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Design, Synthesis and Study of Antibacterial and Antitubercular Activity of Quinoline Hydrazone Hybrids

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Design, Synthesis and Study of Antibacterial and Antitubercular Activity of Quinoline Hydrazone Hybrids Heterocycl. Commun. 2020; 26: 137–147 Research Article Open Access Shruthi T G, Sangeetha Subramanian* and Sumesh Eswaran Design, Synthesis and Study of Antibacterial and Antitubercular Activity of Quinoline Hydrazone Hybrids https://doi.org/10.1515/hc-2020-0109 novel mechanisms of action are necessary to develop novel Received May 21, 2020; accepted August 08, 2020. therapeutic treatment combinations. Among heterocyclic compounds, compounds with a quinoline core have gained Abstract: Emerging bacterial resistance is causing wides- much importance in medicinal chemistry. Quinoline pread problems for the treatment of various infections. compounds are vital structures in medicinal chemistry Therefore, the search for antimicrobials is a never-ending due to their wide spectrum of biological activity, including task. Hydrazones and quinolines possess a wide variety anti-inflammatory [2], anticancer [3,4], antihypertensive of biological activities. Herewith, eleven quinoline hyd- [5], tyrokinase PDGF-RTK-inhibiting [6], anti-HIV [7], razone derivatives have been designed, synthesized, cha- anti-malarial [8,9] and anti-bacterial activity [10,11]. They racterized and evaluated for their antibacterial activity are also known to exhibit excellent anti-TB [12,13,14] and antitubercular potential against Mtb WT H37Rv. Com- properties. For example, Bedaquiline is an important pounds QH-02, QH-04 and QH-05 were found to be pro- quinoline-based anti-TB drug for the treatment of MDR-TB mising compounds with an MIC value of 4 µg/mL against [15]. Quinoline is also a key component of many naturally- Mtb WT H37Rv. Compounds QH-02, QH-04, QH-05, occurring bioactive compounds. and QH-11 were also found to be active against bacterial Hydrazones belong to a class of organic compounds strains including Acinetobacter baumanii, Escherichia coli containing a C = N bond, in which the nitrogen atom is and Staphylococcus aureus. Further, we have carried out nucleophilic and the carbon atom has both electrophilic experiments to confirm the cytotoxicity of the active com- and nucleophilic character. Owing to their biological and pounds and found them to be non-toxic. pharmacological properties, combining hydrazones with Keywords: Quinoline, Hydrazone, Antituberculosis, other heterocyclic compounds leads to diverse biological Antibacterial activity, Cytotoxicity and pharmacological properties. Quinoline hybrids combine polar and nonpolar properties, allowing them to permeate bacterial cells. It is evident from the literature that quinoline-based Introduction hydrazone scaffolds exhibit excellent antibacterial and anti-TB properties. The quinoline hydrazone derivatives There is an urgent need for the screening of new bioactive synthesized by Eswaran et al. showed better anti- molecules with new targets and novel mechanisms of tuberculosis potency than rifampin and isoniazid [16], action to address the emerging problem of antibacterial while new fluorine-substituted hydrazones also exhibited resistance. There are about 558,000 reported cases good anti-tuberculosis potency [17]. These molecules of rifampicin-resistant tuberculosis. Further, 82% also showed remarkable anti-cancer properties [18]. The had multidrug-resistant tuberculosis (MDR-TB), with quinoline hydrazone moiety has tremendously enhanced maximum incidence in India, China and the Russian the anti-TB activity of these compounds. Federation [1]. Discovery of novel chemical scaffolds with We have designed new quinoline derivatives via two synthetic routes. These are the unique scaffolds with quinoline, piperazine or morpholine and hydrazones *Corresponding author: Sangeetha Subramanian, SBST, Vellore present in the molecules. The idea to design these two Institute of Technology, Vellore – 632014, Tamil Nadu, India E-mail: [email protected]; Tel.:+971501099154 completely different scaffolds was motivated by a survey of Shruthi T G, Sumesh Eswaran, Anthem Biosciences Pvt, Ltd., the literature. The intermediate 7-chloro-4-(piperazin-1-yl) Bangalore-560099, Karnataka, India quinoline (5) is an important building block in medicinal Open Access. © 2020 Shruthi T G et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution alone 4.0 License. 138 Shruthi T G et al.: Design, Synthesis and Study of Antibacterial and Antitubercular Activity chemistry, where it is combined with other active triplets; m, multiplet; brs, broad singlet. IR spectra were pharmacophores with diverse pharmacological profiles recorded using a Bruker Alpha FTIR spectrometer using a [19,20,21]. Some 7-chloro-4-(piperazin-1-yl)quinoline- diamond ATR single reflectance module (32 scans). carrying propionic acid hydrazone derivatives synthesized by Inam et al. were shown to be effective as antiprotozoal agents [22]. Hydrazone derivatives of quinoline and their General procedure for the synthesis of compounds Zn(II) complexes, synthesized by Mandewale, M. C. et al., were good antitubercular agents [23] and the 7-chloro-4- Preparation of 2-[(3-chloro-phenylamino)-methylene]- quinolinylhydrazone derivatives synthesized by Candea malonic acid diethyl ester (2) et al. exhibited significant activity comparable with that of the first line drugs, ethambutol and rifampicin [24]. A suspension of 3-chloro-phenylamine (1) 50 g (0.391 mol.) This evidence inspired us to design scaffold 1. 4-hydroxy- in diethyl ethoxymethylenemalonate 119 mL (0.587 mol.) 8-trifluoromethyl-quinoline derivatives were synthesized was heated at 110 °C for 4 h. The reaction mixture was and screened for in vitro anti-TB activity against various cooled to room temperature, the solid formed was strains of Mycobacterium by Thomas et al. [25]. The mode placed in hexane (10 vol.), stirred for 15 min and filtered of action of these active compounds involved docking of to get compound (2) as a pale yellow solid. The isolated receptor enoyl-ACP reductase with the newly synthesized compound was used in the next step without further candidate ligands. This encouraged us to design scaffold 2. purification. Yield: 70 g (60 %) The overall strategy is to attach hydrazones at the second and fourth positions of the quinoline ring and to screen for resulting antimicrobial activity. Preparation of 7-chloro-4-hydroxyquinoline (3) In the present work, all new structures were designed on the basis of combinatorial synthesis, keeping structure- A solution of 2-[(3-chloro-phenylamino)-methylene]- activity relationship studies in mind in line with the current malonic acid diethyl ester (2) 50 g (0.168 mol.) in Dowtherm trend in drug discovery. All compounds were characterized medium (100 mL, 2 vol.) was heated at 240 °C for 4 h. The by NMR spectra as well as mass spectroscopy. Amongst reaction mixture was cooled to room temperature. Hexane the tested compounds, QH-02, QH-04, QH-05 and QH-11 was added and the mixture was stirred for 15 min, after displayed promising antimicrobial activity. which the solid precipitate was filtered and dried to get compound (3) as an off-white solid. Yield: 15 g (49.7 %) 1 H-NMR (CDCl3 400 MHz) δ (ppm): 6.05 (d, 1H, J = 7.6 Hz, ArH), 7.32 (dd, 1H, J = 8.8, 2 Hz, ArH), 7.58 (d, 1H, Experimental J = 2 Hz, ArH), 7.93 (t, 1H, J = 7.2 Hz, ArH), 8.07 (d, 1H, J = 8.8 Hz, ArH), 11.78 (brs, 1H, -OH). 13C-NMR (DMSO 100 MHz) δ Chemistry (ppm): 109.76, 117.90, 123.92, 124.81, 127.75, 136.71, 140.48, 141.26, 176.77. IR (KBr) cm-1: 3065, 2944, 1608, 1559, 814. LC/ All reagents were purchased from Sigma Aldrich. Solvents MS (ESI-MS) m/z = 180 (M+1). used were extra dried. Final purifications were carried out using a Quad Biotage Flash purifier (A Dyax Corp. Company). TLC experiments were performed on alumina- Preparation of 4,7-dichloro-quinoline [26] (4) backed silica gel 40 F254 plates (Merck, Darmstadt, Germany). The plates were illuminated under UV A phosphorus oxychloride (10 mL, 1 vol.) was added to 1 13 (254 nm) and KMnO4. All H and C NMR spectra were 7-chloro-4-hydroxyquinoline (3) (10 g, 0.055 mol.) in a recorded on a Bruker AM-300 (300.12 MHz) and AM-400 round bottom flask equipped with a reflux condenser. (400.13 MHz) (Bruker BioSpin Corp., Germany). Molecular The mixture was heated to reflux for 6 h, then allowed to weights of unknown compounds were checked by LCMS cool to room temperature. The solution was concentrated 6200 series Agilent Technology. The mass spectra of a under high vacuum to a thick oil, then dumped over few were recorded in a 410 Prostar binary PDA detector cracked ice. The resulting solution was neutralized with (Varian Inc., USA). Chemical shifts are reported in ppm saturated NaHCO3 (aq.), and the solid precipitated was (δ) with reference to internal standard TMS. The signals filtered and washed with water. The solid was dried under are designated as follows: s, singlet; d, doublet; t, triplet; vacuum and the crude compound was purified by column dd, doublet of doublets; td, triplet of doublets; tt, triplet of chromatography over silica gel using eluent 30 % ethyl Shruthi T G et al.: Design, Synthesis and Study of Antibacterial and Antitubercular Activity 139 acetate in hexane to afford 4,7-dichloroquinoline as a 1.5 N HCl (pH~6). It was concentrated to remove organic white solid. Yield: 8 g (72.7 %) solvents and the resultant aqueous layer was extracted 1H-NMR (DMSO 400 MHz) δ (ppm): 7.79-7.82 (m, 2H, with ethyl acetate (100 mL x 2). The combined organic ArH), 8.18 (d, 1H, J = 2 Hz, ArH), 8.23 (d, 1H, J = 8.8 Hz, layer was dried over sodium sulphate, filtered and concen- ArH), 8.88 (d, 1H, J = 4.8 Hz, ArH). 13C-NMR (DMSO 100 trated under vacuum to afford a pale yellow solid. Yield: MHz) δ (ppm): 122.42, 124.62, 126.11, 128.53, 129.02, 135.77, 10 g (49.2%) 141.70, 149.18, 152.24. IR (KBr) cm-1: 3433, 1606, 1608, 1553, 1H-NMR (DMSO 400 MHz) δ (ppm): 4.60 (d, 2H), 5.76 1485, 817.
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