synthesis, characterization and biological evaluation

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Nov 30, 2015 - Received 17/11/2015 ... compound 3j was found to be the most potent antimicrobial agent and compound 3k was found to be ... Please cite this article in press as Venepally Vijayendar et al. ... Molecular weights of unknown compounds were ... IR spectra were recorded in chloroform on a Perkin-Elmer.

Indo American Journal of Pharmaceutical Research, 2015

SYNTHESIS, CHARACTERIZATION AND UNDECENOIC ACID BASED OXIME ESTERS

BIOLOGICAL

ISSN NO: 2231-6876

EVALUATION

OF

Venepally Vijayendar1, 3, Shiva Shanker Kaki*1, Ram Chandra Reddy Jala*1, 3, Y. Poornachandra2, 3, C. Ganesh Kumar2, 3, R.B.N. Prasad1,3 1

Centre for Lipid Research, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India. 3 Academy of Scientific and Innovative Research, New Delhi, India. 2

ARTICLE INFO Article history Received 17/11/2015 Available online 30/11/2015 Keywords Oxime Esters, Undecenoic Acid, Hydroxy Benzaldehydes, Antimicrobial Activity, Biofilm Inhibition.

ABSTRACT Various substituted benzaldehydes were converted to corresponding oximes and subsequently esterified with undecenoic acid to obtain novel undecenoic acid based aldoxime esters. The structures of the prepared oxime esters were confirmed using NMR, IR and mass spectral data. These oxime esters were evaluated for their in vitro antimicrobial and antioxidant activities. It was observed that the oxime ester derived from 3-hydroxy benzaldoxime (compound 3j) exhibited promising antimicrobial activity against three gram positive organisms and also against a fungal strain. In addition, the derivative showed good activity in biofilm inhibition assay. In the antioxidant evaluation, oxime ester 3k derived from 2, 3dihydroxy benzaldoxime exhibited excellent antioxidant activity as observed by DPPH radical scavenging activity, superoxide free radical scavenging activity and inhibition of lipid peroxidation assay as compared to commercial antioxidants. From the present study, compound 3j was found to be the most potent antimicrobial agent and compound 3k was found to be promising antioxidant.

Copy right © 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as Venepally Vijayendar et al. Synthesis, Characterization And Biological Evaluation of Undecenoic Acid Based Oxime Esters. Indo American Journal of Pharmaceutical Research.2015:5(11).

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Corresponding authors Dr K. Shiva Shanker & Dr J.R.C. Reddy Centre for Lipid Research, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 007, India. [email protected]; [email protected] +91-40-27193370

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INTRODUCTION Oximes and their derivatives are important class of organic compounds that have been used for many important pharmaceutical and synthetic chemistry applications, and often act as chemical building blocks for the synthesis of agrochemicals and pharmaceuticals [1-3]. Some oxime complexes have been documented to possess anti carcinogenic activities also [4]. Recent reports suggest that oximes are also being explored for their broad spectrum of biological activities such as powerful antioxidants [5, 6], antiinflammatory [7, 8], and antimicrobial [9, 10] activities. Different types of oximes and their derivatives are reported to possess a wide range of biological activities such as insecticidal, miticidal, nematocidal, and antidote activities towards organophosphorous poisons. In particular, oxime esters are reported to possess herbicidal, anti-inflammatory, fungicidal, antidepressant, antiulcer, analgesic activities [2, 11]. Therefore, synthesis and investigation of various oxime ester derivatives have an important role in medicinal research. However, there are very few reports on the studies of oxime esters involving fatty acids as one of the substrates. Among the potential substrates for oximes, hydroxyl and methoxy containing aromatic compounds are interesting group of phytochemicals due to their important biological activities such anti-inflammatory, anticancer, antiviral, antiallergic, antimicrobial and UV filter properties [12-14]. Hence the oximes prepared from these compounds can be used as potential substrates for esterification with biologically active fatty acids. Our previous studies on apocynin oxime esters of different fatty acids revealed that undecenoic acid based oxime ester exhibited promising activity [15]. Literature reports also suggest that among the various fatty acids, undecenoic acid was found to exhibit promising biological activities such as anti-fungal, anti-bacterial, antiviral and anticancer activities [16, 17]. Undecenoic acid is reported to possess anti-bacterial and anti-viral properties that are effective on viral skin infections such as the Herpes simplex virus [18, 19]. Keeping in view of these observations, synthesis and biological studies of oxime esters involving undecenoic acid was envisaged as interesting study. Therefore, in the present study we designed and synthesized different oxime ester derivatives based on undecenoic acid and oximes of various substituted benzaldehydes. The synthesized compounds were investigated for their antibacterial, antifungal, antibiofilm and antioxidant activities. As fatty acids are known to help in host defences against pathogenic microbes, these types of newer hybrid molecules are of interest to study keeping in view of the increasing resistance of microbes to commonly used antibiotics. MATERIALS AND METHODS All the chemicals used in this study were obtained from different commercial sources and were used without any further purification. Reactions were monitored on micro TLC with UV detection. Final purifications were carried out using Rankem silica gel 60-120 mesh. All 1H and 13C NMR spectra were recorded on AVANCE-300 (300 MHz for 1H NMR and 75 MHz for 13CNMR). Chemical shifts are reported in ppm with reference to internal standard TMS. Molecular weights of unknown compounds were identified by ES-MS and HRMS (Electron Spray Ionization Technique). IR spectra were recorded in chloroform on a Perkin-Elmer FT-IR spectrum BX. RESULTS AND DISCUSSION In the present study, we report the synthesis and characterization of novel oxime esters as shown in Scheme 1. As both the oximes and undecenoic acid are known to be biologically active compounds, the combination of these two compounds to produce novel oxime ester hybrids would be an interesting study keeping in view of the biological activity of the product esters. Initially various hydroxy benzaldoximes were prepared starting from phenolic aldehydes by reaction with hydroxylamine hydrochloride in aqueous solution with the aid of sodium acetate to obtain the corresponding oximes in 81-89% yields. The structure of the oxime was confirmed by NMR and mass spectral data. O H

H

O

R1

NH2OH, NaOAC

R2

R4 R3

R

N

1

H

OH Undecenoyl chloride

H2O, 80 °C , 2 h R 2

R 4 DCM, Et 3N, RT R3

N

O

R1 R2

R4 R3

2a-k

3a-k

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The obtained oxime was further acylated with undecenoic acid chloride in the presence of triethyl amine to form respective oximes-N-O-undecenoates in yields ranging from 80-89%. The structures of all the products were confirmed by NMR and MS spectral data. All the product esters showed the expected molecular weight in the mass spectra. 1H and 13C NMR data further confirmed the formation of the oxime ester products. From 1H-NMR spectral data of oxime ester of undecenoic acid, a triplet at δ 2.5 was observed which indicates the protons adjacent to the ester carbonyl and multiplet at δ 5.0 indicates the alkene protons from the undecenoic acid moiety. Different substituted phenolic aldehyde oxime-N-O-undecenoates were prepared according to reported protocols and the details of the product structures are given in Table 1.

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Scheme 1 Synthesis of benzaldehyde oximes and their esters.

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Table 1 Structures of synthesized oxime esters. S. No 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k

R1 OCH3 H H OCH3 H H H H OH H OH

R2 H OCH3 H OCH3 OCH3 OCF3 H OCH3 H OH OH

R3 H H OCH3 H OCH3 H OCF3 OCH3 H H H

R4 H H H H H H H OCH3 H H H

EXPERIMENTAL General procedure for the synthesis of oximes (2a-k) Oximes of phenolic aldehydes were prepared according to a reported method with slight modification [23]. Briefly, the appropriate benzaldehyde (1 eq) was dissolved in water (15 mL) at room temperature. A solution of the hydroxylamine hydrochloride (1.5 eq) and sodium acetate (1.5 eq) in water (25 mL) was added, and the reaction mixture was stirred at 80 °C under nitrogen for 2 h. The progress of reaction was monitored by TLC. After complete conversion, the mixture was cooled and extracted with ethyl acetate (2 x 30 mL) and the combined organic phases were washed with brine solution, dried over sodium sulphate and concentrated to obtain the corresponding oximes. 2-methoxybenzaldehyde oxime (2a) Yield: 89%; IR (ν max cm-1): 3686, 3580, 3320, 2400, 1512, 1216, 762, 669; 1H NMR (CDCl3, ppm): 8.47 (s, 1H), 7.63-7.67(d, J = 7.74 Hz, 1H), 7.30-7.33(t, J = 6.98 Hz, 1H), 6.90-6.99 (m, 2H,), 3.82(s,3H). 3-methoxybenzaldehyde oxime (2b) Yield: 85%; IR (ν max cm-1): 3686, 3580, 3320, 2400, 1512, 1216, 762, 669; 1H NMR (CDCl3, ppm): 8.89 (s, 1H), 8.13(s, 1H), 7.277.32 (m, 1H), 7.11-7.15(m, 2H), 6.92-6.96 (m, 1H), 3.82(s,3H). 4-methoxybenzaldehyde oxime (2c) Yield: 85%; IR (ν max cm-1): 3686, 3580, 3320, 2400, 1512, 1216, 762, 669; 1H NMR (CDCl3, ppm): 9.77 (s, 1H), 8.12(s, 1H), 7.507.53(d, J = 8.30 Hz, 2H), 6.87-6.90 (d, J = 9.06 Hz, 2H), 3.82(s,3H). 2, 3-dimethoxybenzaldehyde oxime (2d) Yield: 81%; IR (ν max cm-1): 3681, 3019, 2927, 2399, 1517, 1425, 1216, 928, 669; 1H NMR (CDCl3, ppm): 3.86(s,3H), 8.48(s, 1H), 7.31-7.33 (d, J = 7.74 Hz, 1H), 7.03-7.09(t, J = 8.12 Hz, 1H), 6.93-6.95 (d, J = 8.12 Hz, 1H), 3.88(s,3H). 3, 4-dimethoxybenzaldehyde oxime (2e) Yield: 82%; IR (ν max cm-1): 3685, 3020, 2928, 2400, 1515, 1424, 1384, 1215, 1025, 928, 760, 669. 1H NMR (CDCl3, ppm): 8.09(s, 1H), 7.22 (s, 1H), 7.02-7.05(dd, 1H), 6.84-6.87 (d, J = 8.12 Hz, 1H), 3.91(s,6H). 3-(trifluoromethoxy) Benzaldehyde oxime (2f) Yield: 83%; IR (ν max cm-1): 3685, 3020, 2929, 2400, 1765, 1519, 1424, 1215, 740, 669. 1H NMR (CDCl3, ppm): 8.93 (s, 1H), 8.16(s, 1H), 7.45-7.46(m, 2H), 7.23-7.25 (d, J = 6.98 Hz, 1H).

2-hydroxybenzaldehyde oxime (2i) Yield: 81%; IR (ν max cm-1): 3377, 3021, 1907, 1711, 1619, 1578, 1492, 1264, 992, 755, 649. 1H NMR (CDCl3, ppm): 8.22 (s, 1H), 7.26-7.29(m, 1H), 7.16-7.18 (dd, 1H), 6.98-7.00(d, J = 8.24 Hz, 1H), 6.90-6.93 (m, 1H).

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2, 4, 6-trimethoxybenzaldehyde oxime (2h) Yield: 89%; IR (ν max cm-1): 3684, 3020, 2930, 2856, 2400, 2229, 1708, 1583, 1416, 1239, 760, 669. 1H NMR (CDCl3, ppm): 8.07(s, 1H),36.79 (s, 2H),.88(s, 9 H).

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4-(trifluoromethoxy) Benzaldehyde oxime (2g) Yield: 87%; IR (ν max cm-1): 3685, 3020, 2929, 2400, 1765, 1519, 1424, 1215, 740, 669. 1H NMR (CDCl3, ppm): 9.59(s, 1H), 8.16(s, 1H), 7.57-7.60(d, J = 8.68 Hz, 2H), 7.22-7.25 (d, J = 8.30 Hz, 2H).

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3-hydroxybenzaldehyde oxime (2j) Yield: 82%; IR (ν max cm-1): 3377, 3021, 1907, 1711, 1619, 1578, 1492, 1264, 992, 755, 649. 1H NMR (CDCl3, ppm): 10.93 (s, 1H), 9.23 (s, 1H), 8.18(s, 1H), 7.33-7.35 (m, 1H), 7.18-7.20(m, 2H), 7.00-7.02 (d, J = 7.71 Hz, 1H). 2, 3-dihydroxybenzaldehyde oxime (2k) Yield: 83%; IR (ν max cm-1): 3685, 3577, 3020, 2400, 1512, 1325, 1215, 761, 669; 1H NMR (CDCl3, ppm): 11.19 (s, 1H), 10.06(s, 1H), 8.76(s, 1H), 8.20(s, 1H), 6.82-7.85(m, 1H), 6.67-6.74 (m, 2H). General procedure for the synthesis of phenolic oxime esters (3a-k) To a stirred solution of undecenoic acid (1 eq.) dissolved in dichloromethane (15 mL) at 0-5 °C under nitrogen atmosphere, oxalyl chloride (1.2 eq.) was added in a drop wise manner over a period of 10 minutes. After complete addition, ice bath was removed and the reaction mixture was stirred at room temperature for 3 h after which the excess oxalyl chloride was removed under vacuum. To the solution of undecenoic acid chloride in dichloromethane was added a solution of phenolic oxime (1 eq.) dissolved in dichloromethane in a drop wise manner over a period of 10 minutes at 0-5°C under nitrogen atmosphere followed by the addition of triethylamine (3-4 drops) and the reaction mixture was stirred at the same temperature for 4 h under nitrogen atmosphere while monitoring the reaction by TLC. After maximum conversion, the reaction mixture was extracted with dichloromethane, washed with water and dried over anhydrous sodium sulphate and concentrated to obtain the crude product. The crude product was purified by column chromatography (30% ethyl acetate in hexane, v/v) to obtain the corresponding oxime ester. 2-methoxybenzaldehyde O-undec-10-enoyl oxime (3a) Yield: 81%; IR (ν max cm-1): 3685, 3020, 2400, 1774, 1518, 1480, 1215, 1087, 761, 669; 1H NMR (CDCl3, ppm): 8.77 (s, 1H), 7.97 (d, J = 9.06 Hz, 1H), 7.40-7.46 (t, J = 7.17 Hz, 1H), 6.90-7.01 (m, 2H), 5.74-5.87 (m, 1H ), 4.91-5.02 (m, 2H,), 3.86 (s, 3H,), 2.43-2.48(t, J = 7.55 Hz, 2H), 2.00-2.07 (m, 2H), 1.67-1.77 (m, 2H,), 1.25-1.37 (m, 10H,), 13C NMR (CDCl3, ppm): 171.02, 157.96, 151.55,138.66,132.54, 127.10, 120.36, 118.15, 113.65, 110.58, 55.11, 33.29, 32.41, 28.40, 24.38; MS (ESI, m/z) [M+Na]+ 340.

3-methoxybenzaldehyde O-undec-10-enoyl oxime (3b) Yield: 80%; IR (ν max cm-1): 3685, 3020, 2400, 1774, 1518, 1480, 1215, 1087, 761, 669; 1H NMR (CDCl3, ppm): 8.32(s, 1H), 7.33(m, 2H), 7.25-7.26 (m, 1H), 7.01-7.04 (dd, 1H), 5.74-5.87 (m, 1H ), 4.91-5.02 (m, 2H,), 3.84 (s, 3H,), 2.44-2.49(t, J = 7.55 Hz, 2H), 2.002.02 (m, 2H), 1.68-1.77 (m, 2H,), 1.31-1.37 (m, 10H,), 13C NMR (CDCl3, ppm): 171.622, 160.208, 156.284, 150.169, 139.448, 131.755, 130.177, 124.780, 122.011, 119.620, 118.728, 117.142, 114.487, 112.163, 55.765, 34.098, 33.129, 29.587, 25.154 ; MS (ESI, m/z) [M+Na]+ 340. 4-methoxybenzaldehyde O-undec-10-enoyl oxime (3c) Yield: 89%; IR (ν max cm-1): 3685, 3020, 2400, 1774, 1518, 1480, 1215, 1087, 761, 669; 1H NMR (CDCl3, ppm): 8.29(s, 1H), 7.667.69 (d, J = 8.87 Hz, 2H), 6.91-6.96(d, J = 8.68 Hz, 2H), 5.74-5.87 (m, 1H ), 4.91-5.02 (m, 2H,), 3.85 (s, 3H,), 2.42-2.47(t, J = 7.55 Hz, 2H), 2.00-2.07 (m, 2H), 1.67-1.77 (m, 2H,), 1.25-1.37 (m, 10H,); MS (ESI, m/z) [M+Na]+ 340; HRMS: 318.20636(C19H28O3N=318.20637). 2, 3-dimethoxybenzaldehyde O-undec-10-enoyl oxime (3d) Yield: 84%; IR (ν max cm-1): ): 3300, 3020, 2400, 1710, 1583, 1450, 1216, 1102, 911, 758, 684; 1H NMR (CDCl3, ppm): 10.43(s, 1H); 7.41-7.43(dd, 1H), 7.13-7.16(d,overlap,, 2H), 5.76-5.84 (m, 1H ), 4.91-5.01 (m, 2H,), 3.99 (s, 3H), 3.91 (s, 3H), 2.45-2.48(t, J = 7.55 Hz, 2H), 2.01-2.06 (m, 2H), 1.70-1.76 (m, 2H,), 1.25-1.41 (m, 10H,), 13C NMR (CDCl3, ppm): 190,4; 178,7; 171,7; 153,3; 152,2; 139,4; 130,0; 124,6; 119,4; 118,4; 115,6; 114,4; 62,6; 56,3; 34,0; 33,1; 29,5; 25,1; MS (ESI, m/z) [M+Na]+ 370; HRMS; 348.21733(C20H30O4N=348.21693).

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3-(trifluoromethoxy) benzaldehyde O-undec-10-enoyl oxime (3f) Yield: 83%; IR (ν max cm-1): 3575, 3305, 3021, 2401, 1705, 1584, 1447, 1215, 760, 669. 1H NMR (CDCl3, ppm): 8.35(s, 1H), 7.667.68(d, J = 7.74 Hz, 1H), 7.61(s, 1H), 7.44-7.50(t, J = 8.12 Hz, 1H), 7.34-7.38(d, J = 6.42 Hz, 1H), 5.74-5.87 (m, 1H ), 4.91-5.02 (m, 2H,), 2.45-2.50(t, J = 7.55 Hz, 2H), 2.00-2.07 (m, 2H), 1.68-1.75 (m, 2H,), 1.29-1.41 (m, 10H,), 13C NMR (CDCl3, ppm): 173,8; 170,5; 153,9; 149,1; 138,6; 131,8; 129,9; 126,2; 123,4; 120,0; 113,6; 50,9; 33,3; 32,2; 24,4; MS (ESI, m/z) [M+Na]+ 394; HRMS; 372.17897.

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3, 4-dimethoxybenzaldehyde O-undec-10-enoyl oxime (3e) Yield: 86%; IR (ν max cm-1): 3300, 3020, 2400, 1710, 1583, 1450, 1216, 1102, 911, 758, 684; 1H NMR (CDCl3, ppm): 9.86(s, 1H), 7.28-7.30 (dd, 1H), 7.08(s, 1H), 6.89-6.91(d, J = 8.24 Hz, 1H), 5.76-5.84 (m, 1H ), 4.91-5.01 (m, 2H,), 3.93 (s, 3H), 3.90 (s, 3H), 2.33-2.36(t, J = 7.55 Hz, 2H), 2.01-2.05 (m, 2H), 1.60-1.66 (m, 2H,), 1.23-1.38 (m, 10H,), 13C NMR (CDCl3, ppm): 191,3; 180,1; 153,2; 149,5; 139,5; 126,8; 119,5; 114,5; 111,6; 110,7; 104,2; 55,8; 34,1; 29,2; 25,0; MS (ESI, m/z) [M+Na]+ 370.

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4-(trifluoromethoxy) benzaldehyde O-undec-10-enoyl oxime (3g) Yield: 85%; IR (ν max cm-1): 3575, 3305, 3021, 2401, 1705, 1584, 1447, 1215, 760, 669. 1H NMR (CDCl3, ppm): 8.35(s, 1H), 7.777.80(d, J = 8.68 Hz, 2H), 7.26-7.28(d, J = 6.79 Hz, 2H), 5.74-5.87 (m, 1H ), 4.91-5.02 (m, 2H,), 2.44-2.49(t, J = 7.55 Hz, 2H), 2.002.07 (m, 2H), 1.68-1.78 (m, 2H,), 1.25-1.41 (m, 10H,), MS (ESI, m/z) [M+Na]+ 394. 2, 4, 6-trimethoxybenzaldehyde O-undec-10-enoyl oxime (3h) Yield: 87%; IR (ν max cm-1): 3020, 2929, 2856, 2400, 1708, 1536, 1414, 1215, 914, 760, 669; 1H NMR (CDCl3, ppm): 8.26(s, 1H), 7.26 (s, 1H), 6.95(s, 1H), 5.76-5.84 (m, 1H ), 4.91-5.01 (m, 2H,), 3.88 (s, 9H), 2.44-2.47(t, J = 7.55 Hz, 2H), 2.03-2.06 (m, 2H), 1.691.75 (m, 2H,), 1.25-1.41 (m, 10H,), 13C NMR (CDCl3, ppm): 190,8; 178,5; 170,9; 155,6; 153,1; 140,7; 138,8; 131,3; 125,0; 113,8; 109,1; 106,3; 105,2; 103,2; 103,7; 60,6; 55,9; 33,4; 32,4; 28,5; 28,7; 24,5; MS (ESI, m/z) [M+H]+ 378; HRMS; 400.20978(C25H31O5Na= 40020944). 2-hydroxybenzaldehyde O-undec-10-enoyl oxime (3i) Yield: 82%; IR (ν max cm-1): 3377, 3021, 1907, 1711, 1578, 1264, 1039, 992, 899. 1H NMR (CDCl3, ppm): 9.85(s, 1H), 8.41 (s, 1H), 7.35-7.40 (t, J = 7.17 Hz, 1H), 7.22-7.26(d, J = 4.34 Hz, 1H), 7.03-7.06 (d, J = 8.30 Hz, 1H), 6.92-6.97 (t, J = 7.36 Hz, 1H), 5.745.85 (m, 1H ), 4.91-5.02 (m, 2H,), 3.86 (s, 3H,), 2.43-2.48(t, J = 7.55 Hz, 2H), 2.00-2.07 (m, 2H), 1.68-1.75 (m, 2H,), 1.25-1.37 (m, 10H,), 13C NMR (CDCl3, ppm): 170.1, 157.1, 145.4, 139.4, 123.0, 120.6, 118.4, 115.0, 114.4, 34.0, 32.6, 29.3, 25.0; MS (ESI, m/z) [M+Na]+ 326. HRMS: 304.19063(C18H26O3N=304.19072). 3-hydroxybenzaldehyde O-undec-10-enoyl oxime (3j) Yield: 82%; IR (ν max cm-1): 3377, 3021, 1907, 1711, 1578, 1264, 1039, 992, 899. 1H NMR (CDCl3, ppm): 8.29 (s, 1H), 7.32 (s, 1H), 7.27-7.29 (m, 1H), 7.14-7.15(d, J = 7.55 Hz, 1H), 6.97-6.99 (dd, 1H), 5.76-5.85 (m, 1H ), 4.91-5.01 (m, 2H,), 2.44-2.48(t, J = 7.55 Hz, 2H), 2.00-2.06 (m, 2H),. 1.69-1.75 (m, 2H,), 1.25-1.41 (m, 10H,), 13C NMR (CDCl3, ppm): 178.8, 172.4, 156.7 , 156.2, 150.2; , 139.3; , 131.3; , 130.2; , 121.6 , 119.6, 114.3, 33.9, 33.0, 29.0, 24.9, MS (ESI, m/z) [M+Na]+ 326. HRMS: 304.19072(C18H26O3N=304.19072). 2, 3-dihydroxybenzaldehyde O-undec-10-enoyl oxime (3k) Yield: 81%; IR (ν max cm-1): 3575, 3308, 3021, 2401, 1705, 1584, 1447, 1260, 1216, 954, 760, 669; 1H NMR (CDCl3, ppm): 10.05 (s, 1H), 8.40 (s, 1H), 7.04-7.05 (dd, 1H), 6.85-6.88(t, J = 7.93 Hz, 1H), 6.80-6.81 (dd, 1H), 5.77-5.85 (m, 1H ), 4.92-5.01 (m, 2H,), 2.442.47(t, J = 7.55 Hz, 2H), 2.02-2.06 (m, 2H), 1.70-1.76 (m, 2H,), 1.25-1.41 (m, 10H); 13C NMR (CDCl3, ppm): 169.8, 158.3, 157.2, 139.1, 133.0, 131.8, 119.7, 117.4, 114.9, 114.1, 33.7, 32.3, 28.8, 24.7; MS (ESI, m/z) [M+Na]+ 342. HRMS: 342.16790(C18H25O4Na=342.16758).

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Biology Methods Antimicrobial activity Antimicrobial activity of the prepared undecenoic acid based phenolic oxime esters was screened using well diffusion method [24] against a panel of pathogenic bacterial strains, including Micrococcus luteus MTCC 2470, Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS16 MTCC 2940, Bacillus subtilis MTCC 121, Escherichia coli MTCC 739, Klebsiella planticola MTCC 530, Pseudomonas aeruginosa MTCC 2453 and Candida albicans MTCC 3017 which were procured from the Microbial Type Culture Collection (MTCC), CSIR-Institute of Microbial Technology, Chandigarh, India. The pathogenic reference strains were seeded on the surface of the media Petri plates, containing Muller-Hinton agar with 0.1 mL of previously prepared microbial suspensions individually containing 1.5 × 10 8 cfu ml-1 (equal to 0.5 McFarland). Wells of 6.0 mm diameter were prepared in the media plates using a cork borer and the prepared molecules at a dose range of 125 - 0.48 µg well-1 were added in each well under sterile conditions in a laminar air flow chamber. Standard antibiotic solution of ciprofloxacin and miconazole at a dose range of 125 - 0.48 µg well-1 and the well containing methanol served as positive and negative controls, respectively. The plates were incubated for 24 h at 37°C for bacterial and 30°C for Candida albicans and the well containing the least concentration showing the inhibition zone was considered as the minimum inhibitory concentration. All experiments were carried out in duplicates and mean values are represented.

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Minimum bactericidal concentration Minimum bactericidal and fungicidal concentration assay [25] were performed in sterile 2.0 mL microfuge tubes against Bacillus subtilis MTCC 121, Staphylococcus aureus MTCC 96, S. aureus MLS16 MTCC 2940, Micrococcus luteus MTCC 2470, Klebsiella planticola MTCC 530, Escherichia coli MTCC 739, Pseudomonas aeruginosaMTCC2453 and for antifungal activity different fungal strains like Candida albicans MTCC 3017, C. albicans MTCC 183, C. albicans MTCC 227, C. albicans MTCC 854, C. albicans MTCC 1637, C. albicans MTCC 3018, C. albicans MTCC 3958, C. albicans MTCC 4748, C. albicans MTCC 7315, C. parapsilosis MTCC 1744, C. aaseri MTCC 1962, C. glabrata MTCC 3019, C. krusei MTCC 3020 and Issatchenkia hanoiensis MTCC 4755 which were procured from the Microbial Type Culture Collection (MTCC), CSIR-Institute of Microbial Technology, Chandigarh, India. The pathogenic Bacillus subtilis strain was cultured overnight in Mueller Hinton broth. Serial dilutions of prepared undecenoic acid based phenolic oxime esters were prepared in Mueller Hinton broth with different concentrations ranging from 0 to150 µg/mL. To the serially diluted undecenoic acid based phenolic oxime esters, 100 µL of overnight cultured bacterial suspension was added to reach a final concentration of 1.5 × 10 8 cfu ml-1 (equal to 0.5 McFarland) and incubated at 37 ºC for 24 h. After 24 h of incubation, the minimum bactericidal concentration (MBC) was determined by sampling 10 µL of suspension from the tubes onto Mueller Hinton agar plates and were incubated for 24 h at 37 ºC to observe the growth of test organisms. MBC is the lowest concentration of prepared undecenoic acid based phenolic oxime esters required to kill a particular bacterium. All the experiments were carried in duplicates. Biofilm inhibition assay The undecenoic acid based phenolic oxime esters were screened in sterile 96 well polystyrene microtiter plates using the modified biofilm inhibition assay [26], against Bacillus subtilis MTCC 121, which were cultured overnight in tryptone soy broth (supplemented with 0.5% glucose). The test compounds of predetermined concentrations ranging from 0 to 250 µg/mL were mixed with the bacterial suspension having an initial inoculum concentration of 5 × 105 CFU/mL. Aliquots of 100 µL were distributed in each well and then incubated at 37 ºC for 24 h under static conditions. The medium was then discarded and washed with phosphate buffered saline to remove the non-adherent bacteria. Each well of the microtiter plate was stained with 100 µL of 0.1% crystal violet solution followed by 30 min incubation at room temperature. Later the crystal violet solution from the plates was discarded, thoroughly washed with distilled water for 3 to 4 times and air dried at room temperature. The crystal violet stained biofilm was solubilised in 95% ethanol (100 µL) and the absorbance was recorded at 540 nm using TRIAD multimode reader (Dynex Technologies, Inc, Chantilly, VA, USA). Blank wells were employed as background check. The inhibition data were interpreted from the dose-response curves, where IC50 value is defined as the concentration of inhibitor required to inhibit 50% of biofilm formation under the above assay conditions. All the experiments were carried out in triplicates and the values are indicated as mean ± S.D. Antioxidant activities DPPH radical scavenging activity Antioxidant activity of prepared undecenoic acid based phenolic oxime esters was assessed on the basis of the free radical scavenging effect on the stable 1, 1-diphenyl-2-picrylhydrazyl (DPPH) by a modified method of Moon and Terao [27] and the DPPH radical scavenging activity was calculated using the formula of Bors et al [28]. Radical scavenging potential was expressed as EC50 value, which represents the test compound concentration at which 50% of the DPPH radicals were scavenged. BHT and α-tocopherol were run in parallel as positive controls. All tests were performed in triplicate and values are represented as mean. DPPH radical scavenging activity (%) = [(Absorbance of control – Absorbance of test sample) / (Absorbance of control)] × 100 Superoxide radical scavenging assay The superoxide radical scavenging activity of prepared undecenoic acid based phenolic oxime esters was performed according to the protocol described by Liu et al [29]. The superoxide radical was generated by phenazine methosulfate - nicotinamide adenine dinucleotide (PMS/NADH) system, which reduces nitro blue tetrazolium (NBT) forming a purple colored formazan. The reaction mixture consisted of 3.0 mL of 16 mM Tris-HCl buffer (pH 8.0) containing 78 mM NADH, 50 µM NBT, 10 µM PMS and various concentrations of test compound and incubated for 5 min at room temperature. After incubation the absorbance was read at 560 nm. BHT and α-tocopherol were run in parallel as positive controls. The scavenging activity of superoxide radical (%) was calculated using the equation:

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[(A560 of control - A560 of sample)/A560 of control] * 100

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Venepally Vijayendar et al.

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Inhibition of lipid peroxidation The inhibition of lipid peroxidation was assayed by measuring the lipid peroxide decomposition product malondialdehyde (MDA) based on reaction with thiobarbituric acid using egg yolk as oxidizable substrate [30].The yolk was taken out from an egg and same volume of PBS (0.1 M, pH 7.45) was added and stirred vigorously. The yolk suspension was mixed with 0.5 mL different concentrations of prepared undecenoic acid based phenolic oxime esters, 0.2 mL 25 mM FeSO4 and 1.3 mL PBS and incubated at 37 o C for 15 min. And the reaction was stopped by adding 0.5 mL 20% trichloroacetic acid and 1 mL of 0.8% thiobarbituric acid and then the mixture was heated at 100 oC for 15 min. The absorbance of all the samples was recorded at 532 nm. BHT and α-tocopherol were run in parallel as positive controls. The inhibition of lipid peroxidation was calculated from the following equation: Inhibition effect (%) = Acontrol – Asample / Acontrol * 100% Biological Evaluation Antimicrobial activity The prepared oxime esters were subjected for antimicrobial and antioxidant activity evaluation following established protocols against seven bacterial and one fungal strain. Antimicrobial activity evaluation results are shown in Table 2 and the compounds which have the minimum inhibitory concentration (MIC) of 125µg/mL or greater than 125µg/mL were considered as less potent or inactive compounds in the present study and hence were not discussed further. From Table 2, it can be observed that all of the prepared oxime esters were found to be inactive against the tested strains except two oxime esters. The oxime ester 3c derived from meta-methoxy benzaldehyde showed activity against one Gram positive organism, Micrococcus luteus MTCC 2470 with a MIC value of 31.2 µg/mL. The other oxime ester 3j was found to exhibit activity against both bacterial and fungal strains. It can be noted that compound 3j exhibited activity against three Gram positive organisms (Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS-16 MTCC 2940 and Micrococcus luteus MTCC 2470) with a MIC value of 15.6 µg/mL for the two Staphylococcus aureus strains whereas the MIC value for Micrococcus luteus MTCC 2470 was found to be 31.2 µg/mL. However, it can be noticed that none of the oxime esters synthesized showed antibacterial activity against Gram negative organisms in the present study. All the compounds prepared in the present study have a basic scaffold of substituted phenolic aldoximes esterified to undecenoic acid. The antibacterial and antifungal activities were compared with Ciprofloxacin and Miconazole as standard drugs, which were found to have MIC values of 0.9 and 7.8µg/mL respectively. It was interesting to observe that the oxime ester 3j exhibited promising antifungal activity against the fungal strain of Candida albicans MTCC 3017 with an MIC of 31.2µg/mL.

Test Compounds

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k Ciprofloxacin (Standard) Miconazole (Standard) a – No activity

>125 >125 >125 >125 >125 >125 >125 >125 >125 15.6 >125 0.9

Bacillus subtilis MTCC 121 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 0.9

Minimum inhibitory concentration (µg/mL) Staphylococcus Micrococcus Klebsiella Escherichia aureus MLSluteus planticola coli MTCC 16 MTCC MTCC 2470 MTCC 739 2940 530 >125 >125 >125 >125 >125 >125 >125 >125 >125 31.2 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 15.6 31.2 >125 >125 >125 >125 >125 >125 0.9 0.9 0.9 0.9

-

-

-

Staphylococcus aureus MTCC 96

-

-

-

Pseudomonas aeruginosa MTCC 2453 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 0.9

Candida albicans MTCC 3017 31.2 -

-

7.8

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Antifungal activity Based on the initial antifungal screening observations, antifungal activity evaluation of 3j was carried out against 12 species of Candida strains and also against Issatchenkia hanoiensis MTCC 4755 and the results were compared with Miconazole as standard drug. The MIC values obtained for the prepared oxime esters and Miconazole are shown in Table 3.

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Table 2 Antimicrobial activity evaluation of the prepared various phenolic oxime esters.

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Table 3 Minimum inhibitory concentration. Test compound C.albicans MTCC 183 C.albicans MTCC 227 C.albicans MTCC 854 C.albicans MTCC 1637 C.albicans MTCC 3018 C.albicans MTCC 3958 C.albicans MTCC 4748 C.albicans MTCC 7315 C.parapsilosis MTCC 1744 C.aaseri MTCC 1962 C. glabrata MTCC 3019 C. krusei MTCC 3020 Issatchenika hanoiensis MTCC 4755

Minimum inhibitory concentration (µg/ml) 3j Miconazole 31.2 7.8 31.2 7.8 62.5 7.8 31.2 7.8 31.2 7.8 31.2 7.8 31.2 7.8 31.2 7.8 31.2 7.8 31.2 7.8 15.6 7.8 62.5 7.8 31.2 7.8

From Table 3, it can be observed that the compound 3j was found to exhibit antifungal activity against all the tested strains. The MIC values were found to be in the range of 15.6 to 62.5µg/mL against all the fungal strains studied. The highest antifungal activity was shown against C. glabrata MTCC 3019 with MIC value 15.6 µg/mL. It was observed that MIC values against majority of the strains were found to be 31.5 µg/mL and the lowest activity was observed on C.albicans MTCC 854 and C. krusei MTCC 3020 with MIC value of 62.5 µg/mL as compared to Miconazole which exhibited an MIC of 7.8µg/mL against all the tested strains. It was earlier reported that the possible mechanism of the antifungal activity is due to the ergosterol biosynthesis inhibition activity exhibited by oxime ester derivative [15]. The minimum fungicidal concentration (MFC) was also determined against the 13 fungal strains and the results are shown in Table 4. Table 4 Minimum fungicidal concentration. Tested strain Candida albicans MTCC 3017 C. albicans MTCC 183 C. albicans MTCC 227 C. albicans MTCC 854 C. albicans MTCC 1637 C. albicans MTCC 3018 C. albicans MTCC 3958 C. albicans MTCC 4748 C. albicans MTCC 7315 C. parapsilosis MTCC 1744 C. aaseri MTCC 1962 C. glabrata MTCC 3019 C. krusei MTCC 3020 Issatchenkia hanoiensis MTCC 4755

Minimum fungicidal concentration (µg/ml) 3j Miconazole 31.2 7.8 62.5 7.8 62.5 7.8 125 7.8 62.5 7.8 62.5 7.8 31.2 7.8 62.5 7.8 62.5 7.8 62.5 7.8 62.5 7.8 31.2 7.8 62.5 7.8 62.5 7.8

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Anti bacterial activity Based on the antifungal activity screening data, compound 3j was further subjected for anti bacterial activity evaluation against seven bacterial species and the results are shown in Table 5. The antibacterial data was compared with Ciprofloxacin as Standard control. From Table 5, it can be observed that the compound 3j was found to exhibit anti bacterial activity against three Gram positive bacterial strains with MIC value of 31.2 µg/mL and it did not show activity against Gram negative organisms whereas the standard Ciprofloxacin exhibited an MIC of 0.9 to 1.9µg/mL against all the tested strains. It was reported that the fatty acids and their derivatives commonly exhibit activity against Gram positive bacteria and show low activity against Gram negative bacteria. Moreover, it was documented that fatty acids with medium to long chain fatty acids exhibit higher activity compared to very long chain fatty acids [20].

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The MFC values were found to be in the range of 31.2 to 125µg/mL against all the fungal strains studied. The MFC value of 31.2 µg/Ml was observed against Candida albicans MTCC 3017, C. albicans MTCC 3958 and C. glabrata MTCC 3019 whereas for other strains, the MIC values were found to be in the range 62.5 to 125µg/mL as compared to Miconazole which exhibited an MFC of 7.8 µg/mL against all the tested strains.

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Table 5 Minimum bactericidal concentration. Test strain Staphylococcus aureus MTCC 96 S. aureus MLS16 MTCC 2940 Micrococcus luteus MTCC 2470

Minimum bactericidal concentration (µg/ml) Ciprofloxacin (Standard control) 3j 31.2 0.9 31.2 0.9 31.2 0.9

Biofilm inhibition Biofilm is formed by a spectrum of microorganisms which may include pathogenic bacteria and they provide a means for these types of organisms to protect themselves against antimicrobial agents. The bacterial biofilms thus formed are reported to cause chronic infections as they show resistance to antibiotics [21]. In view of such type of biofilms, several newer antibiotics have been tested for antibiofilm activity and hence the prepared oxime esters in the present study were explored for biofilm inhibition assay. Based on the antibacterial screening data, the oxime ester derivative 3j was further examined for biofilm inhibition activity and compared with ciprofloxacin and the results of biofilm inhibition assay are given in Table 6. It was found that compound 3j exhibited anti-biofilm activity against Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS16 MTCC 2940 and Micrococcus luteus MTCC 2470. Table 6 Biofilm inhibition assay. Test organism Staphylococcus aureus MTCC 96 S. aureus MLS16 MTCC 2940 Micrococcus luteus MTCC 2470

IC50 values in (μg/mL) 3j Ciprofloxacin (Standard control) 8.8 ± 0.32 0.6 ± 0.06 11.9 ± 0.22 0.4 ± 0.11 17.3 ± 0.51 0.5 ± 0.08

It can be noted that the oxime ester 3j showed good activity against the two S.aureus strains with MIC values of 8.8 and 11.9 µg/mL compared to ciprofloxacin which had MIC value in the range of 0.4 to 0.7 µg/mL against all the strains. The results of anti biofilm activity from the oxime esters suggest that the oxime ester 3j showed higher activity against both Staphyloccus species compared to Micrococcus luteus which could be useful while targeting specific microorganisms for biofilm inhibition by lipophilic bioactives. Based on the structure-activity relationship data analysis, it is revealed that oxime ester derived from mono substituted phenolic hydroxyl at meta position to the oxime functionality showed antimicrobial activity compared to other derivatives in the present study. These results show the importance of location of phenolic hydroxyl position on the phenyl ring to exert antimicrobial action. Antioxidant activity The antioxidant activity evaluation of the newly prepared oxime esters in the present study was studied by three in vitro methods such as 2, 2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging activity, superoxide radical scavenging activity and inhibition of lipid peroxidation assay. The results were compared with BHT and α-tocopherol as standard antioxidants. The amount of compound needed to inhibit the radicals by 50% was estimated and the values are given as their effective concentration (EC50) values. The results obtained for the antioxidant evaluation by the three methods are given in the Table 7. It was observed that among the prepared oxime esters five derivatives showed antioxidant activity. Among the five derivatives only two compounds (3g and 3k) showed activity in all the three methods studied with compound 3k being the most potent antioxidant. Table 7 Antioxidant activities of oxime esters. Inhibition of lipid peroxidation 225.6 ± 0.44 32.1 ± 0.22 44.1 ± 0.23 -

BHT and α-Tocopherol used as reference compounds were found to be better antioxidants in all the assays tested with αTocopherol being more active than BHT. However, oxime ester 3k synthesized from 2, 3-dihydroxy benzaldoxime showed highest antioxidant activity and was found to be superior than the reference compounds in the all the three antioxidant activity assays. It was earlier reported that the difference in antioxidant activity varies according to the substituent present on the aromatic ring and also on the number and position of hydroxyl functional groups [22]. In the present study, the position of hydroxyl and methoxy groups is for the derivatives and this could be the reason for the difference in the antioxidant activities shown by the product oxime esters.

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3d 3e 3g 3h 3k BHT α-Tocopherol

DPPH FRSA Superoxide FRSA EC50 (µg ml-1) (Mean ± S.D.) 187.3 ± 0.52 337.5 ± 0.44 151.2 ± 0.36 133.2 ± 0.32 308.1 ± 0.53 9.8 ± 0.24 8.1 ± 0.18 27.2 ± 0.26 13.2 ± 0.12 10.1 ± 0.18 7.2 ± 0.14

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CONCLUSIONS In this study, novel oxime ester derivatives involving various aromatic aldoximes and undecenoic acid were synthesized and evaluated for antimicrobial and antioxidant activities. Antimicrobial evaluation revealed that among all the compounds one oxime ester (3j) exhibited significant antimicrobial activity and antifungal activity along with biofilm inhibition activity. It was also found that among all the compounds, 3k exhibited potent antioxidant activity as per the three antioxidant activity assays performed in the present study. Bottom line of the present study suggests that there is further need for designing undecenoic acid based potential lipophilic derivatives with improved antimicrobial effects.

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ACKNOWLEDGEMENTS Venepally Vijayendar, acknowledges University Grants Commission (UGC), New Delhi, India, Y. Poornachandra acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi, India, for financial support in the form of Senior Research Fellowship (SRF). The authors have declared no conflict of interests.

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23. Jakob P L, Heinz-Jurgen Bertram. Hydroxy- or Methoxy-Substituted Benzaldoximes and Benzaldehyde-O-alkyloximes as Tyrosinase Inhibitors. Bioorg. Med. Chem. 2001; 9: 1879–1885. 24. Amsterdam D, Susceptibility testing of antimicrobials in liquid media. In: Loman, V. (ed.) Antibiotics in Laboratory Medicine, 4th ed. Williams and Wilkins, Baltimore, MD, 1996: 52–111. 25. NCCLS 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard, 5th ed. NCCLS document M7-A5. NCCLS, Wayne, Pa. 26. Kamal A, Rahim A, Riyaz S, Poornachandra Y, Balakrishna M, Kumar C G, Hussaini S M, Sridhar B, Machiraju P K. Regioselective synthesis, antimicrobial evaluation and theoretical studies of 2-styryl quinolines. Org. Biomol. Chem. 2015; 13: 1347–1357. 27. Moon J H, Terao J, Antioxidant activity of caffeic acid and dihydrocaffeic acid in lard and human low density protein, J. Agric. Food Chem. 1998; 46: 5062. 28. Bors W, Heller W, Michel C, Saran M. Flavonoids as antioxidants: determination of radical-scavenging efficiencies, Methods Enzymol. 1990; 186: 343. 29. Liu F, Ooi V E, Chang S T. Free radical scavenging activities of mushroom polysaccharide extracts. Life Sci. 1997, 60, 763-771. 30. Zhang E X, Yu L J, Studies on polysaccharide from Sargassum thunberg II for its ability to scavenge active oxygen species. Chinese J. Marine Drugs. 1997; 3: 1–4.

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