniazid. Among the 2-(6-chloroquinolin-4-yl)-1-alkoxypropan-2-ol (8i–l) derivatives, compound 8i (R = Cl, R1 = CH3) displayed good activity with MIC 24.9 µM. The –CH3 group was substituted by the − nC3H7 group in compound 8k (R = Cl, R1 = C3H7), and the activity was retained. Whereas the methyl group of ether was substituted by the –C2H5 group in 8j (R = Cl, R1 = C2H5) or − nC4H9 group in 8l (R = Cl, R1 = − nC4H9), the activity decreased by two-fold. The compounds 8j and 8l showed good activity with MIC 47.2 and 42.7 µM, respectively. From the 2-(6-chloroquinolin-4-yl)-1-alkoxypropan-2-ol (8m–p) derivatives, compound 8m (R = F, R1 = CH3) showed moderate activity with MIC 106.4 µM. The -CH3 group of 2-(6-chloroquinolin-4-yl)-1-methoxypropan-2-ol was substituted by the –C2H5 group in the compound 8n (R = F, R1 = C2H5) the activity decreased by four-fold. The –CH3 group of ether was substituted by − nC3H7 and − nC4H9 in the compounds 8o (R = F, R1 = − nC3H7) and 8p (R = F, R1 = − nC4H9), respectively the activity decreased by two-fold.

It is noteworthy that, amongst the sixteen derivatives, ten derivatives exhibited moderate to good antitubercular activity with 9.2–106.4 µM. The structure–activity relationship revealed that the unsubstituted quinoline and methyl, ethyl, and n-butyl group at the ether linkage showed good antitubercular activity; whereas the n-propyl group at the ether linkage showed moderate activity. The quinoline was substituted by the 6-bromo quinoline and the methyl, ethyl, n-propyl, and n-butyl group at the ether linkage showed good antitubercular activity. It was noticed that the activity increased for the n-propyl and n-butyl groups. The quinoline was substituted by the 6-chloro quinoline and the methyl, ethyl, and n-butyl group at the ether linkage antitubercular activity decreased; whereas for the n-propyl group at the ether linkage, antitubercular activity increased. The quinoline was substituted by the 6-fluoro quinoline the activity was decreased for all alkoxy substituents. 1-Methoxy-2-(quinolin-4-yl)propan-2-ol (8a) and 2-(6-bromoquinolin-4-yl)-1-butoxypropan-2-ol (8h) showed comparable activity with that of the standard drug.

Antimicrobial activity

Synthesized 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) derivatives were screened for their antibacterial activity against P. mirabilis, E. coli, B. subtilis, S. albus using well diffusion method (NCCLS 2002; Joshi et al. 2015). Standard drug streptomycin and DMSO were used as the positive and negative control, respectively. Antifungal activity was performed against C. albicans and A. niger using the well diffusion method (NCCLS 2002; Joshi et al. 2015). The antifungal drugs fluconazole and ravuconazole were used as references. All the test solutions were prepared in DMSO at 500 µg/mL concentrations and the wells were filled with 80 µL (40 µg) of the samples, the result of antimicrobial activity in the zone of inhibition (mm) has been presented in Tables S1 and S2.

The antimicrobial activity result analysis of compounds 8a–p showed that most of the compounds exhibited good to moderate antibacterial and antifungal activity. All the synthesized compounds were further evaluated for Minimum Inhibitory Concentration (MIC), ranging from 250 to 3.90 μg/mL. The antimicrobial screening results of MIC in μg/mL have been presented in Table 3.

Table 3.

Antimicrobial activity in MIC (µg/mL) of compounds (8a–p)

Comp R R1 P. mirabilis E. coli B. subtilis S. albus C. albicans A. niger
8a H Methyl > 250 > 250 > 250 125 125 > 250
8b H Ethyl > 250 > 250 250 250 125 250
8c H n-Propyl 62.5 125 > 250 62.5 250 125
8d H n-Butyl > 250 > 250 125 62.5 250 > 250
8e Br Methyl > 250 > 250 > 250 62.5 > 250 > 250
8f Br Ethyl > 250 > 250 > 250 > 250 > 250 > 250
8g Br n-Propyl – 250 250 62.5 250 250
8h Br n-Butyl 125 250 125 > 250 125 > 250
8i Cl Methyl 250 > 250 > 250 250 250 > 250
8j Cl Ethyl – 250 > 250 125 250 > 250
8k Cl n-Propyl 250 > 250 > 250 31.2 125 > 250
8l Cl n-Butyl > 250 125 250 > 250 > 250 250
8m F Methyl – > 250 > 250 250 250 250
8n F Ethyl > 250 31.25 > 250 250 > 250 125
8o F n-Propyl – 250 250 62.5 > 250 > 250
8p F n-Butyl – 125 > 250 250 62.5 > 250
Streptomycin 7.81 7.81 7.81 7.81 NA NA
Fluconazole NA NA NA NA 7.81 7.81
Ravuconazole NA NA NA NA 7.81 31.25
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NA = Not applicable; – = inactive

The antibacterial activity analysis revealed that among the compounds 1-alkoxy-2-(quinolin-4-yl)propan-2-ol (8a–d) compounds 8a (R = H, R1 = CH3) and 8b (R = H, R1 = C2H5) showed moderate activity against S. albus and C. albicans and were found less active against P. mirabilis, E. coli, B. subtilis and A. niger. Compound 8c (R = H, R1 = − nC3H7) showed good activity against P. mirabilis and S. albus and moderate activity against E. coli and A. niger. Compound 8d (R = H, R1 = − nC4H9) showed good activity against S. albus and moderate activity against B. subtilis.

Amongst the compounds 2-(6-bromoquinolin-4-yl)-1-alkoxypropan-2-ol (8e–h), compounds 8e (R = Br, R1 = CH3) and 8g (R = Br, R1 = nC3H7) showed good activity against S. albus. Compound 8h (R = Br, R1 = nC4H9) showed moderated activity against P. mirabilis, B. subtilis and C. albicans. From the compounds, 2-(6-choloroquinolin-4-yl)-1-alkoxypropan-2-ol (8i-l), compounds 8j (R = Cl, R1 = CH3) and 8l (R = Cl, R1 = nC3H7) showed moderate activity against C. albicans and E. coli, respectively. Compound 8k (R = Cl, R1 = nC3H7) showed good activity against S. albus. Among the compounds, 2-(6-fluoroquinolin-4-yl)-1-alkoxypropan-2-ol (8m–p) compound 8n (R = F, R1 = C2H5) showed good activity against E. coli and moderate activity against A. niger. Compounds 8o (R = F, R1 = nC3H7) and 8p (R = F, R1 = nC4H9) showed good activity against S. albus and C. albicans, respectively. It is noteworthy that, among the 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol, (8a–p) derivatives, six compounds showed good activity against S. albus with MIC 31.25–62.5 μg/mL.

Cytotoxicity

Cytotoxicity activity of 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) derivatives were performed on L929, a normal fibroblast cell line from the subcutaneous connective tissue of mouse at 12.5 and 25 µ/mL concentrations. Compounds 8a, 8b, 8c, 8d, 8e, and 8f showed no or less cytotoxicity. Whereas, compounds 8g and 8h showed less than 50% cell viability indicating cytotoxicity (Fig. 2).

Fig. 2.

Fig. 2

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Cell viability (%) against mouse embryonic fibroblast cells (L929)

Experimental

The solvents and chemicals used were laboratory-grade and were purified as per the literature methods. The reaction progress has been monitored by the Thin Layer Chromatography (TLC). TLC was performed on the Merck 60 F-254 silica gel plates using ethyl acetate:hexane (2:8 and 3:7) as eluent. Melting points were determined in capillary tubes in a silicon oil bath using a Veego melting point apparatus and were uncorrected. 1H (500 MHz) NMR and 13C (125 MHz) NMR spectra of all compounds were recorded on the Bruker at either 500 MHz (1HNMR) and 125 MHz (13C NMR), spectrometer instruments. The Bruker Compass Data Analysis 4.2 was used to record HRMS spectra. Thermo Fisher Scientific India Pvt. Ltd supplied silica Gel (200–400 mesh) for column chromatography.

General procedure for ( ±) 6-substituted-4-(2-methyloxiran-2-yl)quinoline (6a-d)

To the stirred solution of potassium hydroxide and trimethyl sulfonium iodide in dimethyl sulphoxide, 1-(6-substituted quinolin-4-yl)ethenone (5a–d) was added at 0–5 °C and the reaction mass was stirred at room temperature for 1–2 h. After the complete conversion of the reactant, the reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and distilled on a rotary evaporator. Purification of the product was accomplished by column chromatography using ethyl acetate:hexane (2:8) as eluent gave 6-substituted-4-(2-methyloxiran-2-yl)quinoline (6a–d).

rac-4-(2-Methyloxiran-2-yl)quinoline (6a)

Yield: 80%; Mp.: 68 °C; 1H NMR (500 MHz, CDCl3) δ 1.80 (s, 3H, C-CH3), 2.94 (d, J = 5.2 Hz, 1H, C–CH2–O), 3.18 (d, J = 5.2 Hz, 1H, C–CH2–O), 7.47 (d, J = 4.4 Hz, 1H, C-3 H), 7.63–7.57 (m, 1H, C-6 H), 7.73 (d, J = 1.2 Hz, 1H, C-7 H), 8.14 (dd, J = 18.0, 8.4 Hz, 2H, C-5, C-8 H), 8.90 (d, J = 4.4 Hz, 1H, C-1 H); 13C NMR (125 MHz, CDCl3) δ 23.8 (C–CH3), 54.4 (C–CH2–O), 57.1 (O–C–CH2), 118.6 (C-3), 124.1 (C-5), 125.6 (C-9), 126.8 (C-6), 129.3 (C-8), 130.3 (C-7), 146.8 (C-4), 148.2 (C-10), 150.4 (C-2).

rac-6-Bromo-4-(2-methyloxiran-2-yl)quinoline (6b)

Yield: 75%; Mp.: 70 °C; 1H NMR (500 MHz, CDCl3) δ 1.80 (s, 3H, C–CH3), 2.96 (d, J = 5.1 Hz, 1H, C–CH2–O), 3.21 (d, J = 5.2 Hz, 1H, C–CH2–O), 7.52 (d, J = 4.4 Hz, 1H, C-3 H), 7.70 (dd, J = 9.0, 2.2 Hz, 1H, C-7 H), 8.08–8.13 (m, 2H, C-8 H, C-5 H), 8.87 (d, J = 4.4 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 23.7 (C–CH3), 54.4 (C–CH2–O), 56.9 (O–C–CH2), 119.5(C-3), 122.1(C-6), 123.1(C-5), 126.4 (C-9), 130.4 (C-8), 132.8 (C-7), 146.2 (C-4), 146.6 (C-10), 150.6 (C-2).

rac-6-Chloro-4-(2-methyloxiran-2-yl)quinoline (6c)

Yield: 76%; Mp.: 74 °C; 1H NMR (500 MHz, CDCl3) δ 1.79 (s, 3H, C–CH3), 2.94 (d, J = 5.1 Hz, 1H, C–CH2–O), 3.19 (d, J = 5.2 Hz, 1H, C–CH2–O), 7.49 (d, J = 4.4 Hz, 1H, C-3 H), 7.67 (dd, J = 9.0, 2.2 Hz, 1H, C-7 H), 8.07–8.13 (m, 2H, C-5 H, C-8 H), 8.89 (d, J = 4.4 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 23.7 (C–CH3), 54.4 (C–CH2–O), 56.0 (O–C–CH2), 119.5 (C-3), 123.0 (C-5), 126.3 (C-9), 130.3 (C-8), 132.0 (C-7), 132.8 (C-6), 146.1 (C-4), 146.6 (C-10), 150.6 (C-2).

rac-6-Fluoro-4-(2-methyloxiran-2-yl)quinoline (6d)

Yield: 70%; Mp. 65 °C; 1H NMR (500 MHz, CDCl3) 1.78 (s, 3H, C–CH3), 2.94 (d, J = 5.2 Hz, 1H, C–CH2–O), 3.18 (d, J = 5.2 Hz, 1H, C–CH2–O),7.45–7.55 (m, 2H, C-7 H, C-3 H), 7.72 (dd, J = 9.7, 2.8 Hz, 1H, C-5 H), 8.15 (dd, J = 9.3, 5.6 Hz, 1H, C-8 H), 8.87 (d, J = 4.4 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 23.5 (C–CH3), 54.3 (C–CH2–O), 57.0 (O–C–CH2), 107.6 and 107.8 (C-5, J = 25.2 Hz), 119.3 and 119.5 (C-7, J = 25.2 Hz), 119.7 (C-3), 126.4 (C-10), 132.9 (C-8), 145.4 (C-4), 146.4 (C-9), 149.6 (C-2), 159.4 and 161.5 (C-6, J = 264.6 Hz).

General procedure for compound ( ±) 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a-p)

To the alcoholic solvent (7a–d) (10 mL), sodium metal (3.0 mmol) was added slowly under a nitrogen atmosphere and continued the reaction by stirring for 5 min. To this sodium alkoxide solution, 6-substituted-4-(2-methyloxiran-2-yl)quinoline (6a–d) was added and the reaction mixture was heated to 70–75 °C for 6 h. Reaction progress was monitored by the TLC. After the complete consumption of starting material, the solvent was distilled on a rotary evaporator. The residue was diluted with water and extracted with ethyl acetate (3 × 30 mL), the organic layer was washed with brine and dried over sodium sulfate and distilled under a vacuum. The crude product was purified by column chromatography furnished 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p).

rac-1-Methoxy-2-(quinolin-4-yl)propan-2-ol (8a)

1H NMR (500 MHz, CDCl3) δ 1.77 (s, 3H, C–CH3), 3.42 (s, 3H, O–CH3), 3.49 (s, 1H, OH), 3.72 (d, J = 9.3 Hz, 1H, C–CH2–O), 4.06 (d, J = 9.3 Hz, 1H, C–CH2–O), 7.47 (d, J = 4.6 Hz, 1H, C-3 H), 7.52–7.55 (m, 1H, C-6 H), 7.66–7.70 (m, 1H C-7 H), 8.13 (dd, J = 8.5, 1.0 Hz, 1H, C-8 H), 8.63 (dd, J = 8.7, 0.7 Hz, 1H, C-5 H), 8.84 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 26.4 (C–CH3), 59.5 (O–CH3), 74.8 (HO–C–), 79.2 (C–CH2–O), 118.5 (C-3), 125.9 (C-5), 126.3 (C-9), 126.4 (C-6), 128.6 (C-8), 130.7 (C-7), 149.4 (C-4), 149.9 (C-10), 149.9 (C-2); HRMS (m/z): calculated for C13H16NO2: 218.1181(M + H) + , found 218.1186.

rac-1-Ethoxy-2-(quinolin-4-yl)propan-2-ol (8b)

1H NMR (500 MHz, CDCl3) δ 1.18 (t, J = 7.0 Hz, 3H, H3C–CH2), 1.76 (s, 3H, C–CH3), 3.57 (q, J = 7.0 Hz, 2H O–CH2–CH3), 3.66 (s, 1H, OH), 3.74 (d, J = 9.4 Hz, 1H, C–CH2–O), 4.07 (d, J = 9.4 Hz, 1H, C–CH2–O), 7.47 (d, J = 4.7 Hz, 1H, C-3 H), 7.52–7.54 (m, 1H, C-6 H), 7.65–7.69 (m, 1H, C-7 H), 8.13 (dd, J = 8.5, 1.0 Hz, 1H, C-8 H), 8.65 (dd, J = 8.7, 0.7 Hz, 1H, C-5 H), 8.82 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 15.0 (H3C–CH2–O), 26.5 (C–CH3), 67.2 (O–CH2), 74.7 (HO–C–), 77.0 (C–CH2–O), 118.5 (C-3), 125.8 (C-5), 126.3 (C-9), 126.5 (C-6), 128.6 (C-8), 130.6 (C-7), 149.3 (C-4), 149.9 (C-10), 150.1 (C-2); HRMS (m/z): calculated for C14H18NO2: 232.1338(M + H) + , found 232.1337.

rac-1-Propoxy-2-(quinolin-4-yl)propan-2-ol (8c)

1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.4 Hz, 3H, H3C–CH2), 1.54–1.58 (m, 2H, H3C–CH2–CH2–O), 1.77 (s, 3H, C–CH3), 3.51–3.43 (m, 2H, O–CH2–CH2), 3.58 (s, 1H, OH), 3.75 (d, J = 9.3 Hz, 1H, C–CH2–O), 4.06 (d, J = 9.3 Hz, 1H, C–CH2–O), 7.47 (d, J = 4.7 Hz, 1H, C-3 H), 7.53 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H, C-6 H), 7.71–7.65 (m, 1H, C-7 H), 8.13 (dd, J = 8.4, 1.0 Hz, 1H, C-8 H), 8.68–8.63 (m, 1H, C-5 H), 8.83 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 10.5 (H3C–CH2–CH2–O), 22.7 (H3C–CH2–CH2–O), 26.5 (C–CH3), 73.4 (O–CH2), 74.9 (HO–C–), 77.1(CH2–CH2–O), 118.5 (C-3), 125.8 (C-5), 126.4 (C-9), 126.5 (C-6), 128.6 (C-8), 130.6 (C-7), 149.3 (C-4), 149.9 (C-10), 150.0 (C-2); HRMS (m/z): calculated for C15H20NO2: 246.1494(M + H) + , found: 246.1498.

rac-1-Butoxy-2-(quinolin-4-yl)propan-2-ol (8d)

1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.4 Hz, 3H, H3C–CH2), 1.35 – 1.26 (m, 2H, H3C–CH2–CH2), 1.56 – 1.49 (m, 2H, H2C–CH2–CH2–O),1.76 (s, 3H, C–CH3), 3.48 – 3.52 (m, 2H CH2–CH2–O), 3.57 (s, 1H, OH), 3.74 (d, J = 9.3 Hz, 1H, C–CH2–O), 4.06 (d, J = 9.3 Hz, 1H, C–CH2–O), 7.47 (d, J = 4.7 Hz, 1H C-3 H), 7.53 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H, C-6 H), 7.67 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H, C-7 H), 8.13 (dd, J = 8.4, 1.0 Hz, 1H, C-8 H), 8.65 (dd, J = 8.7, 0.7 Hz, 1H, C-5 H), 8.83 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 13.8 (H3C–CH2–CH2–CH2–O), 19.3 (H3C–CH2–CH2–CH2–O), 26.5 (C–CH3), 31.5 (H3C–CH2–CH2–CH2–O), 71.6 (O–CH2), 74.8 (HO–C–), 77.2 (H3C–CH2–CH2–CH2–O), 118.5 (C-3), 125.8 (C-5), 126.3 (C-9), 126.5 (C-6), 128.6 (C-8), 130.6 (C-7), 149.3 (C-3), 149.9 (C-10), 150.1 (C-2), HRMS (m/z): calculated for C16H22NO2: 260.1651 (M + H) + , found 260.1651.

rac-2-(6-Bromoquinolin-4-yl)-1-methoxypropan-2-ol (8e)

1H NMR (500 MHz, CDCl3) δ 1.68 (s, 3H, C–CH3), 3.33 (s, 3H, O–CH3), 3.68 (d, J = 9.3 Hz, 1H, C–CH2–O), 3.78 (d, J = 9.3 Hz, 1H, C–CH2–O), 5.26 (s, 1H, OH), 7.42 (t, J = 4.4 Hz, 1H, C-3 H), 7.71–7.63 (m, 1H, C-7 H), 7.89 (d, J = 8.8 Hz, 1H, C-8 H), 8.77 (d, J = 4.4 Hz, 1H, C-2 H), 9.09 (d, J = 2.4 Hz, 1H, C-5 H); 13C NMR (125 MHz, CDCl3) δ 31.4 (C–CH3), 64.2 (O–CH3), 79.5 (HO–C–CH2), 84.8 (C–CH2–O), 124.2 (C-6), 124.5 (C-3), 132.7 (C-10), 134.4 (C-5), 134.6 (C-8), 136.6 (C-7), 152.6 (C-4), 154.9 (C-9), 155.1 (C-2); HRMS (m/z): calculated for C13H15BrNO2: 296.0286(M + H) + , 296.291.

rac-2-(6-Bromoquinolin-4-yl)-1-ethoxypropan-2-ol (8f)

1H NMR (500 MHz, CDCl3) δ 1.21 (t, J = 7.0 Hz, 3H, H3C–CH2–O), 1.73 (s, 3H, C–CH3), 3.45 (s, 1H, OH), 3.63–3.57 (q, J = 7.0 Hz, 2H, O–CH2–CH3), 3.69 (d, J = 9.4 Hz, 1H, C–CH2–O), 4.05 (d, J = 9.4 Hz, 1H, C–CH2–O), 7.43 (d, J = 4.7 Hz, 1H, C-3 H), 7.75 (dd, J = 9.0, 2.2 Hz, 1H, C-7 H), 7.99 (d, J = 9.0 Hz, 1H, C-8 H), 8.84 (d, J = 3.8 Hz, 1H, C-2 H), 8.93 (d, J = 2.1 Hz, 1H, C-5 H); 13C NMR (125 MHz, CDCl3) δ 15.0 (H3C–CH2–O), 26.7 (C–CH3), 67.2 (H3C–CH2–O), 74.8 (HO–C–CH2), 76.8 (C–CH2–O), 119.1 (C-3), 120.1 (C-6), 127.6 (C-10), 129.0 (C-5), 132.1 (C-8), 132.2 (C-7), 148.0 (C-4), 149.2 (C-9), 150.2 (C-2); HRMS (m/z): calculated for C14H17BrNO2: 310.0443(M + H) + , 310.0450.

rac-2-(6-Bromoquinolin-4-yl)-1-propoxypropan-2-ol (8 g)

1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.4 Hz, 3H, H3C–CH2–CH2–O), 1.56–1.61 (m, 2H, H3C–CH2–CH2–O), 1.73 (s, 3H, C–CH3), 3.50 (t, J = 6.6 Hz, 2H, H3C–CH2–CH2–O), 3.69 (d, J = 9.4 Hz, 1H, C–CH2–O), 4.04 (d, J = 9.3 Hz, 1H, C–CH2–O), 7.42 (d, J = 4.6 Hz, 1H, C-3 H), 7.74 (dd, J = 9.0, 1.9 Hz, 1H, C-7 H), 7.98 (d, J = 9.0 Hz, 1H, C-8 H), 8.83 (t, J = 4.6 Hz, 1H, C-2 H), 8.94 (d, J = 1.9 Hz, 1H, C-5 H); 13C NMR (125 MHz, CDCl3) δ 10.5 (H3C–CH2–CH2–O), 22.7 (H3C–CH2–CH2–O), 26.6 (C–CH3), 73.5 (H3C–CH2–CH2–O), 74.9 (HO–C–CH2), 77.0 (C–CH2–O), 119.1 (C-3), 120.1 (C-6), 127.6 (C-10), 129.1 (C-5), 132.1 (C-8), 132.2(C-7), 148.0 (C-4), 149.3 (C-9), 150.1 (C-2); HRMS (m/z): calculated for C15H19BrNO2: 324.0599(M + H) + , found: 324.0606.

rac-2-(6-Bromoquinolin-4-yl)-1-butoxypropan-2-ol (8 h)

1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.3 Hz, 3H, H3C–CH2–CH2–CH2–O), 1.34–1.30 (m, 2H, H3C–CH2–CH2–CH2–O), 1.57–1.53 (m, 2H, H3C–CH2–CH2–CH2–O), 1.73 (s, 3H, C–CH3), 3.48 (s, 1H, HO–), 3.54 (t, J = 6.5 Hz, 2H, O–CH2–CH2–CH2–CH3), 3.69 (d, J = 9.3 Hz, 1H, C–CH2–O), 4.03 (d, J = 9.3 Hz, 1H, C–CH2–O), 7.42 (d, J = 4.7 Hz, 1H, C-3 H), 7.74 (dd, J = 9.0, 2.0 Hz, 1H, C-7 H), 7.98 (d, J = 9.0 Hz, 1H, C-8 H), 8.83 (dd, J = 7.8, 4.7 Hz, 1H, C-2 H), 8.94 (d, J = 2.0 Hz, 1H, C-5 H); 13C NMR (125 MHz, CDCl3) δ 13.8 (H3C–CH2–CH2–CH2–O), 19.3 (H3C–CH2–CH2–CH2–O), 26.6, 31.5 (H3C–CH2–CH2–CH2–O), 71.6 (O–CH2–CH2–CH2–CH3), 74.9 (HO–C–CH2), 76.8 (C–CH2–O), 119.1 (C-3), 120.1(C-6), 127.6 (C-10), 129.1 (C-5), 132.1(C-8), 132.2(C-7), 148.0(C-4), 149.3 (C-9), 150.1(C-2); HRMS (m/z): calculated for C16H21BrNO2: 338.0756(M + H) + , found: 338.0764.

rac-2-(6-Chloroquinolin-4-yl)-1-methoxypropan-2-ol (8i)

1H NMR (500 MHz, CDCl3) δ 1.75 (s, 3H, C–CH3), 3.00 (s, 1H, HO–), 3.40 (s, 3H, O–CH3), 3.75 (d, J = 6.8 Hz, 1H, C–CH2–O), 3.88 (d, J = 6.9 Hz, 1H, C–CH2–O), 7.49 (d, J = 4.4 Hz, 1H, C-3 H), 7.59 – 7.63 (m, 1H, C-7 H), 8.03 (d, J = 9.0 Hz, 1H, C-8 H), 8.82 (d, J = 2.3 Hz, 1H, C-5 H), 8.94 (d, J = 4.7 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 31.3 (C–CH3), 64.2 (O–CH3), 79.5 (HO–C–CH2), 84.7 (C–CH2–O), 124.4 (C-3), 131.0 (C-5), 131.2 (C-10), 132.1 (C-8), 134.1 (C-6), 135.9 (C-7), 152.6 (C-4), 152.4 (C-9), 154.9 (C-2); HRMS (m/z): calculated for C13H15ClNO2: 252.0791(M + H) + , found: 252.0792.

rac-2-(6-Chloroquinolin-4-yl)-1-ethoxypropan-2-ol (8j)

1H NMR (500 MHz, CDCl3) δ 1.21 (t, J = 7.0 Hz, 3H, H3C–CH2–O), 1.73 (s, 3H, C–CH3), 3.45 (s, 1H, HO–), 3.60 (q, J = 7.0 Hz, 2H, O–CH2–CH3), 3.69 (d, J = 9.4 Hz, 1H, C–CH2–O), 4.05 (d, J = 9.4 Hz, 1H, C–CH2–O), 7.43 (d, J = 4.7 Hz, 1H, C-3 H), 7.62 (dd, J = 9.0, 2.3 Hz, 1H, C-7 H), 8.05 (d, J = 9.0 Hz, 1H, C-8 H), 8.75 (d, J = 2.3 Hz, 1H, C-5 H), 8.82 (d, J = 4.7 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 15.0 (H3C–CH2–O), 26.6 (C–CH3), 67.2 (O–CH2–CH3), 74.8 (HO–C–CH2), 76.8 (C–CH2–O), 119.2 (C-3), 125.8 (C-5), 127.1 (C-10), 129.6 (C-8), 131.7 (C-6), 132.0 (C-7), 147.8 (C-4), 149.3 (C-9), 150.0 (C-2); HRMS (m/z): calculated for C14H17ClNO2: 266.0948(M + H) + , found: 266.0955.

rac-2-(6-Chloroquinolin-4-yl)-1-propoxypropan-2-ol (8 k)

1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.0 Hz, 3H, H3C–CH2–CH2–O), 1.57–1.61 (m, 2H H3C-CH2-CH2-O), 1.73 (s, 3H, C–CH3), 3.49 (t, J = 6.6 Hz, 2H, O–CH2–CH2–CH3), 3.60 (s, 1H, HO–), 3.69 (d, J = 9.4 Hz, 1H, C–CH2–O), 4.04 (d, J = 9.4 Hz, 1H, C–CH2–O), 7.42 (d, J = 4.7 Hz, 1H, C-3 H), 7.61 (dd, J = 9.0, 2.3 Hz, 1H, C-7 H), 8.05 (d, J = 9.0 Hz, 1H, C-8 H), 8.77 (d, J = 2.3 Hz, 1H, C-5 H), 8.79 (t, J = 4.7 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 10.5 (H3C–CH2–CH2–O), 22.7 (H3C–CH2–CH2–O), 26.6 (C–CH3), 73.5 (O–CH2–CH2–CH3), 74.9 (HO–C–CH2), 77.0 (C–CH2–O), 119.2 (C-3), 125.8 (C-5), 127.1 (C-10), 129.6 (C-8), 131.7 (C-2), 132.0 (C-7), 147.8(C-4), 149.4 (C-9), 149.9 (C-2); HRMS (m/z): calculated for C15H19ClNO2: 280.1104(M + H) + , found: 280.1107.

rac-1-Butoxy-2-(6-chloroquinolin-4-yl)propan-2-ol (8 l)

1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.0 Hz, 3H, H3C–CH2–CH2–CH2–O), 1.30–1.35 (m, 2H, H3C–CH2–CH2–CH2–O) 1.54–1.56 (m, 2H, H3C–CH2–CH2–CH2–O), 1.73 (s, 3H, C–CH3), 3.50 (s, 1H, HO–), 3.54 (t, J = 6.5 Hz, 2H O–CH2–CH2–CH2–CH3), 3.69 (d, J = 9.3 Hz, 1H, C–CH2–O), 4.04 (d, J = 9.3 Hz, 1H, C–CH2–O), 7.42 (d, J = 4.7 Hz, 1H, C-3 H), 7.62 (dd, J = 9.0, 2.3 Hz, 1H, C-7 H), 8.06 (d, J = 9.0 Hz, 1H, C-8 H), 8.76 (d, J = 2.3 Hz, 1H, C-2 H), 8.81 (d, J = 4.7 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 13.9 (H3C–CH2–CH2–CH2–O), 19.3 (H3C–CH2–CH2–CH2–O), 26.6 (C–CH3), 31.5 (H3C–CH2–CH2–CH2–O), 71.6 (O–CH2–CH2–CH2–CH3), 74.9 (HO–C–CH2), 77.0 (C–CH2–O), 119.2 (C-3), 125.8 (C-5), 127.1 (C-10), 129.6 (C-8), 131.7 (C-2), 132.0 (C-7), 147.8 (C-9), 149.4 (C-9), 150.0 (C-2); HRMS (m/z): calculated for C16H21ClNO2: 294.1261(M + H) + , found: 294.1266.

rac-2-(6-Fluoroquinolin-4-yl)-1-methoxypropan-2-ol (8 m)

1H NMR (500 MHz, CDCl3) δ 1.72 (s, 3H, C–CH3), 3.43 (s, 3H, O–CH3), 3.66 (d, J = 9.4 Hz, 1H, C–CH2–O), 4.02 (d, J = 9.4 Hz, 1H, C–CH2–O), 7.41 (d, J = 4.6 Hz, 1H, C-3 H), 7.45 (ddd, J = 9.3, 7.7, 2.8 Hz, 1H, C-7 H), 8.10 (dd, J = 9.2, 6.0 Hz, 1H, C-8 H), 8.39 (dd, J = 11.7, 2.8 Hz, 1H, C-5 H), 8.76 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 26.2 (C–CH3), 59.4 (O–CH3), 74.9 (HO–C–CH2), 79.0 (C–CH2–O), 110.4 and 110.6 (C-5, J = 23.94 Hz), 118.8 and 119.0 (C-7, J = 21.42 Hz), 119.0 (C-3), 127.0 and 127.1 (C-10, J = 10.08 Hz), 132.7 and 132.8 (C-8, J = 8.82 Hz), 146.5 (C-2), 149.0 and 149.1 (C-4, J = 2.52 Hz), 149.3 and 149.4 (C-9, J = 5.04 Hz), 158.6 and 160.6 (C-6, J = 246.96 Hz); HRMS (m/z): calculated for C13H15FNO2: 236.1087(M + H) + , found: 236.1092.

rac-1-Ethoxy-2-(6-fluoroquinolin-4-yl)propan-2-ol (8n)

1H NMR (500 MHz, CDCl3) δ 1.20 (t, J = 7.0 Hz, 3H, CH3–CH2–O), 1.73 (s, 3H, C–CH3), 3.51 (s, 1H, HO–), 3.60 (q, J = 7.0 Hz, 2H, O–CH2–CH3), 3.69 (d, J = 9.4 Hz, 1H, C–CH2–O), 4.06 (d, J = 9.4 Hz, 1H, C–CH2–O), 7.42 (d, J = 4.6 Hz, 1H, C-3 H), 7.46 (ddd, J = 9.3, 7.7, 2.8 Hz, 1H, C-7 H), 8.11 (dd, J = 9.2, 6.0 Hz, 1H, C-8 H), 8.39 (dd, J = 11.7, 2.8 Hz, 1H, C-5 H), 8.79 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 15.0 (CH3–CH2–O), 26.4 (C–CH3), 67.2 (O–CH2–CH3), 74.8 (HO–C–CH2), 76.7 (C–CH2–O), 110.5 and 110.7 (C-5, J = 23.94 Hz), 118.8 and 119.0 (C-7, J = 23.94 Hz), 119.0 (C-3), 127.1 and 127.2 (C-10, J = 10.08 Hz), 132.7 and 132.8 (C-8, J = 10.08 Hz), 146.6 (C-2), 149.1 and 149.1 (C-4, J = 2.52 Hz), 149.4 and 149.5 (C-9, J = 5.04 Hz), 158.6 and 160.6 (C-6, J = 246.96 Hz); HRMS (m/z): calculated for C14H17FNO2: 250.1243(M + H) + , found: 250.1247.

rac-2-(6-Fluoroquinolin-4-yl)-1-propoxypropan-2-ol (8o)

1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.4 Hz, 3H, CH3–CH2–CH2–O), 1.64 – 1.55 (m, 2H, CH3–CH2–CH2–O), 1.73 (s, 3H, C–CH3), 3.45 (s, 1H, HO), 3.51 (t, J = 7.4 Hz, 2H, O–CH2–CH2–CH3), 3.69 (d, J = 9.3 Hz, 1H, C–CH2–O), 4.05 (d, J = 9.3 Hz, 1H, C–CH2–O), 7.42 (d, J = 4.5 Hz, 1H, C-3 H), 7.46 (ddd, J = 9.3, 7.7, 2.8 Hz, 1H, C-7 H), 8.12 (dd, J = 9.2, 6.0 Hz, 1H, C-8 H), 8.40 (dd, J = 11.7, 2.8 Hz, 1H, C-5 H), 8.80 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 10.5 (CH3–CH2–CH2–O), 22.7 (CH3–CH2–CH2–O), 26.3 (C–CH3), 73.5 (O–CH2–CH2–CH3), 74.9 (HO–C–CH2), 76.9 (C–CH2–O), 110.5 and 110.7 (C-5, J = 23.94 Hz), 118.8 and 119.0 (C-7, J = 22.68 Hz), 119.1 (C-3), 127.2 and 127.1 (C-10, J = 10.08 Hz), 132.7 and 132.8 (C-8, J = 10.08 Hz), 146.6 (C-2), 149.1 and 149.1 (C-4, J = 3.78 Hz), 149.4 and 149.5 (C-9, J = 5.04 Hz), 158.6 and 160.59 (C-6, J = 246.96 Hz); HRMS (m/z): calculated for C15H19FNO2: 264.1400(M + H) + , found: 264.1411.

rac-1-Butoxy-2-(6-fluoroquinolin-4-yl)propan-2-ol (8p)

1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.4 Hz, 3H, CH3–CH2–CH2–CH2–O), 1.35 – 1.30 (m, 2H, CH3–CH2–CH2–CH2–O), 1.59 – 1.51 (m, 2H, CH3–CH2–CH2–CH2–O), 1.73 (s, 3H, C–CH3), 3.50 (s, 1H, HO–), 3.53 (t, J = 6.5 Hz, 2H, O–CH2–CH2–CH2–CH3), 3.70 (t, J = 9.0 Hz, 1H, C–CH2–O), 4.04 (d, J = 9.0 Hz, 1H, C–CH2–O), 7.41 (d, J = 4.6 Hz, 1H, C-3 H), 7.46 (ddd, J = 9.3, 7.7, 2.8 Hz, 1H, C-7 H), 8.11 (dd, J = 9.2, 6.0 Hz, 1H, C-8 H), 8.40 (dd, J = 11.7, 2.8 Hz, 1H, C-5 H), 8.79 (d, J = 4.6 Hz, 1H, C-2 H); 13C NMR (125 MHz, CDCl3) δ 13.8 (CH3–CH2–CH2–CH2–O), 19.3(CH3–CH2–CH2–CH2–O), 26.3 (C–CH3), 31.5 (CH3–CH2–CH2–CH2–O), 71.6 (O–CH2–CH2–CH2–CH3), 74.9 (HO–C–CH2), 76.9 (C–CH2–O), 110.5 and 110.7 (C-5, J = 25.2 Hz), 118.8 and 119.0 (C-7, J = 52.2 Hz), 127.1 and 127.2 (C-10, J = 10.08 Hz), 132.7 and 132.8 (C-8, J = 8.82 Hz), 146.5 (C-2), 149.1 and 149.1 (C-4, J = 2.52 Hz), 149.5 and 149.5 (C-9, J = 5.02 Hz), 158.6 and 160.6 (C-6, J = 246.96 Hz); HRMS (m/z): calculated for C16H21FNO2: 278.1556(M + H) + , found: 278.1561.

Biology

Antitubercular assay

The antitubercular activity against M. tuberculosis H37 RV (ATCC No-27294) strain was carried out using microplate Almar Blue assay (MABA) (Lourenço et al. 2007; Franzblau et al 1998). This methodology is non-toxic, use a thermally stable reagent, and shows a good correlation with the proportional and BACTEC radiometric methods. Briefly, the addition of 200 μL of sterile de-ionized water to all outer perimeter wells of the sterile 96 wells plate to avoid the evaporation of medium in the test wells during incubation. The plates of 96 wells received 100 μL of the Middlebrook 7H9 broth and sequential dilution of compounds was made directly on the plate. Finally, drugs of 100 to 0.2 μg/mL concentrations were tested. The plates were incubated at 37 ºC for 5 days. 10% between 80 and 25 μL of freshly prepared 1:1 mixture of Almar Blue reagent was added to the plate and incubated for 24 h. The development of blue color in the well was interpreted as no bacterial growth, and the pink color was scored as growth. Further, the MIC was defined as the lowest drug concentration which prevented the color change from blue to pink.

Antibacterial activity

The in vitro antibacterial screening was carried out by the well diffusion method (NCCLS 2002; Joshi et al. 2015) against the standard strains of Gram-negative bacteria coli (NCIM 2574), Proteus mirabilis (NCIM 2388) and Gram-positive bacteria Bacillus subtilis (NCIM 2063) and Staphylococcus albus (NCIM 2178). All the strains were procured from the National Collection of Industrial Microorganisms (NCIM) NCL, Pune, India. All bacterial cultures were maintained at 4 ºC over nutrient agar slants throughout the experiment, the cultures were incubated overnight at 37 ºC in nutrient broth. Five hundred microliters of 24-48 h old fresh bacterial culture were spread over the nutrient agar plates. A sterile cotton swab was used for inoculation of the cultures in order to get uniform microbial growth. With the help of well borer, 5 mm diameter wells were punched on the agar plates. The synthesized compounds were dissolved in DMSO. The wells were filled with 80 µL solution of respective synthesized compounds in DMSO. As a vehicle control, DMSO was added to one agar plate. The plates were incubated for a period of 24–48 h at 37 ºC. After the incubation period, the antimicrobial activity was evaluated by measuring the zone of inhibition in mm using a measuring scale and the average was calculated. Each experiment was carried out in 5 replicates. The MIC was evaluated at 250, 125, 62.5, 31.25, 15.62, 7.81 and 3.90 µg/mL concentrations. The lowest concentration that showed no growth was considered the MIC.

Antifungal activity

The in vitro antifungal activity was carried out by the well diffusion method (NCCLS 2002; Joshi et al. 2015) against C. albicans (NCIM 3100) and A. niger (NCIM 504). The fungal strains were obtained from NCIM, NCL, Pune, India. The pure cultures were maintained by routine sub-culturing after every one-month interval on Potato Dextrose Agar slants (Hi-Media lab. Pvt. Ltd, Mumbai, India). Mueller Hinton agar plates were prepared by pouring 20 mL in each sterile petri—plate for fungal assay and allowed to solidify. During the assay, standard fungal cultures were grown on Potato-Dextrose broth. Five hundred microliters of 48–72 h old fresh fungal spore suspension were spread on the agar plates using a sterile cotton swab to get uniform growth. With the help of a well borer, 5 mm diameter wells were punched on the agar plates. The wells were filled with 80 µL of the samples. A standard plate with Fluconazole and Ravuconazole was used as a positive control. The plates were incubated for a period of 48–72 h at 30 °C. After the incubation period, the plates were observed for the clear zone of inhibition and it is measured in mm using a measuring scale and the mean was calculated. The experiments were carried out in five replicates. The micro-dilution susceptibility test in Sabouraud Liquid Medium (Oxoid) was used for the determination of minimum inhibition concentration (MIC). The stock solutions of the test compounds and reference drug were prepared in the DMSO at the concentration of 500 µg/mL. The MIC was evaluated at 250, 125, 62.5, 31.25, 15.62, 7.81, and 3.90 µg/mL concentrations. The tubes were inoculated with the test organisms, grown in the Potato-Dextrose broth. The tubes were kept for incubation for 48–72 h at 30 °C. The lowest concentration that showed no growth was considered the MIC.

Conclusions

In conclusion, a series of 2-(6-substituted quinolin-4-yl)-1-alkoxypropan-2-ol (8a–p) derivatives have been synthesized and screened for antitubercular and antimicrobial activities. Among the sixteen derivatives, thirteen derivatives (8a–m) showed moderate to good antitubercular activity M. tuberculosis, H37RV strain with MIC 3.12–25 µg/mL. Compounds 1-methoxy-2-(quinolin-4-yl)propan-2-ol (8a) and 2-(6-bromoquinolin-4-yl)-1-butoxypropan-2-ol (8 h) showed comparable and two-fold less antitubercular activity in comparison with the standard drug Pyrazinamide and Isoniazid, respectively. Compounds 8c and 8n showed good activity against P. mirabilis, and E. coli., respectively. Six compounds 8c, 8d, 8e, 8g, 8k and 8o exhibited good activity against S. albus with MIC 31.25–62.5 µg/mL. Therefore, the results warrant the need for a synthesis of quinoline-propanol libraries with a modification to ascertain the trend described in this work.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 12176 KB) (11.9MB, docx)

Acknowledgements

ADS expresses her gratefulness to the CSIR-SRF fellowship for the financial support (File No. 08/319(000 4)/2017-EMR-1). The authors are thankful to CSIR-NCL, Pune for supporting the biological activity; DST, New Delhi, S. P. Mandali Pune, and Dr. T. R. Ingle Research Foundation, Pune for the infrastructural support. CIF, Savitribai Phule Pune University, Pune are also acknowledged for their spectral analysis.

Author contributions

Synthesis and purification of compounds: AS, PPT, YN, AC, ALNS. The idea of research scheme, analysis and manuscript writing: YN, PCM.

Declarations

Conflict of interest

These compounds are claimed as exemplifications in a patent application (Mhaske et al. 2021) All authors declare that they have no conflict of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. Bald D, Villellas C, Lu P, Koul A. Targeting energy metabolism in Mycobacterium tuberculosis, a new paradigm in antimycobacterial drug discovery. Mbio. 2017;8:1–11. doi: 10.1128/mBio.00272-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bollu R, Banu S, Kasaboina S, Bantu R, Nagarapu L, Polepalli S, Jain N. Potential anti-proliferative agents from 1,4-benzoxazinone-quinazolin-4(3H)-one templates. Bioorg Med Chem Lett. 2017;27:5481–5484. doi: 10.1016/j.bmcl.2017.10.044. [DOI] [PubMed] [Google Scholar]
  3. Cohen J. Infectious disease. Approval of novel TB drug celebrated-with restraint. Science. 2013;339:130. doi: 10.1126/science.339.6116.130. [DOI] [PubMed] [Google Scholar]
  4. De la Guardia C, Stephens DE, Dang HT, Quijada M, Larionov OV, Lleonart R. Antiviral activity of novel quinoline derivatives against dengue virus serotype-2. Molecules. 2018;23:672–683. doi: 10.3390/molecules23030672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, Hernandez A, Degnan MT, Cook MB, Quenzer VK, Ferguson RM, Gilman RH. Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay. J Clin Microbiol. 1998;36:362–366. doi: 10.1128/jcm.36.2.362-366.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Global tuberculosis report 2020. Geneva: World Health Organization; 2020. License: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240013131. Accessed 08 Aug 2022
  7. Global tuberculosis report 2021. Geneva: World Health Organization; 2021. License: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240037021 Accessed 08 Aug 2022, https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2021 Accessed 08 Aug 2022
  8. Gonçalves RSB, Kaiser CR, Lourenço MCS, de Souza MVN, Wardell JL, Wardell SMSV, da Silva AD. Synthesis and antitubercular activity of new mefloquine-oxazolidine derivatives. Eur J Med Chem. 2010;45:6095–6100. doi: 10.1016/j.ejmech.2010.09.024. [DOI] [PubMed] [Google Scholar]
  9. Gupta SK, Mishra A. Synthesis, characterization & screening for anti-inflammatory & analgesic activity of quinoline derivatives bearing azetidinones scaffolds. Antiinflamm Antiallergy Agents Med Chem. 2016;15:31–43. doi: 10.2174/1871523015666160210124545. [DOI] [PubMed] [Google Scholar]
  10. Hu Y, Gao C, Zhang S, Xu L, Xu Z, Feng L. Quinoline hybrids and their antiplasmodial and antimalarial activities. Eur J Med Chem. 2017;139:22–47. doi: 10.1016/j.ejmech.2017.07.061. [DOI] [PubMed] [Google Scholar]
  11. Hu Y, Zhang S, Xu Z, Lv Z, Liu M, Feng L. 4-Quinolone hybrids and their antibacterial activities. Eur J Med Chem. 2017;141:335–345. doi: 10.1016/j.ejmech.2017.09.050. [DOI] [PubMed] [Google Scholar]
  12. Joshi AB, Mali M, Kulkarni V. Phytochemical screening and antimicrobial activity of stevia rebaudiana leaves. Int J Curr Microbiol App Sci. 2015;4(10):678–685. [Google Scholar]
  13. Kalaria PN, Karad SC, Raval DK. A review on diverse heterocyclic compounds as the privileged scaffolds in antimalarial drug discovery. Eur J Med Chem. 2018;158:917–936. doi: 10.1016/j.ejmech.2018.08.040. [DOI] [PubMed] [Google Scholar]
  14. Keri RS, Patil SA. Quinoline: a promising antitubercular target. Biomed Pharmacother. 2014;68:1161–1175. doi: 10.1016/j.biopha.2014.10.007. [DOI] [PubMed] [Google Scholar]
  15. Lilienkampf A, Mao J, Wan B, Wang Y, Franzblau SG, Kozikowski AP. Structure-activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating Mycobacterium tuberculosis. J Med Chem. 2009;52:2109–2118. doi: 10.1021/jm900003c. [DOI] [PubMed] [Google Scholar]
  16. Lilienkampf A, Pieroni M, Franzblau SG, Bishai WR, Kozikowski AP. Derivatives of 3-isoxazolecarboxylic acid esters—a potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis. Curr Top Med Chem. 2012;12:729–734. doi: 10.2174/156802612799984544. [DOI] [PubMed] [Google Scholar]
  17. Lourenço MCS, de Souza MVN, Pinheiro AC, de Ferreira ML, Gonçalves RSB, Nogueira TCM, Peralta MA. Evaluation of anti-Tubercular activity of nicotinic and isoniazid analogues. ARKIVOC. 2007;2007:181–191. doi: 10.3998/ark.5550190.0008.f18. [DOI] [Google Scholar]
  18. Mabhula A, Singh V. Drug-resistance in Mycobacterium tuberculosis: where we stand. Medchemcomm. 2019;10:1342–1360. doi: 10.1039/c9md00057g. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Marella A, Tanwar O, Saha R, Ali MR, Srivastava S, Akhter M, Shaquiquzzaman M, Alam M. Quinoline: a versatile heterocyclic. Saudi Pharm J. 2013;21:1–12. doi: 10.1016/j.jsps.2012.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mhaske P, Thakare P, Shinde A, Chavan A (2021) Antimicrobial derivatives of substituted quinoline and method of manufacturing the same. IN202121016860 A
  21. Nayak N, Ramprasad J, Dalimba U. New INH-pyrazole analogs: design, synthesis and evaluation of antitubercular and antibacterial activity. Bioorg Med Chem Lett. 2015;25:5540–5545. doi: 10.1016/j.bmcl.2015.10.057. [DOI] [PubMed] [Google Scholar]
  22. NCCLS (National Committee for Clinical Laboratory Standards) (2002) Method for dilution antimicrobial susceptibility tests of bacteria that grow aerobically. Approv. Stand. Wayne PA.; M100-S12
  23. Nguyen L. Antibiotic resistance mechanisms in M. tuberculosis: an update. Arch Toxicol. 2016;90:1585–1604. doi: 10.1007/s00204-016-1727-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ni T, Xie F, Hao Y, Li L, Zhu S, Wu H, Chi X, Yan L, Jiang Y, Zhang D. Discovery of novel orally bioavailable triazoles with potent and broad-spectrum antifungal activity in vitro and in vivo. J Med Chem. 2022;65(24):16665–16678. doi: 10.1021/acs.jmedchem.2c01497. [DOI] [PubMed] [Google Scholar]
  25. Peng XM, Peng LP, Li S, Avula SR, Kannekanti VK, Zhang SL, Tam KY, Zhou CH. Quinazolinone azolyl ethanols: potential lead antimicrobial agents with dual action modes targeting MRSA DNA. Future Med Chem. 2016;8:1927–1940. doi: 10.4155/fmc-2016-0002. [DOI] [PubMed] [Google Scholar]
  26. Rakesh, Bruhn DF, Scherman MS, Singh AP, Yang L, Liu J, Lenaerts AJ, Lee RE. Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids. Bioorg Med Chem Lett. 2016;26:388–391. doi: 10.1016/j.bmcl.2015.12.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sharma A, De Rosa M, Singla N, Singh G, Barnwal RP, Pandey A. Tuberculosis: an overview of the immunogenic response, disease progression, and medicinal chemistry efforts in the last decade toward the development of potential drugs for extensively drug-resistant tuberculosis strains. J Med Chem. 2021;64:4359–4395. doi: 10.1021/acs.jmedchem.0c01833. [DOI] [PubMed] [Google Scholar]
  28. Sheikh BA, Bhat BA, Mehraj U, Mir W, Hamadani S. Mir MA development of new therapeutics to meet the current challenge of drug-resistant tuberculosis. Curr Pharm Biotechnol. 2021;22:480–500. doi: 10.2174/1389201021666200628021702. [DOI] [PubMed] [Google Scholar]
  29. Shvekhgeimer MGA. The Pfitzinger reaction. Chem Heterocycl Compd. 2004;40(3):257. doi: 10.1023/B:COHC.0000028623.41308.e5. [DOI] [Google Scholar]
  30. Sun H, Huang S, Jeyakkumar P, Cai G, Fang B, Zhou C. Natural berberine-derived azolyl ethanols as new structural antibacterial agents against drug-resistant Escherichia coli. J Med Chem. 2022;65(1):436–459. doi: 10.1021/acs.jmedchem.1c01592. [DOI] [PubMed] [Google Scholar]
  31. Thakare P, Shinde A, Chavan A, Nyayanit N, Bobade V, Mhaske P. Synthesis and biological evaluation of new 1,2,3-triazolyl-pyrazolyl-quinoline derivatives as potential antimicrobial agents. ChemistrySelect. 2020;5:4722. doi: 10.1002/slct.201904455. [DOI] [Google Scholar]
  32. Thakare P, Shinde A, Dakhane S, Chavan A, Bobade V, Mhaske P. Synthesis and biological evaluation of novel 4-(6-substituted quinolin4-yl)-N-arylthiazol-2-amine derivatives as potential antimicrobial agents. J Het Chem. 2021;58(9):1867–1877. doi: 10.1002/jhet.4317. [DOI] [Google Scholar]
  33. Thakare P, Dhakane S, Shaikh A, Modak M, Patil A, Bobade V, Mhaske P. Design, synthesis, antimicrobial and ergosterol inhibition activity of new 4-(imidazo[1,2-a]pyridin-2-yl)quinoline derivatives. Polycycl Aromat Comp. 2022;42(8):5282–5299. doi: 10.1080/10406638.2021.1933107. [DOI] [Google Scholar]
  34. Tiberi S, du Plessis N, Walzl G, Vjecha MJ, Rao M, Ntoumi F, Mfinanga S, Kapata N, Mwaba P, McHugh TD, Ippolito G, Migliori GB, Maeurer MJ, Zumla A. Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies. Lancet Infect Dis. 2018;18:e183–e198. doi: 10.1016/S1473-3099(18)30110-5. [DOI] [PubMed] [Google Scholar]
  35. World Health Organization 2020 Meeting Report of the WHO expert consultation on the definition of extensively drug-resistant tuberculosis, https://www.who.int/publications/i/item/meeting-report-of-the-who-expertconsultationon-the-definition-of-extensively-drug-resistant-tuberculosis. Accessed 08 Aug 2022
  36. Zhang Y, Tangadanchu VKR, Cheng Y, Yang RG, Lin JM, Zhou CH. Potential antimicrobial isopropanol-conjugated carbazole azoles as dual targeting inhibitors of Enterococcus faecalis. ACS Med Chem Lett. 2018;9(3):244–249. doi: 10.1021/acsmedchemlett.7b00514. [DOI] [PMC free article] [PubMed] [Google Scholar]

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