MICROWAVE ASSISTED SYNTHESIS, CHARACTERIZATION, MOLECULAR DOCKING AND ANTIMICROBIAL EVALUATION OF 4-NITROCINNAMIDE ANALOGUESHTML Full Text
MICROWAVE ASSISTED SYNTHESIS, CHARACTERIZATION, MOLECULAR DOCKING AND ANTIMICROBIAL EVALUATION OF 4-NITROCINNAMIDE ANALOGUES
M. Soujanya *1 and G. Rajitha 2
Department of Pharmaceutical Chemistry 1, Gokula Krishna College of Pharmacy, JNTU Anantapur, SPSR Nellore, Sullurpet - 524121, Andhra Pradesh, India.
Department of Pharmaceutical Chemistry 2, Institute of Pharmaceutical Technology, Sri Padmavathi Mahila Visvavidyalayam (Mahila University), Tirupati - 517502, Andhra Pradesh, India.
ABSTRACT: A series of novel 2-Benzamido-3-(4-nitrophenyl)-N’-(substituted) benzylidene-acrylohydrazide (4a-l) analogues were designed by incorporating the few pharmacophoric fragments to enhance the activity profile of molecules. Title compounds were synthesized by the microwave irradiation of α-Benzamido-(4-nitro)-cinnamahydrazide (3) reveals with aromatic/ heteroaromatic aldehydes under acidic conditions, characterized by IR, 1H & 13C NMR, Mass and evaluated for antimicrobial activity by using Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Candida albicans strains. Compounds 4e and 4k exhibited significant protection against bacterial strains (MIC: 3.12-50µg/ml; 3.12-100µg/ml respectively) and compound 4h showed better activity (MIC: 12.5 µg/ml) against fungal strain. And also molecular docking interactions with FAB protein for evaluating the antimicrobial activity was done by using XP GLIDE module of Schrodinger suite and this study highlights, all the analogues exhibited significant affinity towards the 5BNM (FAB Protein) have good docking scores (-4.51 to -8.78) than standard drug ciprofloxacin (-4.74). Of the 12 new analogues, compound 4e was identified as most active ligand with good activity profile against bacterial strains and also have higher binding affinity with target.
Molecular Docking, Cinnamides, Acylhydrazones, Antimicrobial activity, MIC and FAB protein
INTRODUCTION: The search for new antimicrobial agents is the challenging area for researchers because of dramatic increasing the resistance of microbial pathogens and it is desirable to find the drugs with improved potency and wider activity spectrum.
In recent years, cinnamic acid derivatives such as cinnamides exhibited a variety of biological activities such as antioxidant, antitumor, antimicrobial, antitubercular, anti-inflammatory, antifungal activity 1 - 5 and are often used as promising precursor for the development of new, highly effective drugs. However, the reactive center (vinyl fragment) of cinnamides was significantly affected by substituent present at various positions of the benzene nucleus 6 - 7. On the other hand scientific literature is more and more focused on acyl hydrazones are well known class of compounds with diverse biological activities such as antitubercular, anticancer, antioxidant, antimicrobial activities 8 -11. In addition to the above facts, some reports showed the importance of nitro substituted antimicrobial drugs for treating urinary tract infections 12 -13. In new drug development studies, hybridization of different pharmacophores in the same frame may lead to development of new compounds having higher biological activity.
FIG. 1: DESIGN STRATEGY ADOPTED FOR DESIGNING OF TITLE COMPOUNDS (4a-l)
In light of the above facts, we planned to synthesize nitro substituted cinnamides linked with the other scaffold acylhydrazone, in hope of obtaining additional antimicrobial spectrum for the treatment of microbial infections and the study was further extended to known the interaction modes of ligand with target assessed by Moleculardocking studies and also predict the molecular properties, toxicity and drug likeness score using in-silico tools.
MATERIALS AND METHODS: All the melting points were determined in open capillaries using Thermonik precision melting point cum boiling point apparatus model C-PMB-2 and are uncorrected. The progress of reactions was monitored by pre-coated TLC plates (E. Merck Kieselgel 60 F254) and the IR spectra were recorded using Perkin-Elmer 1760 spectro photometer.1H NMR and 13C NMR spectra were recorded using Bruker Advance 400 MHz spectrometer in DMSO-d6, using Tetramethyl silane (TMS) as an internal standard. Elemental analyses (C, H, and N) were performed using Perkin Elmer model 240 C analyzer. Reagents and solvents were purchased from Sigma and were used without further puriﬁcation.
Synthesis of 4-(4-nitro)-benzylidene – 2 - phenyl oxazol-5-ones (2): Synthesis of 4-(4-nitro) benzylidene-2-phenyloxazol-5-ones was done accordance with the previously reported method 14.
Synthesis of α-Benzamido-(4-nitro)-cinnama hydrazide (3): 4-(4-Nitro)-benzylidene-2-phenyl oxazol-5-ones 2 (0.01 mmol) was stirred with a solution of hydrazine hydrate (0.02 mmol) in ethanol (25ml) for 30 minutes. The deep yellow colour of oxazolone immediately turns to light yellow color product, which was filtered, washed and purified by recrystallization from methanol 15. FT-IR (νmax, cm-1): 3288 (NH2), 3166 (N-H), 1642 (C=O amide), 1601 (C=N) 1513, 1336 (NO2). 1HNMR (400 MHz, DMSO-d6) δ(ppm): 4.43 (s, 2H, NH2), 7.1 (s, 1H, C= C-H), 7.49-8.20 (m, 9H, Ar C-H), 9.68 (s, 1H, CO-NH-C), 10.02 (s, 1H, CO-NH-N).
Synthesis of 2-Benzamido-3-(4-nitrophenyl)-N’-(substituted) benzylidene - acrylohydrazide (4a-l): Equimolar ratios of α-benzamido-(4-nitro)-cinnamahydrazide (3) and substituted aromatic aldehydes (0.01 mol) were transferred in 250 ml of conical flask containing 45 ml of absolute ethanol and catalytic amount of glacial acetic acid. The resulting mixture was subjected to microwave irradiation at 140 W with 10 sec interval for about 60 - 180 seconds. The reaction was monitored by TLC, allowed to cool at room temperature, filtered and purified by recrystallization from methanol.
SCHEME: (a): (CH3CO)2 O/ZINC OXIDE AND ETHANOL; (b): ABSOLUTE ETHANOL, STIRRING; (c): MICRO WAVE IRRADIATION AT 140 WATTS
|S. no||Com code||R|
|3||4c||4-Dimethyl amino phenyl|
|5||4e||4-Hydroxy, 3-methoxy phenyl|
|8||4h||2,4-Di chloro phenyl|
2-Benzamido-N’-benzylidene-3-(4-nitro) -phenyl acrylohydrazide (4a): Pale yellow crystals, m.p. 160-162ºC, yield 74%. FT-IR (νmax, cm-1): 3210 (N-H), 3000 (Ar C-H), 1637 (C=O amide), 1571 (C=N), 1476 (Ar C=C), 1513, 1336 (NO2). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 7.16 (s, 1H, HC=C), 7.5-8.26 (m, 14H, Ar C-H), 8.42 (s, 1H, HC=N), 10.30 (s, 1H, CO-NH), 11.87 (s, 1H, CO-NH-N). 13C NMR(100 MHz, DMSO-d6) δ(ppm): 166 (C-1), 127 (C-2), 123 (C-3), 163(-NH-CO-),145 (N=CH), 132 (C-1ʹ), 128 (C-2ʹ and C-6ʹ), 129 (C-3ʹ and C-5ʹ), 131(C-4ʹ), 140 (C-1ʺ), 127 (C-2ʺ and C-6ʺ),121 (C-3ʺ and C-5ʺ),147 (C-4ʺ), 133 (C-1 ʹʹʹ), 127(C-2 ʹʹʹ and C-6 ʹʹʹ), 128 (C-3 ʹʹʹ and C-5 ʹʹʹ), 131(C-4 ʹʹʹ). EI-MS m/z: 414 (M+).
2-Benzamido-3-(4-nitrophenyl) - N’- (4-methoxy benzylidene)-acrylohydrazide(4b):Yellow crystals, m.p. 180-182ºC, yield 63%. FT-IR (νmax, cm-1): 3316 (N-H), 3047 (Ar C-H), 2902 (C-H of OCH3), 1647 (C=O amide),1565 (C=N), 1509,1338 (NO2); 1HNMR (400 MHz, DMSO- d6) δ(ppm): 3.81 (s, 3H, OCH3), 7.0-8.2 (m, 13H, Ar C-H), 7.14 (s, 1H, HC=C), 8.63 (s, 1H, HC=N), 10.27 (s, 1H, CO-NH), 11.7 (s, 1H, CO-NH-N); Mass(m/z): 444 (M+).
2-Benzamido-3-(4-nitrophenyl) - N’- (4-dimethyl aminobenzylidene)-acrylohydrazide (4c): Dark yellow crystals, m.p. 220-223ºC, yield 65%. FT-IR (νmax, cm-1): 3302 (N-H), 3102 (Ar C-H), 2901 (C-H of CH3), 1645 (C=O amide), 1582 (N=C), 1514, 1335 (NO2). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 2.9 (s, 6H, N(CH3)2), 7.0-8.2 (m, 13H, Ar C-H), 7.16 (s, 1H, HC=C), 8.65 (s, 1H, HC=N), 10.11 (s, 1H, CO-NH), 11.2 (s, 1H, CO-NH-N).
2-Benzamido - 3 - (4-nitrophenyl) - N’ -(4-nitro benzylidene)-acrylohydrazide (4d): Pale yellow solid, m.p. 191-194ºC, yield 78%. FT-IR (νmax, cm-1): 3237 (N-H), 3043(Ar C-H), 1639 (C=O amide), 1478 (Ar C=C), 1592 (N=C), 1515, 1341 (NO2). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 7.17 (s, 1H, C=C-H), 7.5-8.3 (m, 13H, Ar C-H), 8.51 (s, 1H, HC=N), 10.34 (s, 1H, CO-NH-), 12.1 (s, 1H, CO-NH-N).
2-Benzamido-3-(4-nitrophenyl)-N’ - (4-hydroxy, 3 - methoxybenzylidene) – acrylohydrazide (4e): Half white solid, m.p. 210-212ºC, yield 67%. FT-IR (νmax, cm-1): 3363 (OH), 3233 (N-H), 3002 (Ar C-H), 1665 (C=O amide), 1600 (C=N). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 3.80 (s, 3H, OCH3), 5.3 (s, 1H, OH), 6.9-8.2 (m, 12H, Ar C-H), 7.17 (s, 1H, C=C-H), 8.62 (s, 1H, HC=N), 10.07 (s, 1H, CO-NH-), 11.9 (s, 1H, CO-NH-N). 13C NMR(100 MHz, DMSO-d6) δ(ppm): 167 (C-1), 127 (C-2), 122 (C-3), 163 (-NH-CO-), 144 (N=CH), 126 (C-1ʹ), 115 (C-2ʹ), 150 (C-3ʹ), 149 (C-4ʹ), 115 (C-5ʹ), 123 (C-6ʹ), 141 (C-1ʺ), 127 (C-2ʺ and C-6ʺ), 121 (C-3ʺ and C-5ʺ),147 (C-4ʺ), 133 (C-1 ʹʹʹ), 126 (C-2 ʹʹʹ and C-6 ʹʹʹ), 127 (C-3 ʹʹʹ and C-5 ʹʹʹ), 132(C-4 ʹʹʹ), 56 (-OCH3). EI-MS m/z: 460 (M+).
2-Benzamido-3-(4-nitrophenyl) - N’ - (4-chloro benzylidene)-acrylohydrazide (4f): Pale yellow solid, m.p. 159-161ºC, yield 75%. FT-IR (νmax, cm-1): 3288 (N-H), 3048 (Ar C-H), 1647 (C=O amide), 1481 (Ar C=C), 1591 (N=C), 1511, 1336 (NO2), 631 cm-1 (C-Cl). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 7.1 (s, 1H, C=C-H), 7.5-8.26 (m, 13H, Ar C-H), 8.4 (s, 1H, HC=N), 10.3 (s, 1H, CO-NH-), 11.93 (s, 1H, CO-NH-N).
2-Benzamido-3-(4-nitrophenyl) - N’ - (3, 4-di methoxy benzylidene)-acrylohydrazide (4g): Yellow solid, m.p.170-172 ºC, yield 73%. FT-IR (νmax, cm-1): 3228 (N-H), 3066 (Ar C-H), 2991 (C-H in CH3), 1636 (C=O amide), 1601 (C=N), 1505 (C=C). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 3.73 (s, 6H, (OCH3)2), 6.92-8.21 (m, 12H, Ar C-H), 7.13 (s, 1H, HC=C), 8.3 (s, 1H, HC=N), 10.05 (s, 1H, CO-NH), 11.20 (s, 1H, CO-NH-N). 13C NMR(100 MHz, DMSO-d6) δ(ppm): 165 (C-1), 126 (C-2), 123 (C-3), 162 (-NH-CO-),144 (N=CH), 126 (C-1ʹ), 114 (C-2ʹ), 148 (C-3ʹ ), 149 (C-4ʹ), 116 (C-5ʹ), 121(C-6ʹ), 141 (C-1ʺ), 127 (C-2ʺ and C-6ʺ),122 (C-3ʺ and C-5ʺ),146 (C-4ʺ), 134 (C-1 ʹʹʹ), 127 (C-2 ʹʹʹ and C-6 ʹʹʹ), 128 (C-3 ʹʹʹ and C-5 ʹʹʹ), 132 (C-4 ʹʹʹ), 55 (-OCH3). EI-MS m/z: 474 (M+).
2-Benzamido-3-(4-nitrophenyl) - N’ - (2, 4- di chloro benzylidene)-acrylohydrazide (4h): Off white crystals, m.p. 163-165ºC, yield 79%. FT-IR (νmax, cm-1): 3292 (N-H), 2989 (Ar C-H), 1643 (C=O amide), 1585 (N=C), 1469 (Ar C=C), 1514, 1340 (NO2), 642 (C-Cl). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 7.19 (s, 1H, C=C-H), 7.5-8.2 (m, 12H, Ar C-H), 8.7 (s,1H, HC=N), 10.3 (s, 1H, CO-NH-), 12.1 (s, 1H, CO-NH-N).
2-Benzamido-3-(4-nitrophenyl) - N’ - (3-Phenyl allylidene)-acrylohydrazide (4i): Dark yellow solid, m.p.181-183ºC, yield 77%. FT-IR (νmax, cm-1): 3231 (N-H), 3057 (Ar C-H), 1630 (C=O amide), 1609 (C=N), 1505 (Ar C=C). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 6.9-8.19 (m, 16H, Ar C-H, -CH=CH of cinnamoyl), 7.18 (s, 1H, C=C-H), 8.17-8.19 (d, 1H, HC=N), 10.14 (s,1H, CO-NH ), 11.79 (s, 1H, CO-NH-N).
N’-(Indol-3-yl-methylene) - 2-Benzamido – 3 -(4-nitrophenyl)-acrylohydrazide(4j): Brown crystals, m.p. 196-198 ºC, yield 66%. FT-IR (νmax, cm-1): 3176 (N-H of Indolyl), 3056 (Ar C-H), 1640 (C=O amide), 1579 (N=C), 1458 (Ar C=C), 1517, 1347 (NO2). 1HNMR (400 MHz, DMSO- d6) δ (ppm): 7.15 (s, 1H, C=C-H), 7.16-8.25 (m, 14H, Ar C-H), 8.36 (s, 1H, HC=N), 10.9 (s, 1H, CO-NH-), 12.15 (s, 2H, CO-NH-N, NH of Ind).
2-Benzamido-3-(4-nitrophenyl) - N’ - (4-hydroxy benzylidene)-acrylohydrazide (4k): Off white crystals, m.p. 174-177ºC, yield 67%. FT-IR (νmax, cm-1):3371 (OH), 3275 (N-H), 3078 (Ar C-H), 1644 (C=O amide), 1481 (Ar C=C), 1581 (N=C), 1520, 1331 (NO2). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 7.17 (s, 1H, C=C-H), 7.48-8.14 (m, 13H, Ar C-H), 8.53 (s, 1H, HC=N), 10.15 (s, 1H, CO-NH-), 11.98 (s, 1H, CO-NH-N). 13C NMR(100 MHz, DMSO-d6) δ(ppm): 165 (C-1), 127 (C-2), 123 (C-3), 163 (-NH-CO-), 145 (N=CH), 125 (C-1ʹ), 128 (C-2ʹ and C-6ʹ), 115 (C-3ʹ and C-5ʹ), 158 (C-4ʹ), 141 (C-1ʺ), 127 (C-2ʺ and C-6ʺ), 120 (C-3ʺ and C-5ʺ),146 (C-4ʺ), 134 (C-1 ʹʹʹ), 126 (C-2 ʹʹʹ and C-6 ʹʹʹ), 128 (C-3 ʹʹʹ and C-5 ʹʹʹ), 132 (C-4 ʹʹʹ); EI-MS m/z: 430 (M+).
2-Benzamido-3-(4-nitrophenyl) - N’ - (2-chloro benzylidene)-acrylohydrazide (4l): Light yellow crystals, m.p. 168-171ºC, yield 82%. FT-IR (νmax, cm-1): 3198 (N-H), 3051 (Ar C-H), 1640 (C=O amide), 1481 (Ar C=C), 1577 (N=C), 1518, 1329 (NO2), 643 cm-1 (C-Cl). 1HNMR (400 MHz, DMSO- d6) δ(ppm): 7.13 (s, 1H, C=C-H), 7.57-8.29 (m, 13H, Ar C-H), 8.3 (s, 1H, HC=N), 10.1 (s, 1H, CO-NH-), 11.72 (s, 1H, CO-NH-N). 13C NMR (100 MHz, DMSO-d6) δ(ppm): 166 (C-1), 127 (C-2), 123 (C-3), 164(-NH-CO-),145 (N=CH), 133 (C-1ʹ), 134 (C-2ʹ), 128 (C-3ʹ), 132(C-4ʹ), 126 ( C-5ʹ), 130 (C-6ʹ), 140 (C-1ʺ), 128 (C-2ʺ and C-6ʺ), 121 (C-3ʺ and C-5ʺ), 147 (C-4ʺ), 133 (C-1 ʹʹʹ), 127 (C-2 ʹʹʹ and C-6 ʹʹʹ), 128 (C-3 ʹʹʹ and C-5 ʹʹʹ), 131 (C-4 ʹʹʹ). EI-MS m/z: 448 (M+).
Antimicrobial Activity: All the title compounds were assayed in-vitro for antibacterial activity against two Gram positive (Bacillus subtilis, Staphylococcus aureus), two Gram negative bacterial strains (Escherichia coli, Pseudomonas aeruginosa) and one fungal strain (Candida albicans). The MIC (Minimum inhibitory concentration) was determined by using twofold serial dilution method 16. Ciproflaxin and miconazole were used as reference standards to compare the antibacterial and antifungal activities, respectively. All the title compounds and standard drugs were dissolved in dimethylsulfoxide (stock solution 5 mg/mL). Further dilutions were prepared to get 200, 100, 50, 25, 12.5, 6.25, and 3.125 µg/ml concentrations and control also maintained at the same dilution contains only solvent. The MIC values were obtained from the lowest concentration of the test compound where the tubes remain clear, indicating that the bacterial growth was completely inhibited at this concentration.
Molecular Docking: Molecular docking of compounds (4a-l) with the 3D X-ray crystal structure of E.coli FAB protein (β-ketoacyl-acyl carrier protein synthase III) retrieved from the PDB (Protein Data Bank) incorporated with inhibitor was accessed to predict active site residue. The 3D structure of target (PDB ID: 5BNM) was imported in to maestro v 9.0 and receptor grid of 20x20x20 A° was generated for the 5BNM around the centroid of respective active site using GLIDE (Schrodinger). All the ligands, standard drug were embedded in to the generated grid of FAB protein to access their binding affinities.
In-silico ADME: In the present study molecular properties of compounds (4a-l) were calculated by using Molinspiration online tool 17 and drug likeness score, toxicity profile calculated by OSIRIS program 18 in order to predict the compounds drug likeness score. The %ABS was calculated according to the formula 19.
%ABS = 109-(0.345 x TPSA)
RESULTS AND DISCUSSION:
Chemistry: The synthesis of 2-Benzamido-3-(4-nitrophenyl)-N’-(substituted benzylidene)-acrylo hydrazide (4a-l) were carried out in four steps under green protocols by the action of different aromatic aldehydes on α-Benzamido-(4-nitro)-cinnamahydrazide (3) in acidic conditions by microwave irradiation (Scheme) with high purity and less reaction time. Compounds (3) has been obtained from intermediate compound (2) by the action of hydrazine hydrate, act as strong nucleophile attacks the oxazole ring at highly susceptible carbonyl site and opens the ring.
The IR spectra of the compounds (4a-l) showed NH and C=O stretching bands between 3176 - 3391 cm-1 and 1630 - 1665 cm-1 respectively indicates the formation of title compounds. Appearance of two more bands between 1335 - 1517 cm-1 region indicates the presence of nitro substitution in title compounds.
In addition to the above 1H NMR spectra revealed the formation of title compound by the appearance of singlet between δ11.20-12.15 regions (due to the NH of CO-NH-N=) and absence of singlet at δ 4.43 (due to free NH2 of –CO-N-NH2) present in compound (3). This is supported by the presence singlet in the region of δ 8.17 - 8.70 due to the protons of CH=N groups and showed the multiplet between δ 6.9-8.3 regions indicates the deshielding of aromatic protons by nitro group. Additional support for the structures of title compounds was provided by 13C NMR spectra reveals two peaks around δ 163-166 and a peak between δ 55-56 assigned for carbonyl group of amide and methoxy group respectively. The peaks resonated at δ 114-158 is due to the presence of aromatic carbons and also appearance of signal around δ 145 indicates the presence of C=N linkage. All the title compounds conformed by the appearance of molecular ion peaks between m/z 414-483.
Antimicrobial Activity: The antimicrobial results reveals compound 4e (4-hydroxy, 3-methoxy-phenyl) showed pronounced antibacterial activity (MIC: 3.12 µg/ml) than standard ciprofloxacin (MIC: 6.25 µg/ml) against Gram negative strain (E.coli, P.aeruginosa) due to the presence of methoxy group ortho to the hydroxyl group 20. Table 1 reveals, none of the title compounds exhibits higher activities (MIC between 6.25-200 µg/ml) against two Gram positive strains compared with standard (3.12 µg/ml) and few compounds 4e (12.5 µg/ml), 4h (6.25 µg/ml) exhibited considerable activity against S. aureus and B. subtilis compared with standard drug. The SAR data indicates the antimicrobial activity profile of title compounds were altered by the nature of substitution on phenyl ring such as EDG enhances the activity than EWG substituted derivatives (4e>4d towards E.coli) and this finding was supported by the previous results 13, 20. It was anticipated that, the introduction of one more electron withdrawing group enhances the activity of title compounds but the results were in contrast to the expectations. From the antifungal data we identify compound 4h (12.5µg/ml) only displayed good activities comparable with standard (6.25 µg/ml) it might be due to the presence of second halogen elevates the log p values responsible for better activity 21 and remaining all showed lesser activity.
Molecular Docking: Further, experimental observations were followed up with molecular docking studies and the data highlights all the compounds showed potent E coli FabH inhibition than standard (-4.74) except few compounds (4c, 4d) (Table 1). Among all compound 4k (-8.78) which is the most potent FabH inhibitor forms four hydrogen bond (2.38, 1.74, 2.10, 1.83ºA) with target (Fig. 2), also have lowest binding energy -72.74 Kcal/mol. From the binding modes of title compounds with target protein, we understood Asn 247, His 244, Cys112, Phe 304, Asn 274, Arg 151, Gly 209 amino acid residues constitute the active site of enzyme, depicted in Fig. 2 and Fig. 3. The docking results strengthened that antibacterial activities of the synthetic compounds were probably correlated to their FabH inhibitory activities and compound 4k, 4e are the potent inhibitors of FabH.
TABLE 1: ANTIMICROBIAL ACTIVITY AND DOCKING SCORES OF COMPOUNDS (4a-l)
|MIC (µg/ml)||Docking scores with FAB protein|
|Sno||Code||EC||PA||SA||BS||CA||NHB||HB (ºA)||AA||DS||BE (kcal/mol)|
|2||4b||50||100||100||50||50||2||2.35 1.75||His 244 Asn 247||-6.35||-69.34|
|5||4e||3.12||3.12||12.5||12.5||50||3||2.26 1.86 2.38||Cys 112 Phe 304 Asn247||-7.47||-76.38|
|7||4g||100||50||200||100||50||3||2.49 2.10 2.59||Cys 112 Asn 247 Asn 274||-6.38||-71.97|
|10||4j||100||200||200||100||100||1||1.90 2.16||Asn 247||-6.36||-71.76|
|4k||3.12||6.25||25||50||100||4||2.38 1.74 2.10 1.83||Cys 112 Phe 304||-8.78||-72.74|
|12||4l||12.5||12.5||25||12.5||25||2||1.86 2.56||Gly 209||-7.36||-74.82|
EC: E.coli; PA: Pseudomonas aeruginosa; SA: Staphylococcus aureus; BS: Bacillus subtilis; CA: Candida albicans; NHB: No of hydrogen bonds; HD: Hydrogen bond distance; AA: Amino acid; DS: Docking score; BE: Binding free energy
FIG. 2: DOCKING INTERACTION OF 4K WITH 5BNM
FIG. 3: DOCKING INTERACTION OF 4E WITH 5BNM
FIG. 4: DOCKING INTERACTION OF STANDARD WITH 5BNM
In-silico ADME: All the compounds obeyed Lipinski rule of five is important for assessing of compounds oral bioavailability. It is clear from the Table 2 that log P values of all the compounds found to be in the acceptable criteria (3.96-5.90) and TPSA (Total polar surface area) is another key property that has been linked to bioavailability. It was found that all the compounds showed TPSA between 116 -136 predict good oral bioavailability except compound 4d, 4e and it is important to note all compounds have %absorption between 53-69. The results reveals all compounds have 1.95-1.28 as Druglikeness score and devoid from toxicity except compound 4c (Table 2).The results of in-silico data indicates that, these compounds may have the potential to become a lead compound.
TABLE 2: MOLECULAR DESCRIPTORS OF TITLE COMPOUNDS (4a-l)
|S. no.||C code||Log P||Log S||TPSA||% abs||n- Hba||n-hbd||n-ROTB||Mw||Mu||Tu||Ir||Re||Dl|
Log P: Lipophilicity; Log S: Solubility; TPSA: Total polar surface area; n-Hba: No of hydrogen bond acceptors; n-Hbd: No of hydrogen bond donars; n-ROTB: No of rotatable bonds; Mw: Molecular weight; Mu: Mutagenic; Tu: Tumerigenic; Ir: Irritant; Re: Reproductive effect; Dl: Druglikeness; G: No Risk; R: High Risk.
CONCLUSION: A new series of 4-nitro-cinnamamide analogues were synthesized with good yields, shorter reaction time by using microwave technique and screened for antimicrobial and docking studies. It could be seen clearly from our studies compound 4e, 4k exhibited good antimicrobial activity due to the presence of important pharmacophore features responsible for more affinity of ligand with the active site of target and also need further mechanistic studies for optimization of their properties.
ACKNOWLEDGEMENT: The authors are thankful Laila impex, Vijayawada for providing spectral data and also thanks to the management, principal of Gokula Krishna College of Pharmacy for providing necessary lab facilities.
CONFLICTS OF INTEREST: Authors declare no conflicts of interest.
- Eleni P, Dimitra HL, Konstantinos L and George G: Novel cinnamic acid derivatives as antioxidant and anticancer agents: Design, synthesis and modeling studies. Molecules 2014; 19: 9655-9674.
- Gangadhara S, Prasad CH and Venkateswarlu P: Synthesis, antimicrobial and antioxidant activities of novel series of cinnamamide derivatives having morpholine moiety. Med chem 2014; 4:778-783.
- Juan David G: Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity. Molecules 2014; 19: 19292-19349.
- Hadjipavlou-Litina D and Pontiki E: Aryl acetic and cinnamic acids as lipoxygenase inhibitors with antioxidant, anti-inflammatory and anticancer activity. Methods Mol Biol 2015; 1208: 361-377.
- Korosec B, Sova M, Turk S, Krasevec N, Novak M, Lah L, Stojan J, Podobnik B, Berne S, Zupanec N, Bunc M, Gobec S and Komel R: Antifungal activity of cinnamic acid derivatives involves inhibition of benzoate 4-hydroxylase (CYP53). J Appl Microbiol 2014: 116: 955-66.
- Prateek Sharma: Cinnamic acid derivatives: A new chapter of various pharmacological activities. Chem. Pharm. Res 2011; 3: 403-423.
- Bogdashev NN, Tukhovskaya NA and Pogrebnyak AV: Relationship between biological activity and thermodynamic properties of 5, 5-dimethyl-1,3-cyclohexanedione derivatives. Pharm Chem J 1998; 32: 31-33.
- Lilia M, Coralia B, Ion B, Carmen CD, Anamaria H, Otilia B, Petre I, Anca P, Arnaud T and Irina Z: Synthesis and biological activities of some new isonicotinic acid 2(2-hydroxy-8-substituted-tricyclo[7.3.1.07]tridec-13-ylidene)-hydrazides. Bioorg Med Chem 2015; 23: 401-410.
- Kamath PR, Sunil D, Ajees AA, Pai KS and Biswas S: N’-((2-(6-bromo-2oxo-2H-chromen-3yl) - 1H – indol - 3-yl) methylene) benzohydrazide as a probable Bcl-2/Bcl-Xl inhibitor with apoptotic and anti-metastatic potential. Eur J Med Chem 2016; 120: 134-137.
- Huda SK, Azhar A, Nurdiana N, Thorsten H, Azlina AA, Kin WK and Wageeh AY: Correlation of antioxidant activities with theoretical studies for new hydrazone compounds bearing a 3,4,5-trimethoxy benzyl moiety. Eur J Med Chem 2015; 103: 497-505.
- Soujanya M, Lakshmi Narayana M, Sarala Devi T, Anusha S and Rajitha G: Microwave assisted rapid, efficient synthesis and screening of acyl hydrazone derivatives for antibacterial activity. IJPT 2014; 6: 6193-6202.
- Adam MP, Aleksandra S, Beata S, Grzegorz M and Pawe S: Synthesis and evaluation of antimicrobial activity of hydrazones derived from 3-oxido-1H-imidazole-4-carbohydrazides. Eur J Med Chem 2013; 64: 389-395.
- Lukasz P and Anna B: Synthesis and investigation of antimicrobial activities of nitro furazone analogues containing hydrazide-hydrazone moiety. Saudi pharmaceutical journal 2017;http://dx.doi.org/10.1016/j.jsps.2017.05.006 (article in press).
- Ghulam F, Nighat A, Muhammad AV, Nazia F, Uzma RM, Mahboob AK, Lubna I and Mehreen L: Synthesis, spectroscopic characterization and pharmacological evaluation of oxazolones derivatives. J Serb. Chem. Soc 2013; 78: 1127-1134.
- Rajitha G, Prasad KV, A Umamaheswari, Prardhan D and Bharathi K. Synthesis, biological evaluation, and molecular docking studies of N-(α- acetamido cinnamoyl) aryl hydrazine derivatives as anti-inflammatory and analgesic agents. Med Chem Res 2014; 23: 5204–5214.
- Shadomy S and Espinel AA: Manual of Clinical Microbiology. Am Soc Microbial. Washington, DC, 1980; 647.
- Molinspiration cheminformatics [homepage on the internet], Available fromhttp://www.molinspiration.com/ cgi-bin/properties.
- Molecular property prediction-osiris property explorer [home page on the internet], Available from http://www.organic-chemistry.org/prog/peo/.
- Vishwanathan B, Gurupadayya BM and Sairam KV: In silico and antithrombotic studies of 1,3,4-oxadiazoles derived from benzimidazole. Bangladesh J Pharmacol 2016; 11: 67-74.
- Xiao LW, Yan BZ, Jian-FT, Yu SY, Ruo QC, Fei Z and Hai-Liang Z: Design, synthesis and antibacterial activities of vanillic acylhydrazone derivatives as potential β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors. Eur J Med Chem 2012; 57: 373-382.
- Daniela S, Bruna B, Adriana B, Simone C, Melissa DA, Daniela R, Emanuela Mari, Lucia P and Alessandra Z: Synthesis, anti-Candida activity and cytotoxicity of new (4-(4-iodophenyl)thiazol-2-yl)hydrazine derivatives. Eur J Med Chem 2012; 53: 246-253.
How to cite this article:
Soujanya M and Rajitha G: Microwave assisted synthesis, characterization, molecular docking and antimicrobial evaluation of 4-nitrocinnamide analogues. Int J Pharm Sci Res 2017; 8(9): 3786-94.doi: 10.13040/IJPSR.0975-8232.8(9).3786-94.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
M. Soujanya *and G. Rajitha
Department of Pharmaceutical Chemistry, Gokula Krishna College of Pharmacy, JNTU Anantapur, SPSR Nellore, Sullurpet, Andhra Pradesh, India.
15 February, 2017
12 May, 2017
27 May, 2017
01 September, 2017