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Synthesis, Antimicrobial, Antioxidant and Nematicidal Activity of (2E,4E)-5-(Benzo[d] [1,3]dioxol-5yl)penta-2,4-dienamides.

Byline: Aneela Wahab, Amina Sultana, Khalid Mohammed Khan, Sikandar K. Sherwani, Zeba Perveen and Aneela Karim

Summary: The amides of piperic acid have been synthesized via the condensation of piperic acid with amines. The structural characterization was done by IR, 1H-NMR, EI-MS and elemental analysis. The amides 3a-3o were evaluated for their biological activity. It has been found that among others the newly synthesized compound 3f, 3k, 3m, and 3o have great potential against root-knot nematode Meloidogyne incognita that usually affect tomato crop. These compounds exhibited 92, 96, 82 and 95% mortality rate at lethal concentration (LC50) 4.4, 3.4, 4.5 and 3.5 mg/mL, respectively.

Conventionally used nematicide furadan was taken as standard. Compound 3h, 3c and, 3j exhibited significant anti-oxidant activities against 1,1-diphenylpicrylhydrazil (DPPH) radical with 80, 70 and 72% inhibition (EC50 = 625, 937 and 937.5 g/mL), respectively. Ascorbic acid was used as standard. When tested for antimicrobial activity 3m was found to be the most active one showing zone of inhibition in the range of 18-30 mm against all tested microbial strains. Good biological activities of synthetic amides indicate their ability to behave as a good antimicrobial and nematicidal agent.

Keywords: Piperic acid, Amide, Nematicidal activity, Anti-microbial, Anti-oxidant activity.

Introduction

Amides and its derivatives are an important functionality in both natural and synthetic bioactive compounds such as niacin amide is vitamin B [1] fatty acid amides, anandamide is analgesic [2] oleamide that is present in cerebrospinal fluid induces sleep [3] while erucamide stimulates formation of new blood vessels [4] and a natural painkiller found in brain peptide is enkephalins [5]. Many researchers have found that different amide derivatives possessing antimicrobial [6] antituberculosis [7] and antiinsecticidal [8] properties. Amides are the main character of meprobamate (tranquillizer) and sulfathiazole (bacteriostatic) synthetic drug [9]. Likewise piperine, an amide isolated from piper species is a naturally occurring alkaloid [10, 11].

It exhibited valuable therapeutic activities such as antidepressant [12], anti-inflammatory [13], synergistic and antimicrobial [14]. Furthermore, it acts as an enhancer of bioavailability for many medicines [15, 16]. Its synthetic analogues have been examined for their trypanosomal activity against trypanosoma cruzi [17]. The inspiration of biological importance and valuable uses in pharmaceutical and industrial application of amides, it is aimed to synthesize amides of piperic acid in addition to evaluate their antimicrobial, nematicidal and antioxidant activity.

The plant parasitic nematodes markedly affect the mass and quality of many cultivated crops that results in drastic thrashing of economy and cultivation [18]. These phytoparasite locate their host using carbon dioxide as an attractant to induce changes in them [19]. Like alfa alfa shoot stunting by Ditylenchus dipsaci [20] potato cyst by Globodera species and certain grape diseases are due to Xiphinema index [21]. Similarly, Meloidogyne species are root-knot nematodes. It usually attacks tomato crop which is cultivated all over the world. The parasitic attack produce galling in their roots due to which growth controlling component are affected, thus the net result is the loss of nutrients and yield [22].

It is being reported here the synthesis of amides of piperic acid (3a-3o) from piperin (1) (scheme-1). Among these 3f, 3j, 3k, 3m and 3o are newly synthesized amides. The structures of all synthetic compounds were elucidated by IR, 1H- NMR, EIMS. All compounds gave satisfactory CHN elemental analyses. All compounds were screened for their biological activities. All of them showed significant antimicrobial, antioxidant and nematicidal activity (Table-1 and 2).

Table-1: In vitro anti-bacterial and anti-fungal activity of compounds 3a-3o

###Organisms###3a###3b###3c###3d###3e###3f###3g###3h###3i###3j###3k###3l###3m###3n###3o###Standard

###Bacteria###Streptomycine

###S. pneumonia###-###-###-###-###-###-###-###-###-###-###-###-###-###-###35

###P. vulgaris###-###-###-###-###-###-###-###30###-###-###-###-###25###-###-###30

###S. aureus###-###-###-###-###-###-###-###-###14###-###-###-###30###-###-###25

###P. stutzeri###-###-###10###-###-###-###-###-###16###-###-###16###29###-###-###15

###P. aeruginosa###-###7###14###-###16###16###12###-###16###-###18###-###19###-###-###15

###E. coli###-###-###-###-###-###-###-###-###-###-###14###-###20###-###16###20

###Fungi###Ketoconazole

###Rhizopus###-###-###-###-###-###-###-###-###-###-###-###-###7###-###-###22

###A. niger###-###-###-###-###-###-###-###-###-###-###-###-###5###-###-###24

###A. flavis###-###-###-###-###-###-###-###-###-###-###-###-###5###-###-###24

###C. albican###-###-###-###-###-###-###-###-###-###-###-###-###6###-###-###22

Table -2: In vitro nematicidal and antioxidant activity of compounds 3a-3o

###Nematicdal activity###Antioxidant activity

###Compounds###Moratlity rate %###LC20###LC50###LC90###% inhibition###EC50

###of M.incgnita###mg/mL###mg/mL###mg/mL###mm###g/mL

###3a###98 0.02###3.6###4.2###5.2###12###-

###3b###92 0.03###4.1###5.8###6.0###-###-

###3c###83 0.02###4.2###5.8###6.6###70###937

###3d###90 0.02###2.6###3.0###4.4###-###-

###3e###20 0.02###20.2###26.7###31.0###58###100

###3f###92 0.04###3.2###4.4###5.8###44###-

###3g###12 0.02###22.4###34.3###37.6###-###-

###3h###14 0.06###19.3###22.6###34.2###80###625

###3i###80 0.02###3.3###3.8###4.4###15###-

###3j###21 0.04###18.7###22.5###31.8###72###937.5

###3k###96 0.03###2.5###3.4###4.1###47###-

###3l###13 0.02###28.6###39.0###40.1###44###-

###3m###82 0.02###3.3###4.5###4.9###57.9###100

###3n###21 0.03###20.1###31.3###39.2###-###-

###3o###95 0.01###2.2###3.5###4.3###40

###Furadan###100###-###-

###(1g/ mL)

###Ascorbic acid###-###-###-###-###80###8.3

###Furadan###100###-###-

###(1g/ mL)

###Ascorbic acid###-###-###-###-###80###8.3

Experimental

General

All the solvents and reagents used for chemical reaction were purchased from E. Merck, Germany. The reactions were monitored by TLC which was carried out on pre-coated silica gel glass plates (Kieselgel60, 254, E. Merck, Germany). The melting points were determined in glass capillary using Gallen Kamp melting point apparatus and were uncorrected. EIMS spectra were taken on JEOL JMS600H. The 1H-NMR spectra were recorded on Avance AV-300, 400, 500 and 600 MHz in deuterated methanol or DMSO-d6 with an internal standard, tetramethylsilane (TMS). IR spectra were performed on a JASCO-302-A spectrophotometer. For elemental analysis a Carlo Erba Strumentazione- Mod-1106, Italy, was used.

Bioassay Protocol

Collection of Pathogenic Organism

All the bacterial and fungal pathogens were obtained from the Department of Microbiology, Federal Urdu University of Arts, Science and Technology, Karachi, Pakistan.

Preparation of Culture

To culture bacterial stains Muller Hinton agar (Oxoid) and Muller Hinton broth (Oxoid) were used as media and Sabourd dextrose agar (SDA) plates for fungal strains.

Antibacterial Activity

The disc diffusion method [21] was used to determine the antibacterial activity of the synthetic compounds (3a-3o). Autoclaved Muller Hinton broth was used to maintain bacterial pathogens in log phase for 2 h with constant shaking. 100 mg/mL of stock solution was prepared by dissolving pure compounds in DMSO. Sterile filter discs (7 mm in diameter) containing 10 L of stock solution were used for screening. The Mueller Hinton agar (Oxoid) plates were seeded with 24 h old culture grown in Mueller Hinton broth (Oxoid). The prepared discs were placed on to the surfaces at different positions and plates were incubated at 37 C for 24 h. Results were recorded by measuring the zone of inhibitions in mm. DMSO was used as negative control and streptomycin was used as positive control.

Antifungal Activity

Antifungal activity of synthetic compounds (3a-3o) was also determined by disc diffusion method as described above. A homogeneous mixture of fungal culture was prepared and the SDA plates were seeded with this suspension. Sterile filter discs containing 10 L of stock solution were placed on to the surfaces at different positions. Plates were incubated at room temperature for one week. After incubation diameter of zone of inhibitions was noted in mm. The ketoconazole was used as standard.

Antioxidant Activity

Antioxidant activity of the compounds (3a-3o) was determined by using the procedure described in [22]. The stable radical solution of 1, 1-diphenyl- 2-picrylhydrazyl (DPPH) was prepared in ethanol (300 M). 10 L of test samples and 90 L solution of stable radical (DPPH) was added in 96-well microtiter plates and incubated at 37 C for 30 minutes. Absorbance was measured at 515 nm by means of a spectrophotometer. Percent inhibition of radicals by treatment of test sample was found out by comparison with DMSO as negative control. Ascorbic acid was used as standard.

Equation

The EC50 value calculated denotes the concentration (in g/ml) of sample required to scavenge 50% of DPPH.

Nematicidal Activity

The nematicidal activity was determined through the procedure applied in [23]. The results were expressed in terms of percent mortality and LC20, LC50 and LC90 i.e. lethal concentration required to kill 20, 50 and 90% nematodes. The test concentrations were prepared by adding 40 L of synthetic drug stocks to 460 L of fresh tap water in a 12-well plate. The mixing-plate was gently shaken by hands around 2 min to allow the drug to mix well. After that, 150 mL of the solution was transferred into 24 well test plates. Next, 90 L of the nematode suspension containing approximately 150 second stage juveniles was added into the wells and gently mix for another 2 min then kept standing overnight at 24 C. After 24 h the dead and alive nematodes were counted under stereoscopic binocular microscope to evaluate the mortality rate. Nematodes were considered dead when no movement was observed even after mechanical prodding. The % mortality was calculated from an average of triplicate.

In order to determine the toxicities, lethal concentration was determined at LC20, LC50 and LC90 mg/mL.

Preparation of (2E,4E)-5-(benzo[d][1,3]dioxol-5- yl)penta-2,4-dienoic acid (Piperic acid, 2) [24].

Piperin 1 (5 g, 0.0175 mol) was refluxed with 20% methanolic KOH (300 ml) at 150 C for 24 h. The reaction was monitored by TLC. After complete hydrolysis methanol was distilled under vacuum. The resulting mixture was suspended in hot distilled water, acidify with HCl (2N) and the precipitates thus obtained were filtered, washed with ice cold water, dried and recrystallized from ethanol to afford pale yellow crystals of piperic acid 2. Yield:

94%; m.p: 215-216 C, IR (KBr) max cm-1: 2940, 1673, 1597, 1447; H-NMR: (300 MHz, DMSO-d6): d 12.17 (1H, s, -COOH), 7.01 (1H, dd, J3/2,4 = 15.6, 8.10 Hz, H-3), 6.89-7.32 (5H, m, olefinic and Ar-H), 6.04 (2H, s, O-CH2-O), 6.01 (1H, d, J2,3 = 15.6 Hz, H-2); EI-MS: m/z (rel.abund.%), 218 (M , 82), 201 (6), 173 (100), 143 (31), 121 (2), 115 (63); Anal. calcd for C12H10O4 (218.06): C, 66.05; H, 4.62; Found: C, 66.00; H, 4.63.

General procedure for the preparation of amides of Piperic acid (3a-3o)

Piperic acid 2 (0.5 g, 0.00229 mol) in dry dichloromethane (15 mL) was stirred for 10 min by keeping on an ice bath under nitrogen atmosphere. Freshly distilled SOCl2 (thionyl chloride) (2 mL, 0.27mol) was added drop wise, the resultant solution was then stirred for 2 h till the appearance of orange- brown coloration. The excess SOCl2 was removed on a rotary evaporator under reduced pressure leaving orange-brown acid chloride residue. It was dissolved in dry dichloromethane (10 mL) then condensed with appropriate amine (0.59 g, 0.00688 mol in 5 mL dichloromethane).

The content was then refluxed at 60 C for 2-2.5 h. The reaction progress was determined through TLC analysis (n-hexane-EtOAc, 7:3). The reaction content was diluted with distilled water; organic layer was separated out, washed with water (2A-25mL), dried over anhydrous Na2SO4 and concentrated. Thereafter the crude product was purified by column chromatography over silica gel using n-hexane-EtOAc with increasing gradient to afford compound 3a. Other compounds 3b-o was synthesized in the similar way.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-1-(piperidin1-yl)penta-2,4-dien-1-one (3a)

Yield: 74%; m.p: 130-131 C, IR (KBr) max cm-1: 1631, 1490, 844; 1H-NMR: (500 MHz, MeOD); d 7.28 (1H, dd, J3/2,4 = 15.0, 14.0 Hz, H-3), 6.94 (2H, m, H-4/5), 6.89 (2H, m, H-10/11), 6.82 (1H, s, H-7), 6.59 (1H, d, J2,3 = 15.0 Hz, H-2), 5.95 (2H, s, O- CH2O), 3.60 (4H, m, -N(CH2)2), 1.69 (2H, m, H-4'), 1.59 (4H, bs, H-3'/5'); EI-MS: m/z (rel. abund. %), 285 (M+, 36), 201 (71), 173 (60), 159 (13), 143 (36), 115 (100), 84 (18); Anal. calcd for C17H19NO3 (285. 14): C, 71.56; H, 6.71; N, 4.91; Found: C, 71.54; H, 6.73; N, 4.90.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-1- morpholinopenta-2,4-dien-1-one (3b)

Yield: 89%; m.p: 159-160 C, IR (KBr) max cm-1: 2941, 1633, 1491, 997; 1H-NMR: (500 MHz, MeOD): d 7.33 (1H, dd, J3/2,4 = 15.0, 14.0 Hz, H-3), 6.95 (2H, m, H-4/5), 6.89 (2H, m, H-10/11), 6.86 (1H, s, H-7), 6.58 (1H, d, J2,3 = 15.0 Hz, H-2), 5.96 (2H, s, O-CH2-O), 3.70 (4H, m, N(CH2)2), 3.61 (4H, m, O (CH2)2); EI-MS: m/z (rel. abund. %), 287 (M+, 94), 201 (100), 173 (60), 115 (68), 86 (6); Anal. calcd for C16H17NO4 (287.12): C, 66.89; H, 5.96; N, 4.88; Found: C, 66.87; H, 5.97; N, 4.86.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-1-(4- methylpiperazin-1-yl)penta-2,4-dien-1-one (3c)

Yield: 71%; m.p: 178-189 C, IR (KBr) max cm-1: 2954, 1630, 845; 1H-NMR: (500 MHz, MeOD): d 7.31 (1H, dd, J 3/2,4= 15.0, 14.0 Hz, H-3), 6.78-7.08 (5H, m, olefinic and Ar-H), 6.59 (1H, d, J2,3 = 15.0 Hz, H-2), 5.95 (2H, s, OCH2O), 3.29 (4H, m, H- 2'/6'), 2.48 (4H, bs, H-3'/5'), 2.33 (3H, s, NCH3): EI- MS: m/z (rel. abund. %), 300 (M+, 28), 201 (23), 173 (32), 143 (16), 115 (46), 99 (48), 70 (100); Anal. calcd for C17H20N2O3 (300.15): C, 67.98; H, 6.71; N, 9.33; Found: C, 67.97; H; 6.72; N, 9.35.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)penta-2,4- dienamide (3d)

Yield: 81%; m.p: 102-105 C, IR (KBr) cm-1: 3021, 1644, 970; 1H-NMR (300 MHz, MeOD): d 7.24 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.77-7.08 (5H, m, olefinic and Ar-H), 6.12 (1H, d, J2,3 = 15.0 Hz, H-2), 5.95 (2H, s, OCH2O), 5.47 (2H, s, -NH2); EI-MS: m/z (rel. abund. %), 217 (M+, 68), 173 (100), 143 (31), 115 (80), 96 (14), 44 (8); Anal. calcd for C12H11NO3 (217.07): C, 66.35; H, 5.10: N, 6.45; Found: C, 66.33; H, 5.12; N, 6.44.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N- phenylpenta-2,4-dienamide (3e)

Yield: 87; m.p: 173-175 C, IR (KBr) max cm-1: 3215, 1639, 890; 1H-NMR: (500 MHz, MeOD): d 7.61 (2H, d, J2',3' = 7.5 Hz, H-2'/6'), 7.40 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 7.29-7.08 (3H, m, H- 3'/4'/5'), 6.79-7.10 (5H, m, olefinic and Ar-H), 6.25 (1H, d, J2,3 = 15.0 Hz, H-2), 5.96 (2H, s, OCH2O); EI-MS: m/z (rel. abund, %), 293 (M+, 12) 201 (92), 173 (11), 115 (100), 92 (3), 77 (10); Anal. calcd for C18H15NO3 (293.11): C, 73.71; H, 5.15; N, 4.78; Found: C, 73.69; H, 5.13: N, 4.79.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-p- tolylpenta-2,4-dienamide (3f)

Yield: 81%; m.p: 190-191 C, IR (KBr) max cm-1: 3198, 1647, 929; 1H-NMR: (500 MHz, MeOD): d 7.88 (1H, s, -CONH), 7.60 (2H, d, J = 8.5, H- 2'/6'), 7.41 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 7.22 (2H, d, J3',2' = 8.5 Hz, H-3'/5'), 6.79-7.10 (5H, m, olefinic and Ar-H), 6.01 (1H, d, J2,3 = 15.0 Hz, H-2), 5.96 (2H, s, O-CH2-O), 2.21 (3H, s, Ar-CH3); EI-MS: m/z (rel. abund, %), 307 (M+, 76), 217 (13), 201 (45), 187 (6), 173 (100), 143 (60), 115 (79); Anal. calcd for C19H17NO3 (307.12): C, 74.25; H, 5.58; N, 4.56; Found: C, 74.24; H, 5.59; N, 4.54.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-(4- chlorophenyl)penta-2,4-dienamide (3g)

Yield: 80%; m.p: 118-120 C, IR (KBr) max cm-1: 3291, 1638, 997; 1H-NMR: (300 MHz, MeOD): d 7.63 (2H, d, J2',3'= 8.7 Hz, H-2'/6'), 7.46 (2H, d, J3',2' = 8.7 Hz, H-3'/5'), 6.70-7.40 (6H, m, olefinic and Ar-H), 6.23 (1H, d, J2,3 = 15.0 Hz, H-2), 5.97 (2H, s, OCH2O); EI-MS: m/z (rel. abund. %), 327 (M+, 13), 201 (79), 173 (18), 143 (22), 121 (32); Anal. calcd for C18H14ClNO3 (327.07): C, 65.96; H, 4.31; N, 4.27; Found: C, 65.93; H, 4.30; N, 4.25.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-(4- methoxyphenyl)penta-2,4-dienamide (3h)

Yield: 71%; m.p: 163-165 C, IR (KBr) max cm-1: 3350, 1649; 1H-NMR: (300 MHz, MeOD): d 8.17 (1H, s, -CONH-), 6.70-7.47 (10H, m, olefinic and Ar-H), 6.00 (1H, d, J2/3 = 15.0 Hz, H-2), 5.93 (2H, s, OCH2O), 3.76 (3H, s, OCH3); EI-MS: m/z (rel. abund %), 323 (M+, 64), 307 (8), 293 (6), 201 (14), 173 (6), 143 (10), 121 (13), 115 (17); Anal. calcd for C19H17NO4 (323.12): C, 70.58; H, 5.30; N, 4.33; Found: C, 70.57; H, 5.30; N, 4.34.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N- propylpenta-2,4-dienamide (3i)

Yield: 76%; m.p: 128-129 C, IR (KBr) max cm-1: 3263, 1634, 1539, 787; 1H-NMR: (300 MHz, MeOD): d 7.40 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.78-7.10 (5H, m, olefinic and Ar-H), 6.09 (1H, d, J2,3 = 15.0 Hz, H-2), 5.96 (2H, s, OCH2O), 5.91 (1H, s, CONH), 3.52 (2H, m, H-2'), 1.68 (2H, m, H-3'), 1.00 (3H, t, J4',3' = 7.2 Hz, H-4'); EI-MS: m/z (rel. abund %), 259 (M+, 13), 218 (83), 201 (30), 173 (100), 143 (45), 115 (69); Anal. calcd for C15H17NO3 (259.12): C, 69.48; H, 6.61; N, 5.40; Found: C, 69.45; H, 6.60; N, 5.41.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N- mesitylpenta-2,4-dienamide (3j)

Yield: 92%; m.p: 265-269 C, IR (KBr) max cm-1: 3259, 1633, 845; 1H-NMR: (300 MHz, MeOD): d 7.40 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.79-7.11 (7H, m, olefinic and Ar-H), 6.34 (1H, d, J2,3 = 15.0 Hz, H-2), 5.97 (2H, s, OCH2O) 2.25 (3H, s, p-CH3), 2.16 (6H, s, 2 x o-CH3); EI-MS: m/z (rel. abund %), 335 (M+, 57), 201 (100), 171 (34), 143 (47), 135 (26), 115 (61), 89 (9); Anal. calcd for C21H21NO3 (335.15): C, 75.20; H, 6.31; N, 4.18; O, 14.31; Found: C, 75.19; H, 6.32; N, 4.20.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-(4- methylpiperazin-1-yl)penta-2,4-dienamide (3k)

Yield: 72%; m.p: 70-71 C, IR (KBr) max cm-1 3330, 1628, 1194; 1H-NMR: (300 MHz, MeOD): d 7.38 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.79-7.09 (5H, m, olefinic and Ar-H), 6.10 (1H, d, J 2,3= 15.0 Hz, H-2), 5.97 (2H, s, OCH2O), 3.50 (4H, bs, N-N(CH2)2), 3.35 (4H, bs, (CH2 )2N), 2.91 (3H, s, N-CH3); EI-MS: m/z (rel. abund %), 315 (M+, 15), 300 (4), 217 (19), 201 (96), 173 (14), 143 (9), 114 (28), 99 (85); Anal. calcd for C17H21N3O3 (315.16): C, 64.74; H, 6.71; N, 13.32; Found: C, 64.72; H, 6.70; N, 13.33.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-1-(pyrrolidine1-yl)penta-2,4-dien-1-one (3l)

Yield: 67%; m.p: 141-143 C, IR (KBr) max cm-1: 1649, 1448, 929; 1H-NMR: (300 MHz, MeOD): d 7.37 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.78-7.09 (5H, m, olefinic and Ar-H), 6.44 (1H, d, J2,3 = 15.0 Hz, H-2), 5.96 (2H, s, O-CH2-O), 3.59 (4H, m, H2'/5'), 1.98 (4H, m, H-3'/4'); EI-MS: m/z (rel. abund %), 271 (M+, 90), 201 (100), 173 (20), 143 (14), 115 (53), 70 (6); Anal. calcd for C16H17NO3 (271.12): C, 70.83; H, 6.32; N, 5.16; Found: C, 70.81; H, 6.33; N, 5.17.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-(4- iodophenyl)penta-2,4-dienamide (3m)

Yield: 75%; m.p: 115-117 C, IR (KBr) max cm-1: 3321, 1627, 987; 1H-NMR: (600 MHz, MeOD): d 7.72 (2H, d, J2',3' = 8.4 Hz, H-2'/6'), 6.90 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.80 (2H, d, J3',2' = 8.4 Hz, H-3'/5'), 6.83-7.54 (5H, m, olefinic and Ar-H), 5.96 (2H, s, O-CH2-O), 5.94 (1H, d, J2,3 = 15.0 Hz, H-2), 3.63 (1H, s, -CONH-); EI-MS: m/z (rel. abund %), 419 (M+, 8), 418 (9), 218 (41), 173 (47), 143 (23), 115 (62), 43 (100); Anal. calcd for C18H14NO3I (419.00): C, 51.57; H, 3.37; N, 3.34; Found: C, 51.55; H, 3.39; N, 3.35.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-benzylpenta2,4-dienamide (3n)

Yield: 76%; m.p: 170-173 C, IR (KBr) max cm-1: 3239, 1623; 1H-NMR: (400 MHz, MeOD): d 7.29 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.78-7.23 (10H, m, olefinic and Ar-H), 6.13 (1H, d, J2,3 = 15.0 Hz, H-2), 5.95 (2H, s, OCH2O), 4.45 (2H, s, N-CH2); EI-MS: m/z (rel. abund. %), 307(M+, 54), 218 (52), 201 (24), 173 (92), 143 (35), 115 (77), 106 (100), 91 (37), 77 (20), Anal. calcd for C19H17NO3 (307.12): C, 74.25; H, 5.58; N, 4.56; Found: C, 74.21; H, 5.59; N, 4.58.

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methoxy4-methylphenyl)penta-2,4-dienamide (3o)

Yield: 71%; m.p: 201-203 C, IR (KBr) max cm-1: 3257, 1647; 1H-NMR: (300 MHz, MeOD): d 7.40 (1H, dd, J3/2,4 = 15.0, 10.0 Hz, H-3), 6.79-7.10 (8H, m, olefinic and Ar-H), 6.26 (1H, d, J2,3 = 15.0 Hz, H-2), 5.96 (2H, s, OCH2O), 3.82 (3H, s, -OCH3), 2.13 (3H, s, -CH3); EI-MS: m/z (rel. abund. %), 337 (M+, 35), 215 (25), 201 (100), 143 (34), 115 (78); Anal. calcd for C20H19NO4 (337.13): C, 71.20; H, 5.68; N, 4.15; Found: C, 71.17; H, 5.69; N, 4.17.

Indicates newly synthesized compounds.

Result and Discussion

Piperin (1) was subjected to basic hydrolysis to give piperic acid (2) which was then reacted with thionyl chloride (SOCl2) and condensed with amine resulting in the formation of corresponding amide (3a-3o). It is also important noted that compounds 3f, 3j, 3k, 3m, and 3o are synthesized for the first time.

All the synthetic compounds (3a-3o) were screened for their antimicrobial activity by measuring zone of inhibition via disc diffusion protocol against Streptococcus pneumonia, Proteus vulgaris, Streptococcus aureus, Pseudomonas stutzeri, Pseudomonas aeruginosa, and Escherichia coli bacterial strains and Rhizopus, Aspergillus niger, Aspergillus flavus and Candida albican fungal strains.

The compound 3m was found highly active against all tested bacterial strains except S. pneumonia showing 25, 30, 29, 19 and 20 mm zone of inhibition for P. vulgaris, S. aureus, P. stutzeri, P. aeruginosa, and E.coli, respectively. Compound 3h showed excellent zone of inhibition, 30 mm against P. vulgaris. Compound 3i and 3l were good active against P. stutzeri with zone of inhibition 16 mm each. The same zone of inhibition was observed by compounds 3e, 3f and 3i while compound 3k showed 18 mm zone of inhibition for P. aeruginosa. Only compound 3m showed weak antifungal activity against all applied fungal strains.

The compounds 3a-3o was also screened for their in vitro antioxidant activity. Compounds 3h, 3j and 3c showed significant antioxidant activity having 80, 72 and 70% inhibition of DPPH radical along with EC50 values 625, 937.5 and 937 g/mL, respectively, whereas compounds 3e and 3m found to have moderate antioxidant activity with % inhibition 58 and 57.9, respectively, displaying EC50 value 100 g/ml.

All the synthetic amides (3a-3o) were further tested for their nematicidal activity against Meloidogyne incognita (root-knot nematode). This nematode destroyed the nutrients, quality and quantity of crops generally of tomatoes. The compounds 3a, 3k, 3o, 3b, 3f and 3d exhibited promising antianemic property, showing mortality rate 98, 96, 95, 92, 92 and 90% with LC50 values 4.2, 3.4, 3.5, 5.8, 4.4 and 3.0 mg/mL, respectively.

Conclusion

On the basis of bioassay screening it has been observed that the synthetic compounds 3m possess promising antimicrobial activity, whereas 3h exhibited excellent antioxidant activity and compound 3a showed highest % mortality against root-knot nematode (M. incognita). It is conclude that the amides of piperic acid have potential to become suitable lead candidate against various types of microbial infections and they can also be used as pesticides for killing root-knot nematodes.

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