Home About us Editorial board Current issue Ahead of print Archives Submit article Instructions Subscribe Login  Contact Search


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 6  |  Issue : 2  |  Page : 79-87

In-vitro antimicrobial screening and molecular docking studies of synthesized 2-chloro-N-(4-phenylthiazol-2-yl)acetamide derivatives


Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India

Date of Web Publication7-Aug-2015

Correspondence Address:
Sandhya Bawa
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi - 110 062
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-6555.162452

Rights and Permissions
  Abstract 

Introduction: Glucosamine-6-phosphate (GlcN6P) synthase biosynthetic pathway has been identified as potential targets for the development of new antimicrobial agents. Aim: A series of 2-chloro-N-(42-phenylthiazol-25-yl)acetamide derivatives (3a-r) was synthesized and evaluated their antimicrobial activity. Materials and Methods: The 2-chloro-N-(Para substituted phenylthiazol-25-yl) acetamide (2a-c) were synthesized by stirring intermediates (1a-c) with 2-chloroacetylchloride in dichloromethane in the presence of K2CO3. The intermediate (2a-c) were further reacted with different secondary amine such as pyrrolidine, N-methyl piperazine, N-ethyl piperazine, thiomorpholine, morpholine, piperidine etc in ethanol in presence of TEA Triethylamine (TEA) to get desired compounds (3a-r). Compounds were characterized by a spectroscopic technique such as Fourier transform infraredFTIR, 1 H-NMR, 13 C-NMR, and mass spectrometry. The synthesized thiazole derivatives (3a-r) were screened for anti-bacterial and anti-fungal activity against Escherichia coli, Staphylococcus aureus NCTC 6571, Pseudomonas aeruginosa NCTC 10662, CandidaC. albicans (MTCC-183), AspergillusA. niger (MTCC 281) NCTC 10418 and AspergillusA. flavus (MTCC 277). Result and Conclusion: The results of anti-bacterial screening revealed that among all the screened compounds, eight compounds viz. 3b, 3c, 3d, 3e, 3i, 3j, 3k, and 3p showed moderate to good anti-bacterial and antifungal activity having minimum inhibitory concentration (MIC) between 6.25- and 25 µg/ml. While compound 3d showed the most promising antibacterial activity against E. coli and S. aureus, while the compound 3j showed promising antifungal activity with MIC value 6.25 µg/ml against C. albicans, A. niger and A. flavus. In addition, all these eight potential molecules were also examined for possible binding on enzyme GlcN6Pglucosamine-6-phosphate synthase by molecular docking studies on (PDB ID 1JXA).

Keywords: Acetamide, antibacterial, antifungal, docking, thiazoles


How to cite this article:
Ali R, Kumar S, Afzal O, Bawa S. In-vitro antimicrobial screening and molecular docking studies of synthesized 2-chloro-N-(4-phenylthiazol-2-yl)acetamide derivatives. Drug Dev Ther 2015;6:79-87

How to cite this URL:
Ali R, Kumar S, Afzal O, Bawa S. In-vitro antimicrobial screening and molecular docking studies of synthesized 2-chloro-N-(4-phenylthiazol-2-yl)acetamide derivatives. Drug Dev Ther [serial online] 2015 [cited 2017 Jul 28];6:79-87. Available from: http://www.ddtjournal.org/text.asp?2015/6/2/79/162452


  Introduction Top


The advent of clinically significant species of multi-drug resistance strains of bacteria and fungi such as methicilin resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus and Candida species have made the treatment of infectious diseases a tenacious problem and turning into as an important global health delinquent. [1],[2],[3],[4] To mitigate the situation, there will continually be a vibrant need to discover new chemotherapeutic agents to prevent the development of resistance and that preferably shorten the duration of therapy.

Glutamine-dependent amidotransferases play a central role in cellular metabolism; it is responsible for utilization of the amide nitrogen of glutamine in a variety of biosynthetic reactions. There structural elucidation and mechanism of action deliver a significant insinuations for the discovery of new therapeutic agents. [5],[6] Trivial enzyme viz. glucosamine-6-phosphate (GlcN6P) synthase (GlmS, L-glutamine: D-fructose-6P amidotransferase, EC2.6.1.16) involve in hexosamine metabolism, which is isomerizes fructose 6-phosphate into GlcN6P in the presence of glutamine and finally form an N-acetylglucosamine, which is found in all class of organisms, but in bacteria and fungi it is necessary for cell wall formations such as peptidoglycan in bacteria and chitin, mannoproteins in fungi. In human beings, N-acetylglucosamine is used for biosynthesis of glycoproteins and mucopolysaccharides. Fact is that in all kind of cells the GlcN6P synthase is present. [7] In the prokaryotic cell, the inactivation of GlcN6P synthase even for a short time is lethal. But, due to the longer lifespan of mammalian cells, the depletion of amino sugar pool for a short time is not lethal. [8] This difference in the metabolism of the enzyme has enabled GlcN6P synthase an important target for drug discovery.

In the recent years, heterocyclic compounds containing thiazole ring system have fascinated medicinal chemists because of their diverse biological activities such as antibacterial, [9] anti-inflammatory, [10] antitumor, [11] schizophrenia, [12] antifungal, [13] anti-HIV, [14] antitubercular, [15] antiprotozoal, [16] antiallergic, [17] hypertension, [18] antimalarial, [19] etc. The thiazole derivatives [Figure 1]a-c having potent antimicrobial activity were reported by Sarojini et al. [20] with minimum inhibitory concentration (MIC) 6.25 μg/ml and their docking study on GlcN6P synthase (PDB Id: 1JXA) predicted that as a plausible inhibitor of the enzyme. Their study showed that compounds having a number of interactions with various active site residues of GlcN6P synthase. Similarly thiazole derivative [Figure 1]d was synthesized and evaluated by Gahtori et al. [21] and reported as a most potent antimicrobial agent, more potent than streptomycin having MIC 3.125 μg/ml. Another thiazole compound [Figure 1]e having MIC 1.56 μg/ml against Escherichia coli was synthesized and reported by Jing et al. [22] Likewise, Karegoudar et al. [23] reported the antimicrobial activity of thiazole derivative [Figure 1]f against various bacterial strain having MIC 6.25 μg/ml.

Keeping in view the assessment of this fertile nucleus, we hereby reported the synthesis of novel 2-chloro-N-(2-phenylthiazol-5-yl) acetamide derivatives and evaluated for their in-vitro antibacterial and antifungal activity coupled with molecular docking studies.
Figure 1: (a-f) Structures of various thiazole derivatives having potent antimicrobial activity

Click here to view



  Results and Discussion Top


Chemistry

The different para-substituted phenylthiazol-5-amines were synthesized as per the scheme outlined in [Figure 2]. Various acetophenone and thiourea were reacted in the presence of iodine to give 2-amino-4-phenylthiazole (1a-c). [24] For cyclization purpose, any of the halogens can be used but in this reaction we used iodine because it is easy to handle. [25] The 2-chloro-N-(Para substituted phenylthiazol-2-yl) acetamide (2a-c) were synthesized by stirring intermediates (1a-c) with 2-chloroacetylchloride in dichloromethane in the presence of K 2 CO 3 . [26],[27] The intermediate (2a-c) were further reacted with different secondary amine such as pyrrolidine, N-methyl piperazine, N-ethyl piperazine, thiomorpholine, morpholine, piperidine etc in ethanol in presence of Triethylamine (TEA) to get desired compounds (3a-r).
Figure 2: Route of synthesis of 2-substituted-N-(Para substituted phenylthiazol-2-yl)acetamide derivatives (3a-r). Reagent and conditions: (A) Iodine, abs. EtOH, refluxes (B) 2-chloroacetylchloride, pyridine, stirring then reflux. (C) TEA. Ethanol, reflux

Click here to view


The structures of varied 2-substituted-N-(P-substituted phenylthiazol-2-yl)acetamide derivatives were elucidated by combined use of infrared (IR), 1 H and 13 C-NMR and mass spectral (MS) data. The presence of the thiazole ring in compounds (1a-c) was supported by the appearance of two quaternary signals of (C-2, C-4) at d value 151.8 and 169.7 ppm in 13 C-NMR spectrum of compound 1a. This was further supported by a mass spectrum of compound 1a (m/z 177.19). The formation of acetamide derivatives for compound 2c were established by locating characteristics peak of COCH 2 Cl group, which was observed at d value 4.37 ppm integrating for two protons in 1 H-NMR. In 13 C-NMR this particular function was observed at d value 43.1 and 165.4 ppm for CH 2 and CO group respectively for compound 2c. In IR spectra the characteristics absorption band of the compound appeared in the region 3167 for -NH- stretching, 1666 and 1632 for C=O and C=N stretching band for compound (2c). The characteristic IR band of representative compound (3a-c) were observed in the region 3160-3190/cm for -NH- stretching, 1650-1680/cm for the C=O and 1630-1650 for C=N cm−1 stretching. Synthesis of compound (3a-r) was identify -NHCO- group by 1 H-NMR observed at d value 9-11 ppm (D 2 O exchangeable), while the H-3 proton in thiazole ring was observed at d 6.8-7.0 ppm as singlet. The synthesis was further confirmed by mass spectrometry in which molecular ion peak was registered at m/z 288.19 (M+) and M + 2 peaks at 290.19 for compound 3a. The synthesis of compounds was established by identifying the characteristics -CH 2 CO- peak in NMR. In 1 H-NMR spectra of compounds (3a-r) the signal due methylene proton of -CH 2 CO- group was resonated at d value 3.30-3.42 ppm integrating for two protons. While in 13 C-NMR, the methylene carbon was located at d value 63.8 for compound 3a. All these observations confirm successful synthesis of compounds.

Antibacterial activity

The varied 2-Substituted-N-(Para substituted phenylthiazol-2-yl)acetamide derivatives were tested for their antibacterial activity against Gram-positive and Gram-negative bacterial strains viz. E. coli NCTC 10418, S. aureus NCTC 65710, Pseudomonas aeruginosa NCTC 10662 by disc diffusion method at a concentration range of 6.25, 12.5, 25, 50, 100 and 200 μg/ml. [28] The results of the antibacterial activity are represented as MIC the concentration at which no visible growth was observed (zone of inhibition in mm) shown in [Table 1]. The compound N-(2-phenylthiazol-5-yl)-2-thiomorpholino acetamide 3d showed the most promising antibacterial activity among all the screened compounds having MIC of 6.25 μg/ml against the E. coli and S. aureus, bacterial strains respectively. The compounds 3b, 3c, 3e, 3i, 3j, 3k, and 3p showed moderate activity having MIC in between 12.5 and 25 μg/ml. The least potent compound were 3a, 3f, 3g, 3h, 3m, 3n, 3o, 3q and 3r. The overall result indicated that un-substituted phenyl ring containing thiazole derivative were the most potent followed by the chloro substituted phenyl derivatives. The antibacterial results of unsubstituted phenyl ring containing thiazole derivative indicate that thiomorpholine and morpholine rings possess best antibacterial activity, followed by the 4-methyl and 4-ethylpiperazine derivatives. The pyrrolidine and piperidine derivative 3a and 3f gives least antibacterial activity among them.
Table 1: Antimicrobial activity data of synthesized compounds (3a-r)


Click here to view


Antifungal activity

The varied 2-substituted-N-(P-substituted phenylthiazol-2-yl)acetamide derivatives were also screened for antifungal activity [29],[30] against three fungal strains viz. C. albican, Aspergillus flavus, Aspergillus niger serial plate dilution method at a concentration range of 6.25, 12.5, 25, 50, and 100 μg/ml. The results of the antifungal activity are represented as MIC the concentration at which no visible growth was observed (zone of inhibition in mm) shown in [Table 1]. The compound N-(2-(4-chlorophenyl)thiazol-5-yl)-2-thiomorpholinoacetamide 3j showed the most promising antifungal activity among all the screened compounds at MIC 6.25 μg/ml having zone of the inhibition of 9.0, 9.5, and 8.5 mm against the Candida albicans, A. niger and A. flavus fungal strains, respectively. The compound 3d, 3e, 3i, and 3k showed moderate activity between 12.5 and 25 μg/ml concentration and the remaining test compound showed least potent against the C. albicans, A. niger and A. flavus fungal strains. The antifungal results of chloro-substituted phenyl ring containing thiazole derivative indicate that thiomorpholine possesses best antifungal activity, followed by the morpholine, 4-ethylpiperazine and unsubstituted phenyl ring containing thiomorpholine and morpholine derivatives. Overall chloro-substituted phenyl ring containing thiazole derivative indicates that thiomorpholine possesses best antifungal activity due to the chloro-substitution, which may increases the lipophilicity in a fungal cell wall.

Computational studies

To understand the mechanism of action underlying activity of most active compound 3d and 3j, we proceeded to examine the interaction of compound 3d and 3j with microbial glucosamine-6-phosphate synthase (PDB code: 1JXA). [31] All docking runs were carried out as per Glide XP Docking protocol in Schrodinger 9.4. [32],[33] The XP Glide score obtained for compound 3d and 3j was found to be −7.56 and −7.82 respectively. The three-dimensional and two-dimensional interaction diagram of most potent compounds are shown in [Figure 3], [Figure 4], [Figure 5] and [Figure 6] . The compound 3d having the most potent antibacterial activity among all the synthesized compounds showed interaction with the key amino acid residues GLH488, LEU601, GLU58, ALA602, VAL399, SER401, GLY350, GLU351, SER347, CYS-300, THR352, SER303, THR352, VAL605 and LEU484. The C=O group and NH group of acetamide of compound 3d formed H-bond network with the amino acid residue VAL605 and Val399 at 1.65 and 1.90 Ε respectively. Similarly compound 3j having potent antifungal activity showed hydrophobic interactions with amino acid GLH488, LEU484, TRP74, SER604, VAL399, GLY350, VAL605, GLN348, SER349, SER303, THR302, CYS300 and LYS487 located in the binding pocket and played vital roles in the interaction of compound 3j with the enzyme. The C=O and N from thiomorpholine of compound 3j formed H-bond network with the amino acid SER604 and VAL605 at 1.77 and 2.01 Ε respectively.
Figure 3: Two-dimensional diagram showing hydrogen bonding interaction of compound 3d for antibacterial with active sites of enzyme glucosamine-6-phosphate synthase (PDB ID:1JXA)

Click here to view
Figure 4: Three-dimensional diagram showing hydrogen bonding interaction of compound 3d for antibacterial with active sites of enzyme glucosamine-6-phosphate synthase (PDB ID:1JXA)

Click here to view
Figure 5: Two-dimensional diagram showing hydrogen bonding interaction of compound 3j for antifungal with active sites of enzyme glucosamine-6-phosphate synthase (PDB ID:1JXA)

Click here to view
Figure 6: Three-dimensional diagram showing hydrogen bonding interaction of compound 3j for antifungal with active sites of enzyme glucosamine-6-phosphate synthase (PDB ID:1JXA)

Click here to view


The absorption, distribution, metabolism and excretion (ADME) properties are crucial determinants for the successful development of new drugs. Unfavorable ADME properties can lead to rejection of a drug in the later stages of drug process. [34] The most promising compounds were further analyzed for ADME, Lipinski's "rule of 5" and Jorgensen's "rule of 3" using QikProp tool of Schrodinger which is built using experimental details of 710 compounds including 500 drugs and heterocyclic compounds. The QikProp properties [35] of these compounds are listed in [Table 2]. QikProp calculates properties like molecular weight, molecular volume, number of H-bond donors, number of H-bond acceptors, polar surface area, QPlogPo/w (Predicted octanol/water partition coefficient), percentage of human oral absorption and violations related to Lipinski's "rule of 5" [36] and Jorgensen's "rule of 3" [37] to filter out compounds with clear-cut undesirable properties. Compounds that satisfy Lipinski's "rule of 5" and Jorgensen's "rule of 3," are considered drug-like and these compounds are more likely to be orally available. All these promising compounds showed excellent ADME properties and passed Lipinski's "rule of 5" and Jorgensen's "rule of 3," having no violations and also showed that they have potential of >75% orally bioavailable. The excellent ADME property of these hits makes them promising candidates for future development as antimicrobial and antifungal agents.
Table 2: QikProp properties of all the compounds (3b, 3c, 3d, 3e, 3i, 3j, 3k, and 3p) calculated from QikProp tool of Schrodinger


Click here to view



  Materials and Methods Top


Chemistry

All chemicals and reagents were obtained from various manufacturers and used without of further purification. The reactions were monitored and the purity of the compounds was checked by thin layer chromatography (TLC) and spot being located under iodine vapors or UV-light. Melting points were determined by the open capillary method with electrical melting point apparatus and are uncorrected. IR spectra were recorded as KBr (pellet) on bio rad Fourier transform-IR spectrophotometer and 1 H and 13 C-NMR spectra were recorded on Bruker DP×300 MHz spectrophotometer using dimethyl sulfoxide (DMSO)-d6 or CDCl 3 as a NMR solvent. Mass spectra (MS-ESI) were recorded on a JEOL-AccuTOF JMS-T100 LS mass spectrometer and elemental analysis were performed on a Vario-EL III CHNOS- Elemental analyzer and were within ±0.4% of the theoretical values.

Synthesis of 2-amino-4-substituetedphenylthiazole (1a-c)

2-Amino-4-phenylthiazole derivatives (1a-c) were synthesized by reported method [24],[25] mixture containing of (10 mmol) of substituted acetophenone and (20 mmol) of thiourea in previously dissolved iodine in anhydrous ethanol taken in a round bottom flask and refluxed overnight. This crude reaction mixture was cooled and extracted with ether to remove unreacted substituted acetophenone and iodine. This residue was then dissolved in boiling water and filtered to remove sulfur. Then the solution was cooled somewhat and made basic with ammonium hydroxide. The aminothiazole was separated and recrystallized with alcohol, Yield: 78-85%.

Synthesis of 2-chloro-N-(P-substituted phenylthiazol-5-yl)acetamide (2a-c)

2-chloro-N-(para substituted phenylthiazol-5-yl)acetamide (2a-c) was synthesized by reported method. [26],[27] A mixture of 1a-c (10.0 mmol) in pyridine (10.0 ml), and dropwise chloroacetyl chloride (12.0 mmol) was added with continuous stirring slowly. The course of addition was 20 min. The solution mixture was heated on a boiling water bath up to reaction is completed. The mixture was kept to attain room temperature and then poured onto crushed ice. The separated solid was filtered off, washed repeatedly with water, dried and recrystallized from ethanol to give 2a-c, Yield: 80-84%.

Synthesis of 2-Substituted-N-(P-substituted phenylthiazol-2-yl)acetamide derivatives (3a-r)

A mixture of 2-chloro-N-(P-substituted phenylthiazol-5-yl)acetamide (2a-c) (5.0 mmol) with different heterocyclic amines and K 2 CO 3 ( 10.0 mmol) in acetone taken in a round bottom flask and refluxed for 6-8 h. The reaction was monitored on TLC. After the reaction completion, the solvent was removed by vacuum distillation and the residue was treated with sodium bicarbonate (5% w/v) to remove acid impurities. The residue was washed with water, dry and recrystallize with ethanol to give 2-substituted-N-(para substituted phenylthiazol-2-yl)acetamide derivatives (3a-r).

N-(4-Phenylthiazol-2-yl)-2-(pyrrolidin-1-yl)acetamide 3a

Yield: 67%; m.p.: 142-144°C; IR (KBr) cm−1 : 3160 (N-H), 1668 (C=O), 1638 (C=N), 1556 (C=C), 1024 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 1.74-1.79 (m, 4H, 2×CH 2 ), 2.61-2.68 (m, 4H, 2×CH 2 ), 3.40 (s, 2H, CH 2 ), 6.90 (s, 1H, thiazole), 7.49 (s, 1H, Ar-H), 7.98 (d, 2H, Ar-H J = 7.5 Hz), 8.21 (d, 2H, Ar-H J = 7.1 Hz), 10.32 (bs, 1H, CONH , D 2 O exchangeable). 13 C-NMR (75 MHz, DMSO-d 6); d 23.14, 59.92, 63.85, 129.22, 129.65, 143.38, 143.82, 151.61, 169.24 (C=O). ESI-MS: m/z 288.19, (M+). Anal. calcd for C 15 H 17 N 3 OS: C 62.69, H, 5.96, N 14.62. Found: C 62.76, H 5.98, N 14.66%.

2-(4-Methylpiperazin-1-yl)-N-(4-phenylthiazol-2-yl)acetamide 3b

Yield: 67%; m.p.: 168-170°C; IR (KBr) cm−1 : 3168 (N-H), 1669 (C=O), 1632 (C=N), 1540 (C=C), 1028 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 2.26 (s, 3H, CH 3 piperizine), 2.39-2.44 (m, 4H, 2×CH 2 ), 2.43-2.47 (m, 4H, 2×CH 2 ), 3.36 (s, 2H, CH 2 ), 6.92 (s, 1H, thiazole), 7.47 (s, 1H, Ar-H), 7.59 (d, 2H, Ar-H J = 7.5 Hz), 8.46 (d, 2H, Ar-H J = 7.1 Hz), 10.39 (bs, 1H, CONH , D 2 O exchangeable). ESI-MS: m/z 317.18 (M+), anal. calcd for C 16 H 20 N 4 OS: C 60.73, H 6.37, N 17.71. Found: C 60.81, H 6.39, N 17.74%.

2-(4-Ethylpiperazin-1-yl)-N-(4-phenylthiazol-2-yl)acetamide 3c

Yield: 72%; m.p.: 208-210°C; IR (KBr) cm−1 : 3210 (N-H), 1671 (C=O), 1642 (C=N), 1562 (C=C), 1032 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d1.32 (t, 3H, CH 2 CH 3 piperazin), 2.44 (q, 2H, CH 2 CH 3 piperazin), 2.43-2.47 (m, 8H, 4×CH 2 ), 3.39 (s, 2H, CH 2 ), 7.12 (s, 1H, thiazole), 7.51 (s, 1H, Ar-H), 7.66 (d, 2H, Ar-H J = 7.6 Hz), 8.23 (d, 2H, Ar-H J = 7.1 Hz), 10.92 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 17 H 22 N 4 OS: C 61.79, H 6.71, N 16.95. Found: C 61.84, H 6.73, N 16.98%.

N-(4-Phenylthiazol-2-yl)-2-thiomorpholino acetamide 3d

Yield: 69%; m.p.: 130-132°C; IR (KBr) cm−1 : 3189 (N-H), 1659 (C=O), 1622 (C=N), 1552 (C=C), 1028 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 2.59-2.63 (m, 4H, 2×CH 2 ), 2.82-2.87 (m, 4H, 2×CH 2 ), 3.37 (s, 2H, CH 2 ), 6.99 (s, 1H, thiazole), 7.54 (s, 1H, Ar-H), 7.77 (d, 2H, Ar-H J = 7.5 Hz), 8.24 (d, 2H, Ar-H J = 7.1 Hz), 11.00 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 15 H 17 N 3 OS 2 : C 56.40, H 5.36, N 13.15. Found: C 56.48, H 5.39, N 13.18%.

2-Morpholino-N-(4-phenylthiazol-2-yl)acetamide 3e

Yield: 58%; m.p.: 118-120°C; IR (KBr) cm−1 : 3178 (N-H), 1668 (C=O), 1633 (C=N), 1542 (C=C), 1024 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 2.71-2.78 (m, 4H, 2×CH 2 ), 3.82-3.89 (m, 4H, 2×CH 2 ), 3.41 (s, 2H, CH 2 ), 6.92 (s, 1H, thiazole), 7.49 (s, 1H, Ar-H), 7.68 (d, 2H, Ar-H J = 7.52 Hz), 8.11 (d, 2H, Ar-H J = 7.1 Hz), 11.12 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 15 H 17 N 3 O 2 S: C 59.38, H 5.65, N 13.85. Found: C 59.46, H 5.67, N 13.88%.

N-(4-Phenylthiazol-2-yl)-2-(piperidin-1-yl)acetamide 3f

Yield: 67%; m.p.: 152-154°C; IR (KBr) cm−1 : 3166 (N-H), 1668 (C=O), 1645 (C=N), 1550 (C=C), 1036 (C-N). 1 H-NMR (300 MHz, DMSO-d6 ); d 1.63-1.76 (m, 6H, 3×CH 2 ), 2.49-2.53 (m, 4H, 2×CH 2 ), 3.38 (s, 2H, CH 2 ), 6.88 (s, 1H, thiazole), 7.51 (s, 1H, Ar-H), 7.69 (d, 2H, Ar-H J = 7.5 Hz), 8.22 (d, 2H, Ar-H J = 7.1 Hz), 10.89 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 16 H 19 N 3 OS: C 63.76, H 6.35, N 13.94. Found: C 63.81, H 6.36, N 13.99%.

N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(pyrrolidin-1-yl)acetamide 3 g

Yield: 74%; m.p.: 166-168°C; IR (KBr) cm−1 : 3172 (N-H), 1656 (C=O), 1642 (C=N), 1539 (C=C), 1024 (C-N). 752 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); d 1.65-1.74 (m, 4H, 2×CH 2 ), 2.56-2.61 (m, 4H, 2×CH 2 ), 3.41 (s, 2H, CH 2 ), 6.91 (s, 1H, thiazole), 7.61 (d, 2H, Ar-H J = 7.5 Hz), 8.06 (d, 2H, Ar-H J = 7.1 Hz), 9.89 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 15 H 16 ClN 3 OS: C 55.98, H 5.01, N 13.06. Found: C 56.10, H 5.04, N 13.10%.

N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 3 h

Yield: 79%; m.p.: 186-188°C; IR (KBr) cm−1 : 3169 (N-H), 1656 (C=O), 1638 (C=N), 1555 (C=C), 1030(C-N). 760 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); d 2.31 (s, 3H, CH 3 piperazine), 2.41-2.49 (m, 8H, 2×CH 2 ), 3.31 (s, 2H, CH 2 ), 6.90 (s, 1H, thiazole), 7.61 (d, 2H, Ar-H J = 7.6 Hz), 8.12 (d, 2H, Ar-H J = 7.1 Hz), 10.44 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 16 H 19 ClN 4 OS: C 54.77, H 5.46, N 15.97. Found: C 54.81, H 5.48, N 15.99%.

N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide 3i

Yield: 80%; m.p.: 228-230°C; IR (KBr) cm−1 : 3172 (N-H), 1677 (C=O), 1632 (C=N), 1542 (C=C), 1028 (C-N). 754 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); d1.26(t, 3H,CH 2 CH 3 piperazin), 2.46 (q, 2H, CH 2 CH 3 piperazin), 2.42-2.49 (m, 8H, 4×CH 2 ), 3.43 (s, 2H, CH 2 ), 6.89 (s, 1H, thiazole), 7.69 (d, 2H, Ar-H J = 7.5 Hz), 8.22 (d, 2H, Ar-H J = 7.1 Hz), 10.89 (bs, 1H, CONH , D 2 O exchangeable). ESI-MS: m/z 365.11(M+), 367.11(M + 2). Anal. calcd for C 17 H 21 ClN 4 OS: C 55.96, H 5.80, N 15.35. Found: C 55.99, H 5.83, N 15.38%.

N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-thiomorpholinoacetamide 3j.

Yield: 78%; m.p.: 148-150°C; IR (KBr) cm−1 : 3188 (N-H), 1678 (C=O), 1628 (C=N), 1556 (C=C), 1024 (C-N). 750 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); d 2.51-2.59 (m, 4H, 2×CH 2 ), 2.82-2.89 (m, 4H, 2×CH 2 ), 3.43 (s, 2H, CH 2 ), 6.78 (s, 1H, thiazole), 7.61 (d, 2H, Ar-H J = 7.5 Hz), 8.10 (d, 2H, Ar-H J = 7.1 Hz), 10.58 (bs, 1H, CONH , D 2 O exchangeable). ESI-MS: m/z 354.10 (M+), 356.10 (M + 2). Anal. calcd for C 15 H 16 ClN 3 OS 2 : C 50.91, H 4.56, N 11.87. Found: C 50.99, H 4.58, N 11.90%.

N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-morpholinoacetamide 3k

Yield: 76%; m.p.: 136-138°C; IR (KBr) cm−1 : 3211 (N-H), 1660 (C=O), 1645 (C=N), 1560 (C=C), 1030 (C-N). 762 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); d 2.47-2.53 (m, 4H, 2×CH 2 ), 3.43 (s, 2H, CH 2 ), 3.71-3.79 (m, 4H, 2×CH 2 ), 6.89 (s, 1H, thiazole), 7.61 (d, 2H, Ar-H J = 7.5 Hz), 8.06 (d, 2H, Ar-H J = 7.0 Hz), 9.98 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 15 H 16 ClN 3 O 2 S: C 53.33, H 4.77, N 12.44. Found: C 53.38, H 4.79, N 12.47%.

N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(piperidin-1-yl)acetamide 3l

Yield: 69%; m.p.: 178-180°C; IR (KBr) cm−1 : 3212 (N-H), 1662 (C=O), 1638 (C=N), 1560 (C=C), 1034 (C-N). 755 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); d 1.63-1.74 (m, 6H, 3×CH 2 ), 2.47-2.51 (m, 4H, 2×CH 2 ), 3.34 (s, 2H, CH 2 ), 6.93 (s, 1H, thiazole), 7.63 (d, 2H, Ar-H J = 7.4 Hz), 8.08 (d, 2H, Ar-H J = 7.0 Hz), 9.82 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 16 H 18 ClN 3 OS: C 57.22, H 5.40, N 12.51. Found: C 57.29, H 5.43, N 12.54%.

2-(Pyrrolidin-1-yl)-N-(4-p-tolylthiazol-2-yl)acetamide 3 m

Yield: 66%; m.p.: 148-150°C; IR (KBr) cm−1 : 3176 (N-H), 1663 (C=O), 1638 (C=N), 1560 (C=C), 1030 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 1.74-1.81 (m, 4H, 2×CH 2 ), 2.41(s, 3H, Ar-CH 3 ) 2.59-2.61 (m, 4H, 2×CH 2 ), 3.38 (s, 2H, CH 2 ), 6.89 (s, 1H, thiazole), 7.35 (d, 2H, Ar-H J = 7.5 Hz), 7.73 (d, 2H, Ar-H J = 7.0 Hz), 9.97 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 16 H 19 N 3 OS: C 63.76, H 6.35, N 13.94. Found C 63.82, H 6.37, N 13.95%.

2-(4-Methylpiperazin-1-yl)-N-(4-p-tolylthiazol-2-yl)acetamide 3n

Yield: 64%; m.p.: 172-174°C; IR (KBr) cm−1 : 3168 (N-H), 1664 (C=O), 1637 (C=N), 1562 (C=C), 1024 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 2.31 (s, 3H, CH 3 piperazin), 2.39 (s, 3H, Ar-CH 3 ) 2.41-2.46 (m, 4H, 2×CH 2 ), 2.47-2.51 (m, 4H, 2×CH 2 ), 3.38 (s, 2H, CH 2 ), 6.89 (s, 1H, thiazole), 7.41 (d, 2H, Ar-H J = 7.4 Hz), 7.76 (d, 2H, Ar-H J = 7.0 Hz), 9.82 (bs, 1H, CONH , D 2 O exchangeable). ESI-MS: m/z331.14 (M+). Anal. calcd for C 17 H 22 N 4 OS: C 61.79, H 6.71, N 16.95. Found: C 61.83, H 6.73, N 16.98%.

2-(4-Ethylpiperazin-1-yl)-N-(4-p-tolylthiazol-2-yl)acetamide 3o

Yield: 60%; m.p.: 214-216°C; IR (KBr) cm−1 : 3178 (N-H), 1656 (C=O), 1640 (C=N), 1538 (C=C), 1024(C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 1.22 (t, 3H, CH 2 CH 3 piperazin), 2.38 (s, 3H Ar-CH 3 ) 2.41 (q, 2H,CH 2 CH 3 piperazin), 2.43-2.48 (m, 8H, 4×CH 2 ), 3.32 (s, 2H, CH 2 ), 6.91 (s, 1H, thiazole), 7.33 (d, 2H, Ar-H J = 7.5 Hz), 7.72 (d, 2H, Ar-H J = 7.0 Hz), 10.28 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 18 H 24 N 4 OS: C 62.76, H 7.02, N 16.26. Found: C, 62.77, H 7.04, N 16.25%.

2-Thiomorpholino-N-(4-p-tolylthiazol-2-yl)acetamide 3p

Yield: 64%; m.p.: 142-144°C; IR (KBr) cm−1 : 3178 (N-H), 1658 (C=O), 1634 (C=N), 1553 (C=C), 1022 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 2.41 (s, 3H, Ar-CH 3 ), 2.59-2.63 (m, 4H, 2×CH 2 ), 2.78-2.86 (m, 4H, 2×CH 2 ), 3.39 (s, 2H, CH 2 ), 6.89 (s, 1H, thiazole), 7.41 (d, 2H, Ar-H J = 7.4 Hz), 7.82 (d, 2H, Ar-H J = 7.1 Hz), 9.88 (bs, 1H, CONH , D 2 O exchangeable). Anal. calcd for C 16 H 19 N 3 OS 2 :C 57.63, H 5.74 N, 12.60. Found: C 57.67, H 5.76, N,12.63%.

2-Morpholino-N-(4-p-tolylthiazol-2-yl)acetamide 3q

Yield: 64%; m.p.: 124-126°C; IR (KBr) cm−1 : 3176 (N-H), 1662 (C=O), 1632 (C=N), 1546 (C=C), 1026 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 2.40 (s, 3H, Ar-CH 3 ), 2.59-2.64 (m, 4H, 2×CH 2 ), 3.39 (s, 2H, CH 2 ), 3.69-3.74 (m, 4H, 2×CH 2 ), 6.91 (s, 1H, thiazole), 7.39 (d, 2H, Ar-H J = 7.4 Hz), 7.82 (d, 2H, Ar-H J = 7.1 Hz), 10.18 (bs, 1H, CONH , D 2 O exchangeable). ESI-MS: m/z 318.18(M+). Anal. calcd for C 16 H 19 N 3 O 2 S: C 60.54, H 6.03, N 13.24. Found: C 60.59, H 6.05, N 13.27%.

2-(Piperidin-1-yl)-N-(4-p-tolylthiazol-2-yl)acetamide 3r

Yield: 67%; m.p.: 154-156°C; IR (KBr) cm−1 : 3208 (N-H), 1668 (C= O), 1640 (C=N), 1563 (C=C), 1030 (C-N). 1 H-NMR (300 MHz, DMSO-d 6); d 1.69-1.77 (m, 6H, 3×CH 2 ), 2.41 (s, 3H, Ar-CH 3 ), 2.49-2.54 (m, 4H, 2×CH 2 ), 3.34 (s, 2H, CH 2 ), 6.91 (s, 1H, thiazole), 7.39 (d, 2H, Ar-H J = 7.4 Hz), 7.82 (d, 2H, Ar-H J = 6.9 Hz), 10.10 (bs, 1H, CONH , D 2 O exchangeable).) 13 C-NMR (75 MHz, DMSO-d 6); d 22.32, 25.18, 56.82, 64.17, 128.27, 142.33, 144.17, 152.13, 169.20 (C=O) ESI-MS: m/z316.10(M+). Anal. calcd for C 16 H 21 N 3 OS: C 64.73, H 6.71, N 13.32. Found: C 64.76, H 6.73, N 13.36%.

Antibacterial activity

Antibacterial activity of newly synthesized compounds was evaluated by cup plate method against E. coli (NCTC, 10418), S. aureus (NCTC, 65710), P. aeruginosa (NCTC, 10662) strains. Nutrient agar was used as the culture medium. Tween 80 (0.01%) in normal saline was used for suspension of the bacterial spore for lawning purpose. 50 ml of liquid agar medium was poured into each Petri dish (15 cm diameter). Bacterial suspension was spread over the solid agar medium and plates were kept in anincubator at 37°C for 1 h for drying. Wells were completed on these seeded agar plates using an agar punch and DMSO was used as solvent for the preparation of test samples at conc. Range of 6.25, 12.5, 25.0, 50, 100 and 200 μg/ml were added into each well, labeled previously. DMSO was used as a control. This procedure was repetitive for each bacterial strain and the plates were incubated at 37°C for 24 h. The MIC was noted by seeing the lowest concentration of the test drug at which there was no visible growth. Antimicrobial activity of each compound (3a-r) was compared with standard cefixime and results have been summarized as MIC (average zone of inhibition of two reading in millimeter) in [Table 1].

Antifungal activity

The synthesized compounds were evaluated for their in-vitro antifungal activity by serial plate dilution method. Suspension of corresponding species of fungal strain (3.0 ml) was transferred in normal saline water, for lawning. 20 ml of agar media was poured into each of the petri dish, excess of the suspension was decanted, and the plates were kept in an incubator at 37°C for 1 h for drying. Wells were completed on these seeded agar plates using an agar punch and DMSO was used as solvent for the preparation of test samples at concentration range of 6.25, 12.5, 25.0, 50, 100, and 200 μg/ml were added into each well labeled. DMSO was used as control. This procedure was repetitive for each bacterial strain and the plates were incubated at 37°C for 72-84 h. Antifungal activity was determined by measuring the diameter of the inhibition zone. The MIC was noted by seeing the lowest concentration of the test drug at which there was no visible growth. The activity of each compound (3a-r) was compared with standard fluconazole in DMSO and results have been summarized as MIC (average zone of inhibition of two reading in millimeter) in [Table 1].

Computational studies

Docking studies were performed for synthesized molecule 3d and 3j using the Glide module in the Schrodinger 9.4 program. The crystal structures of the proteins complex (PDBId: 1JXA) were downloaded from the RCSB protein data bank (http://www.rcsb.org/pdb/home/home.do) and prepared with the protein preparation wizard module in Schrodinger 9.4. Binding site of the ligand was created by keeping the co-crystallized ligand at the center of a rectangular box drawn in the receptor. Binding site is also known as receptor grid generation. A 20 Å grid space was defined for the co-crystallized ligand using the Glide grid module of the software. For low-energy conformers and to correct the chirality of all the ligands the LigPrep module was used. Where by producing the ring conformations and penalizing the nonpolar amide bond conformations ligands were kept flexible, whereas the receptor was kept rigid during the course of the docking studies. All other parameters of the Glide module were set as default values.

Absorption, distribution, metabolism and excretion important parameter of physicochemical properties were predicted using QikProp3.6 (Schrodinger) which calculates the numerous parameter such as molecular weight, molecular volume, number of H-bond donors, number of H-bond acceptors, polar surface area, QPlogPo/w (Predicted octanol/water partition coefficient) percentage of human oral absorption and violations related to Lipinski's "rule of 5" and Jorgensen's "rule of 3" to screen the compound to know the disagreeable properties. Before using the QikProp the compound was neutralized by using of LigPrep which were treated for calculation of ADME properties.


  Acknowledgment Top


The authors are thankful to Jamia Hamdard for providing necessary facility and IIT-Delhi and CDRI Lucknow for recording spectral data.

 
  References Top

1.
He Y, Wu B, Yang J, Robinson D, Risen L, Ranken R, et al. 2-piperidin-4-yl-benzimidazoles with broad spectrum antibacterial activities. Bioorg Med Chem Lett 2003;13:3253-6.  Back to cited text no. 1
    
2.
Cetinkaya Y, Falk P, Mayhall CG. Vancomycin-resistant enterococci. Clin Microbiol Rev 2000;13:686-707.  Back to cited text no. 2
    
3.
Deresinski S. Methicillin-resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey. Clin Infect Dis 2005;40:562-73.  Back to cited text no. 3
    
4.
Rice LB. Emergence of vancomycin-resistant enterococci. Emerg Infect Dis 2001;7:183-7.  Back to cited text no. 4
    
5.
Karegoudar P, Karthikeyan MS, Prasad DJ, Mahalinga M, Holla BS, Kumari NS. Synthesis of some novel 2,4-disubstituted thiazoles as possible antimicrobial agents. Eur J Med Chem 2008;43:261-7.  Back to cited text no. 5
    
6.
Narayana B, Vijaya Raj KK, Ashalatha BV, Kumari NS, Sarojini BK. Synthesis of some new 5-(2-substituted-1,3-thiazol-5-yl)-2-hydroxy benzamides and their 2-alkoxy derivatives as possible antifungal agents. Eur J Med Chem 2004;39:867-72.  Back to cited text no. 6
    
7.
Milewski S, Chmara H, Andruszkiewicz R, Borowski E, Zaremba M, Borowski J. Antifungal peptides with novel specific inhibitors of glucosamine 6-phosphate synthase. Drugs Exp Clin Res 1988;14:461-5.  Back to cited text no. 7
    
8.
Teplyakov A, Obmolova G, Badet B, Badet-Denisot MA. Channeling of ammonia in glucosamine-6-phosphate synthase. J Mol Biol 2001;313:1093-102.  Back to cited text no. 8
    
9.
Tsuji K, Ishikawa H. Synthesis and anti-pseudomonal activity of new 2-isocephems with a dihydroxypyridone moiety at C-7. Bioorg Med Chem Lett 1994;4:1601-6.  Back to cited text no. 9
    
10.
Karabasanagouda T, Adhikari, VA, Dhanwad R, Parameshwarappa G. Synthesis of some new 2-(4-alkylthiophenoxy)-4-substituted-1,3-thiazoles as possible anti-inflammatory and antimicrobial agents. Ind J Chem 2008;47B(01):144-52.    Back to cited text no. 10
    
11.
Popsavin M, Spaic S, Svircev M, Kojic V, Bogdanovic G, Popsavin V. 2-(3-Amino-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide: A new tiazofurin analogue with potent antitumour activity. Bioorg Med Chem Lett 2006;16:5317-20.  Back to cited text no. 11
    
12.
Jaen JC, Wise LD, Caprathe BW, Tecle H, Bergmeier S, Humblet CC, et al. 4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: A novel class of compounds with central dopamine agonist properties. J Med Chem 1990;33:311-7.  Back to cited text no. 12
    
13.
Bharti SK, Nath G, Tilak R, Singh SK. Synthesis, anti-bacterial and anti-fungal activities of some novel Schiff bases containing 2,4-disubstituted thiazole ring. Eur J Med Chem 2010;45:651-60.  Back to cited text no. 13
    
14.
Bell FW, Cantrell AS, Högberg M, Jaskunas SR, Johansson NG, Jordan CL, et al. Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs. J Med Chem 1995;38:4929-36.  Back to cited text no. 14
    
15.
Xiaoyun L, Xiaobo L, Baojie W, Scott GF, Lili C, Changlin Z, et al. Synthesis and evaluation of anti-tubercular and antibacterial activities of new 4-(2,6-dichlorobenzyloxy)phenyl thiazole, oxazole and imidazole derivatives. Part 2. Eur J Med Chem 2012;49:164-71.  Back to cited text no. 15
    
16.
Tapia RA, Alegria L, Pessoa CD, Salas C, Cortés MJ, Valderrama JA, et al. Synthesis and antiprotozoal activity of naphthofuranquinones and naphthothiophenequinones containing a fused thiazole ring. Bioorg Med Chem 2003;11:2175-82.  Back to cited text no. 16
    
17.
Hargrave KD, Hess FK, Oliver JT. N-(4-substituted-thiazolyl)oxamic acid derivatives, a new series of potent, orally active antiallergy agents. J Med Chem 1983;26:1158-63.  Back to cited text no. 17
    
18.
Patt WC, Hamilton HW, Taylor MD, Ryan MJ, Taylor DG Jr, Connolly CJ, et al. Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors. J Med Chem 1992;35:2562-72.  Back to cited text no. 18
    
19.
Makam P, Thakur PK, Kannan T. In vitro and in silico antimalarial activity of 2-(2-hydrazinyl)thiazole derivatives. Eur J Pharm Sci 2014;52:138-45.  Back to cited text no. 19
    
20.
Sarojini BK, Krishna BG, Darshanraj CG, Bharath BR, Manjunatha H. Synthesis, characterization, in vitro and molecular docking studies of new 2,5-dichloro thienyl substituted thiazole derivatives for antimicrobial properties. Eur J Med Chem 2010;45:3490-6.  Back to cited text no. 20
    
21.
Gahtori P, Ghosh SK, Singh B, Singh UP, Bhat HR, Uppal A. Synthesis, SAR and antibacterial activity of hybrid chloro, dichloro-phenylthiazolyl-s-triazines. Saudi Pharm J 2012;20:35-43.  Back to cited text no. 21
    
22.
Jing RL, Dong DL, Rong RW, Jian S, Jing DJ, Qian DR, et al. Design and synthesis of thiazole derivatives as potent FabH inhibitors with antibacterial activity. Eur J Med Chem 2014;75:438-47.  Back to cited text no. 22
    
23.
Karegoudar P, Karthikeyan MS, Prasad DJ, Mahalinga M, Holla BS, Kumari NS. Synthesis of some novel 2,4-disubstituted thiazoles as possible antimicrobial agents. Eur J Med Chem 2008;43:261-7.  Back to cited text no. 23
    
24.
Dodson RM, King LC. The reaction of ketones with halogens and thiourea. J Am Chem Soc 1945;67:2242.  Back to cited text no. 24
    
25.
Kantilal PA, Pankaj VM. Synthesis and biological activity of n-{5-(4-methylphenyl) diazenyl-4-phenyl- 1, 3-thiazol-2-yl}benzamide derivatives. Quim Nova 2011;34:771-4.  Back to cited text no. 25
    
26.
Sharshira EM, Hamada NM. Synthesis, Characterization and Antimicrobial Activities of Some Thiazole Derivatives. Am J Org Chem 2012;2:69-73  Back to cited text no. 26
    
27.
Narendra S, Uma SS, Niranjan S, Sushil K, Umesh KS. Synthesis and antimicrobial activity of some novel 2-amino thiazole derivatives. J Chem Pharm Res 2010;2:691-8.  Back to cited text no. 27
    
28.
Davis WW, Stout TR. Disc plate method of microbiological antibiotic assay. I. Factors influencing variability and error. Appl Microbiol 1971;22:659-65.  Back to cited text no. 28
    
29.
Kumar S, Bawa S, Drabu S, Gupta H, Machwal L, Kumar R. Synthesis, antidepressant and antifungal evaluation of novel 2-chloro-8-methylquinoline amine derivatives. Eur J Med Chem 2011;46:670-5.  Back to cited text no. 29
    
30.
Barry AL. The antimicrobial susceptibility test: Principle and Practice. Philadelphia: Illus Lea and Febiger; 1976. p. 180. [Biol. Abstr. 1977, 64, 25183].  Back to cited text no. 30
    
31.
Ronkin SM, Badia M, Bellon S, Grillot AL, Gross CH, Grossman TH, et al. Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase. Bioorg Med Chem Lett 2010 1;20:2828-31.  Back to cited text no. 31
    
32.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177-96.  Back to cited text no. 32
    
33.
Maestro. Version 9.4. New York: Schrödinger, LLC; 2013.  Back to cited text no. 33
    
34.
Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br J Pharmacol 2011;162:1239-49.  Back to cited text no. 34
    
35.
QikProp. Version 3.6. New York: Schrödinger, LLC; 2013.  Back to cited text no. 35
    
36.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:3-26.  Back to cited text no. 36
    
37.
Duffy EM, Jorgensen WL. Prediction of Properties from Simulations: Free Energies of Solvation in Hexadecane, Octanol, and Water. J Am Chem Soc 2000;122:2878-88.  Back to cited text no. 37
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2]


This article has been cited by
1 Review on fungal enzyme inhibitors potential drug targets to manage human fungal infections
Jayapradha Ramakrishnan,Sudarshan Singh Rathore,Thiagarajan Raman
RSC Adv.. 2016; 6(48): 42387
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Results and Disc...
Materials and Me...
Acknowledgment
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1429    
    Printed76    
    Emailed0    
    PDF Downloaded288    
    Comments [Add]    
    Cited by others 1    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]