Int J Pharm Pharm Sci, Vol 8, Issue 1, 67-75Original Article


AN IN SILICO STUDY OF NOVEL FLUOROQUINOLONES AS INHIBITORS OF DNA GYRASE OF STAPHYLOCOCCUS AUREUS

GHALIA SABBAGH*, THANAA MURAD**

*Department of Pharmaceutical Chemistry and Quality Control, **MSC Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Aleppo University, Aleppo University Street, Aleppo, Syria
Email: ghaliaaa@hotmail.com

 Received: 30 Jul 2015 Revised and Accepted: 18 Nov 2015

ABSTRACT

Objective: This study is an attempt to identifying an effective fluoroquinolones (FQ) s against STAPHYLOCOCCUS AUREUS (S. aureus) by in silico analysis of 150 (FQ) compounds using iGemDock v2.1 tool.

Methods: Structure of DNA gyrase (2XCT) was retrieved from the Protein Data Bank (PDB) and the structures of (FQ) compounds were selected from literature survey of 400 novel compounds and the physical, chemical and molecular characteristics of each compound were obeyed for drug-relevant properties based on “Lipinski’s rule of five, then a total of 150 (FQ)s were docked against the protein of the 2XCT enzyme.

Results: From this study, it was found that the compound (1) [(3R,7E)-9-fluoro-7-(isonicotinoylhydrazono)-3-methyl-10-(4-methylpiperazin-1-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid] and the compound (2) [1-cyclopropyl-6-fluoro-7-{4-[(8-hydroxyquinolin-2-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] showed the best interaction value against 2XCT enzyme, the binding energy was (-104. 58 kcal/mol), (-26. 5kcal/mol) respectively whereas the reference ciprofloxacin (CIP) was (-74. 33 kcal/mol).

Conclusion: Further in vitro studies of these compounds against the enzyme will lead a new pathway to drug discovery.

Keywords: S. aureus, (FQ)s, 2XCT, DNA gyrase, Lipinski’s rule, iGemdock, In silico.

© 2016 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

INTRODUCTION

S. aureus is an opportunistic, anaerobic Gram-positive coccal pathogen, found on the mucous membranes and the human skin, which shows extreme adaptability to antibiotic pressure [1]. It can cause a range of illnesses from minor skin infections to life-threatening diseases [2], and it is still one of the five most common causes of nosocomial infection and community-acquired methicillin-resistant S. aureus (MRSA) [3]. Today, the spread of multi-resistant bacteria becomes major concern in the hospital environment, where the glycopeptides, vancomycin and teicoplanin are considered as the last resort drugs against (MRSA) [4-6]. Therefore, the search for new structural ligands and novel targets of attack as a means to overcome bacterial resistance is an important research goal [7, 8].

Modern approaches toward development of new potential inhibitors are based on knowledge of structure and function of proteins specific to bacteria like DNA gyrase which is member of the topoisomerase enzymes that are able to relax supercoiled DNA in a reaction coupled to the hydrolysis of ATP [9,10], whereas it is characteristic and essential bacterial enzyme when it is inactivated, it leads to bacterial cell death. For this reason, gyrases have been chosen as targets for antibacterial agents [11-13]. DNA gyrase consists of two subunits, A and B, of molecular mass 97 and 90 kDa, respectively, with the active enzyme being an A2B2 complex. The A subunit of DNA gyrase is involved in DNA breakage and reunion while the B subunit catalyzes the hydrolysis of ATP [14, 15]. There are many agents that target this enzyme such as (FQ)s coumarins, and cyclothialidines while all have their own limitations [16]. (FQs), e.g., ciprofloxacin, inhibit the DNA breakage-reunion cycle by forming a constant complex with DNA and the enzyme DNA gyrase [17]. They have gained immense importance during the last two decades because of their potent antibacterial activity against wide varieties of gram-positive and gram-negative pathogenic bacteria with minimum toxic side effects [18, 19]. The (FQs) were introduced in 1980s, they have a relatively simple molecular nucleus which consists of a bicyclic ring structure, and there is a substitution at position N-1, a carboxyl group at position 3, a keto group at position 4, a fluorine atom at position 6 and a nitrogen heterocyclic moiety at the C-7 position [20-23]. To date, many (FQ)s as antibacterial agents have been developed and synthesized to be used in clinical trials with significant improvement in the antibacterial spectrum and activity [24].

In silico methods are used to analyze the target structures for possible binding sites, generate candidate molecules, check for their drug-likeness, dock these molecules with the target, rank them according to their binding affinities, and further optimize the molecules to improve binding characteristics [25]. This work is an attempt to survey a number of novel (FQ)s that are synthesized in the last years, then do a virtual screening that allows studying the compounds in silico and comparing them with the reference and select, theoretically, the best compounds based on binding energy as inhibitors of DNA gyrase of S. aureus.

MATERIALS AND METHODS

Protein preparation

The receptor enzyme, required for the docking study that related to S. aureus has been retrieved from the(PDB) which is a key resource in areas of structural biology, and it is a fundamental repository for 3D structure data of large molecules [26]. The enzyme PDB ID-2XCT [27-30] was designated on this site and it had a resolution factor 3.35 A°. The enzyme was downloaded then saved in pdb file format and the 3D of it was shown in fig. 1. We defined the active site of (2XCT) based on the x-ray complex structure of protein (2XCT) and binding ligand (CIP), fig. 2, whereas that ligand was discovered and developed by Bayer A. G. and subsequently approved by the US Food and Drug Administration (FDA) in 1987, and it was the most widely used of the second-generation of (FQ)s antibiotic that came into clinical use in the late 1980s and early 1990s [31, 32].

Generation and optimization of ligands

The (FQ) s, fig. 3, which was reported here, had been selected after an extensive literature survey. In fact, we had selected a total of 400 new compounds of (FQ)s [33,34,35-40,41,42,65], and they were drawn in the two-dimensional (2D) structures using ACD chemsketch software [66]. Then the compounds were saved in mol format and converted to mol2 format using the OPEN BABEL software [67]. After that a total of 150 (FQ) compounds had been selected for in silico study based on “Lipinski’s rule of five”[68-69], where the molecular properties such as cLogp, number of hydrogen bond donors and acceptors and polar surface area were obtained from: www.molinspiration.com [70].

Fig. 1: (A) 3D structure of 2XCT protein, (B) the reference ligand (ciprofloxacin)


Fig. 2: 3D Binding site of 2XCT with reference inhibitor (Ciprofloxacin)


Fig. 3: the parent structure of fluoroquinolones

Protein-ligand docking

In this research, we used iGemdock software [71, 73] to dock the enzyme (2XCT) with 150 (FQ)s, which it is available for free and was used in various previous researches  [74-77].

iGemdock v2. 1

In order to carry out docking simulation of the enzyme (2XCT) with 150 (FQ)s, we used the iGemdock v2. 1 as molecular docking tool. iGemdock is an integrated virtual screening (VS) environment from preparations through post-screening analysis with pharmacological interactions. iGemdock generates protein-compound interaction profiles by providing interactive interfaces to prepare both the binding site of the target enzyme and the screening compounds library. Then each compound in the library is docked into the binding site by using the in-house docking tool iGemdock. Afterward, iGemdock infers the pharmacological interactions and clusters the screening compounds for the post-screening analysis based on profiles of electrostatic (E), hydrogen-bonding (H), and Van der Waal’s (V) interactions and compound structures. Finally, iGemdock ranks and visualizes the screening compounds by combining the pharmacological interactions and energy-based-scoring function of iGemdock.

Virtual screenings of the 150 compounds were performed in the docking tool iGemdock. The docking consisted protocol "accurate docking" by setting population size of 800 is set with 80 generations and 10 solutions. After the completion of the docking, the post-docking analysis was performed to find the docking pose and its energy values. The empirical scoring function of iGemdock was estimated using:

Energy = vdW+Hbond+Elec

Here, the vdW term is van der Waal energy; H bond and Elect terms are hydrogen bonding, energy, and electro statistic energy, respectively.

Table 1 illustrates the structure of 30 studied compounds and shows the structure and the IUPAC name of the compounds.

RESULTS AND DISCUSSION

In silico docking is the best approach to check utility of any chemical as a drug before going through any in vivo or in vitro analysis to shorten out the experiments and cost cutting. A literature survey was done for new compounds of (FQ)s, then a total of 150 compounds were selected based on Lipinski’s rule of five and they were docked against the enzyme DNA gyrase of S. aureus using iGemdock to understand its interactive analysis before they have been proposed to study its in vitro antibacterial activity.

The objective of the current work is to evaluate the theoretical antibacterial activity against S. aureus of the novel (FQ)s that have been synthesized in recent years by using the docking studies. In this perspective, synthesized compounds like that mentioned in table (1) were selected and (CIP), a known DNAgyrase inhibitor, was used as the standard, and then the docking studies were performed using iGemdock v2. 1, and the results displayed that all the selected (FQs) showed lesser binding energy ranging between (-104. 58 kcal/mol) to (-47.33 kcal/mol) as it shows in table 2 when compared with the standard (-74.33 kcal/mol). So, these molecular docking analyses could deliver the most potent 2XCT inhibitors for the prevention and treatment of infections caused by S. aureus.

Table 1: The structure of 30 screened fluoroquinolone compounds

S. No.

IUPAC name

Structure

Ref.

1

(3R,7E)-9-fluoro-7-(isonicotinoylhydrazono)-3-methyl-10-(4-methylpiperazin-1-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

62

2

1-cyclopropyl-6-fluoro-7-{4-[(8-hydroxyquinolin-2-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

43

3

6-{4-[(2Z)-2-[(aminocarbonyl)hydrazono]-2-(4-methoxyphenyl)ethyl]piperazin-1-yl}-4-ethyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid

64

4

4-ethyl-7-fluoro-6-{4-[(2Z)-2-hydrazono-2-phenylethyl]piperazin-1-yl}-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid

64

5

tert-butyl 1-cyclopropyl-6-fluoro-4-oxo-7-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]-1,4-dihydroquinoline-3-carboxylate

46

6

(3R,7E)-7-(benzoylhydrazono)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

62

7

1-ethyl-6-fluoro-7-(4-{[3-hydroxy-6-(hydroxymethyl)-4-oxo-4H-pyran-2-yl]methyl}piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

63

8

isopropyl 1-cyclopropyl-6-fluoro-4-oxo-7-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]-1,4-dihydroquinoline-3-carboxylate

46

9

propyl 1-cyclopropyl-6-fluoro-4-oxo-7-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]-1,4-dihydroquinoline-3-carboxylate

46

10

methyl 1-cyclopropyl-6-fluoro-4-oxo-7-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]-1,4-dihydroquinoline-3-carboxylate

58

11

6-fluoro-7-{4-[(8-hydroxyquinolin-2-yl)methyl]piperazin-1-yl}-1-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

43

12

6-fluoro-1-(2-fluoro-4-nitrophenyl)-7-{4-[(8-hydroxyquinolin-2-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

43

13

1-cyclopropyl-6-fluoro-7-{4-[(2E)-2-hydrazono-2-phenylethyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

60

14

1-cyclopropyl-6-fluoro-7-{4-[(2E)-2-(hydroxyimino)-2-phenylethyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

60

15

7-{4-[(2E)-2-(5-chloro-2-thienyl)-2-(phenoxyimino)ethyl]piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

46

16

4-ethyl-7-fluoro-1-oxo-6-{4-[(2Z)-2-phenyl-2-(phenylhydrazono)ethyl]piperazin-1-yl}-1,4-dihydronaphthalene-2-carboxylic acid

65

17

5-fluoro-4-{4-[(8-hydroxyquinolin-2-yl)methyl]piperazin-1-yl}-3-methyl-7-oxo-2,3-dihydro-7H-[1,2]oxazino[4,3,2-ij]quinoline-8-carboxylic acid

43

18

7-{4-[(2E)-2-(5-chloro-2-thienyl)-2-(phenoxyimino)ethyl]piperazin-1-yl}-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

46

19

6-(4-{(2Z)-2-[(aminocarbonyl)hydrazono]-2-phenylethyl}piperazin-1-yl)-4-ethyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid

65

20

(3R,7E)-7-[(4-chlorobenzoyl)hydrazono]-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

62

21

7-{4-[(2E)-2-(5-chloro-2-thienyl)-2-(phenoxyimino)ethyl]piperazin-1-yl}-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

46

22

1-ethyl-6-fluoro-4-oxo-7-[4-(phenylsulfonyl)piperazin-1-yl]-1,4-dihydroquinoline-3-carboxylic acid

36

23

6-fluoro-7-(4-methylpiperidin-1-yl)-1-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

48

24

1-ethyl-6-fluoro-7-{4-[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

57

25

1-ethyl-6-fluoro-7-{4-[(8-hydroxyquinolin-2-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

43

26

9-fluoro-10-{4-[(2E)-2-(hydroxyimino)-2-(2-thienyl)ethyl]piperazin-1-yl}-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

59

27

7-(4-{[6-(chloromethyl)-3-hydroxy-4-oxo-4H-pyran-2-yl]methyl}piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

63

28

1-cyclopropyl-6-fluoro-4-oxo-7-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl]-1,4-dihydroquinoline-3-carboxylic acid

57

29

1-{[4-(acetylamino)phenyl]sulfonyl}-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylic acid

50

30

1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylic acid

54

Table 2: The docking binding energy values results using iGemdock

S. No.

VW. force (kcal/mol)

H Bond (kcal/mol)

Elec. energy (kcal/mol)

Total binding energy(kcal/mol)

1

-90.19

-14.49

0.1

-104.58

2

82.98

-18.42

0

-101.4

3

-68.74

-31.14

-1.45

-101.33

4

-73.13

-24.95

-1.15

-99.22

5

-82.91

-15.62

0

-98.52

6

-88.58

-9.63

0.16

-98.04

7

-89.07

-6.6

0

-95.67

8

-80.42

-15.17

0

-95.59

9

-79.28

-16.19

0

-95.57

10

-78.05

-16.58

0

-94.62

CIP

-60.38

-15.88

1.92

-47.33

Post-screening analysis

All the (FQ)s in the post-screening analysis PDB ID-2XCT, in comparison to the reference (CIP), were as potential antibacterial drugs of S. aureus with good docking energy with the target protein especially the compound No. 1[(3R,7E)-9-fluoro-7-(isonicotinoyl-hydrazono)-3-methyl-10-(4-methylpiperazin-1-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid] and the compound No.2 [1-cyclopropyl-6-fluoro-7-{4-[(8-hydroxyquinolin-2-yl)methyl] piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] which they had better drug activity, as they showed the most favorable binding energy whereas the first compound binds to DNA gyrase with high binding affinity (-104. 58 kcal/mol) and the second (-101. 4 kcal/mol). Our study showed that the compound No. 1 that was synthesized in 2013 by (Sahu Susanta K., Pandeya Surendra N.) and it evaluated as a new inhibitor of E coli. Whereas the compound No. 2 was synthesized in 2005 by(Yue-Ling Zhao, Yeh-Long Chen, et al.) as anti tubercular agent. Here in this study they were good agents against DNA gyrase of S. aureus based on binding energies, in comparison to the (CIP). Also the compound (3) [6-{4-[(2Z)-2-[(aminocarbonyl) hydrazono]-2-(4-methoxyphenyl)ethyl] piperazin-1-yl}-4-ethyl-7-fluoro-1-oxo-1,4dihydronaphthalene-2-carboxylic acid] and the compound (4) [4-ethyl-7-fluoro-6-{4-[(2Z)-2-hydrazono-2-phenylethyl] piperazin-1-yl}-1-oxo-1, 4-dihydro-naphthalene-2-carboxylic acid] that were synthesized in 2014 by (Mehul M. Patel and Laxman J. Patel) disappeared an acceptable energies, so they could be an effective against S. aureus.

The interactions and fitness scores of the compound suggest that these compounds can as an antimicrobial activities drug against gram-positive S. aureus.

Table 3 shows residues that are associated with the amino acids in the binding site of the compound No. 1 that it was the best in Elec energy and the reference. Fig. 4 illustrates the interactions of the compound No. 1 with protein pocket which have the most favorable binding energy.

Table 3: Pharmacological interactions and Residues involved in the binding site

PDB ID

Predicted pharmacologic interactions

Compound 1

CIP

2XCT

H-M GLU 435

-3.5

0

H-S GLU 435

-3.5

0

H-S ASP 437

-4.2

0

H-S LYS 460

0

-3.5

H-S ASN 475

0

-6.2

H-S ARG 1122

-3.3

-12

V-M GLU 435

-7.7

-6.1

V-S GLU 435

-7.5

6.6 -

V-M GLY 436

-14.4

11.4 -

V-M ASP 437

-16.6

0

V-S ASP 437

-12.8

3.6 -

V-M ARG 458

0

-3.2

The green and grey color represents the amino acids involved in(H)hydrogen bonding and(V) van der Waals are interaction types M and S are Main chain and Side chain.


Fig. 4: The compound (1) with the reference CIP and their interactions with the amino acids of the binding site

Lipinski’s rule

Lipinski et al. formulated the ’Rule of Five’ to predict drug-likeness, which consists of four important properties, each related to the number 5. The rule is based on data in the literature for a large number of compounds, including all known drugs that correlate physical properties with oral bioavailability. The compounds are more likely to be membrane permeable and easily absorbed by the body if it matches the following criteria:

1. The molecular weight of less than 500 mg/mol

2 . Has a high lipophilicity (log p less than 5)

3 . Hydrogen bond donors less than 5

4 . Hydrogen bond acceptor is less than 10

The rule describes molecular properties important for a drug's pharmacokinetics in the human body, including their Absorption, Distribution, Metabolism, and Excretion (ADME). The rule is important for drug development where a pharmacologically active lead structure is optimized step-wise for increased activity and selectivity, as well as drug-like properties as described by Lipinski's rule.

The table 4 depicts the values related to the Lipinski’s rule of five. From the table it is evident that all the ten studied compounds obey the Lipinski’s rule. The molecular docking studies and Lipinski’s rules facilitate drug development avoiding expensive post clinical experiments.

Veber rule and molar refractivity

1-Veber Rule: In particular, compounds which meet only the two criteria of:

  1. Rotatable bond count≤10.
  2. Polar surface area (PSA) equal to or less than 140 Å2 are predicted to have good oral bioavailability .

2-Molar Refractivity: between (40-130) is used as measurement of the real volume of the molecule and it is also related to the forces which govern the ligand-receptor interactions [79].

The 10 high ranked lead molecules were prioritized to follow Lipinski’s guidelines of five, veber rule and molar refractivity based on the likeliness drug properties are listed in table 4.

Table 4: The Lipinski’s and Veber properties of the selected 10 ligands

S. No.

Molecular Formula1

M W2 *

g/mol

logP2 #

HD2 *

HA2 *

RB2 *

PSA2

MR1 *
 

Value to be

500 >

5 >

5 >

10 >

=10 >

140>

40-130

1

C25H26FN5O4

480.49

-1.43

2

9

4

112.30

126.4

2

C27H30FN5O5

488.51

0.679

2

8

5

98.90

130.4

3

C27H30FN5O5

464.5

1.22

2

7

6

137.56

137.01

4

C25H27FN4O3

450

0.735

2

7

6

99.23

122.69

5

C27H29FN4O4

492.5

2.09

0

7

6

84.75

129.19

6

C25H25ClFN5O4

479.50

-0.28

2

8

4

99.41

131.04

7

C23H24FN3O2

473.451

-2.331

3

10

6

136.45

115.42

8

C26H27FN4O4

478.5

2.69

0

7

6

84.75

125.27

9

C26H27FN4O4

478.51

2.84

0

7

5

84.75

125.32

10

C27H25FN4O4

450.46

1.97

0

7

5

84.75

128.74

CIP

C17H18FN3O3

331.34

-1.27

2

6

3

74.57

83.25

1-Calculated by ACD (Available Chemical Directory) 2-calculated by: www. molinspiration. Com, *PSA: Polar Surface Area,*MW: Molecular weight, *HD: H bond donor, *HA: H bond acceptor. *RB: rotatable bonds. *MR: Molar refractivity#Octanol/Water partition coefficient


CONCLUSION

The present study has given an insight into the searching of new fluoroquinolones as DNA gyrase of S. aureus inhibitors. Various in silico tools like Lipinski filter and molecular docking has been utilized to select the best compounds as antibacterial inhibitors of S. aureus whereas the synthesized derivative [(3R,7E)-9-fluoro-7-(isonicotinoyl-hydrazono)-3-methyl-10-(4-methylpiperazin-1-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid] showed good antibacterial activity theoretically, then further in vitro studies should be applied to evaluate the biological activity. Thus, the in silico study has been helpful in promising molecules enabling the minimization of time spend for searching compounds and can be considered as good method for screening of novel fluoroquinolones to target another enzyme.

ABBREVIATION

(FQ)s: Fluoroquinolones )S. aureus: S staphylococcus aureus, MRSA: Methicillin-Resistant S. Aureus, CIP: Ciprofloxacin, iGemdock: iGeneric Evolutionary Method Docking, PDB: Protein Data Bank, ADME: Absorption, Distribution, Metabolism, and Excretion

ACKNOWLEDGMENT

The authors would like to thank all the management of Aleppo University and all the staff of Faculty of Pharmacy for assistance. There is no known conflict of interest associated with the publication and there has been no significant financial support for this work that could have influenced its outcome.

CONFLICT OF INTERESTS

Declared None

REFERENCES

  1. Tiwari HK, Das AK, Sapkota D, Sivarajan K, Pahwa VK. Methicillin resistant Staphylococcus aureus prevalence and antibiogram in a tertiary care hospital in western Nepal. J Infect Dev Countries 2009;3:21-4.
  2. Chambers HF. The changing epidemiology of Staphylococcus aureus. Emerging Infect Dis 2001;7:182-7.
  3. Cole A, Tahk S, Oren A, Yoshioka D, Kim YH, Park A, et al. Determinants of S. aureus nasal carriage. Clin Diagn Lab Immunol 2001;6:1064-9.
  4. Robert J, Bismuth R, Jarlier V. Decreased susceptibility to glycopeptides in methicillin‑resistant Staphylococcus aureus. J Antimicrob Chemother 2006;57:506-11.
  5. Bal M, Saha B, Singh AK, Ghosh A. Identification and characterization ofa vancomycin‑resistant S. aureus isolated from Kolkata (South Asia). J Med Microbiol 2008;57:172-9.
  6. Foster JK, Joseph R, Lentino RS, Divincenzo C. Comparison of in vitro activity of quinolone antibiotic and vancomycin against gentamicin‑and methicillin‑resistant S. aureus time‑kill kinetic studies. Antimicrob Agents Chemother 1986;30:823-9.
  7. Gould IM, David MZ, Esposito S. New insights into meticillin-resistant S. aureus (MRSA) pathogenesis, treatment and resistance. Int J Antimicrob Agents 2012;39:104-12.
  8. Brown DF, Edwards DI, Hawkey PM, Morrison D, Ridgway GL, Towner KJ, et al. Guidelines for the laboratory diagnosis and susceptibility testing of methicillin-resistant S. aureus (MRSA). J Antimicrob Chemother 2005;56:1000-18.
  9. Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem Allied Res India 2001;70:369-73.
  10. Schoeffler AJ, Berger JM. DNA topoisomerases are harnessing and constraining energy to govern chromosome topology. Q Rev Biophys 2008;41:101-41.
  11. Laponogov I, Sohi MK, Veselkov DA, Pan X-S, Sawhney R, Thompson AW, et al. Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases. Nat Struct Mol Biol 2009;16:667–9.
  12. Bax DB, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 2010;466:935-9.
  13. Levine C, Hiasa H, Marians KJ. DNA Gyrase and topoisomerase IV: biochemical activities, physiological roles during chromosome replication and drug sensitivities. Biochim Biophys Acta Bio member 1998;1400:29-43.
  14. Gallert M, Mizuuchi K, Mary O’dea H, Nash AH. DNA gyrase: an enzyme that introduces superhelical turns in to DNA. Proc Natl Acad Sci USA 1976;73:3872-6.
  15. Drlica K, Zhao X. DNA Gyrase, Topoisomerase IV, and the 4-Quinolones. Microbiology and molecular biology reviews. Microbiol Mol Biol Rev 1997;61:377-92.
  16. Angehrn P, Buchmann S, Funk C, Goetschi E, Gmuender H, Hebeisen. “New Antibacterial agents derived from the DNA gyrase inhibitor cyclothialidine”. J Med Chem 2004;47:1487-93.
  17. Hooper DC. Mode of action of (FQ)s. Drugs 1999;58:6-10.
  18. Hooper DC. Mechanisms of action and resistance of older and newer (FQ)s. Clin Infect Dis 2000;31:24-8.
  19. Hooper DC. Mechanisms of quinolone resistance. Clin Infect Dis 1999;2:38-55.
  20. Emami S, Shafiee A, Foroumadi A. Structural features of new quinolones and relationship to antibacterial activity against Gram-positive bacteria. Mini Rev Med Chem 2006;6:375-86.
  21. Prabodh Chander Sharma, Ankit Jain, Sandeep jain. (FQ) Antibacterials: a review on chemistry microbiology and therapeutic prospects. Acta Poloniae Pharm Drug Res 2009;66:587-98.
  22. GS Tillotson. Quinolones: structure-activity relationships and future predictions. J Med Microbiol 1996;44:320-4.
  23. Daniel T, W Chu, Prabhavathi B. Fernandest: structure-activity relationships of the (FQ)s. Am Soc Microbiol 1989;33:131-5.
  24. Roy Akhilesh, Sardar SM, Salve B, Rishi Pathak DD. Studies on synthesis and biological evaluation of some substituted (FQ)s. Int J Chem Tech Res 2009;1:34-45.
  25. Venkatachalam CM, Jiang X, Oldfield T, Waldman M, Ligand Fit. A novel method for the shape-directed rapid docking of ligands to protein active sites. J Mol Graphics Modell 2003;21:289–99.
  26. Research collaboratory for structural bioinformatics. Protein Data Bank; 2015. Available from http://www.pdb.org. [Last accessed on 26 Mar 2015].
  27. Nikola Minovski, Andrej Perdih, Marjana Novic, Tom Solmaje. Cluster-based molecular docking study for in silico identification of novel 6-(FQ)s as potential inhibitors against mycobacterium tuberculosis. J Comput Chem 2013;34:790–9.
  28. Bax DB, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 2010;466:935–9.
  29. Margerrison EEC, Hopewell R, Fisher LM. The nucleotide sequence of the Staphylococcus aureus gyr A-gyr B locus ending the DNA gyrase A and B protein. J Bacteriol 1992;174:1596-663.
  30. Brockbank SMV, Barth PT. Cloning, Sequencing, and expression of the DNA gyrase genes from Staphylococcus aureus. J Bacteriol 1993;175:3269-77.
  31. Majed M, Masadeh, Karem H. Ciprofloxacin-induced antibacterial activity is attenuated by phosphodiesterase inhibitors. Curr Ther Res 2015;77:14-7.
  32. Goossens H, Ferech M, Coenen S, Stephens P, Ferech, Coenen, et al. "Comparison of outpatient systemic antibacterial use in 2004 in the United States and 27 European countries". Eur Surveillance Antimicrobial Consumption Project Group Clin Infect 2007;8:1091-8.
  33. Reanau Thomas E, Sanchez Joseph P, Gage Jeffrey W, Dever A, Shapiro Martin A. Structure-activity relationships of the quinolone antibacterials against mycobacteria: effect of structural changes At N-1 And C-7. J Med Chem 1996;39:729-35.
  34. Baton Sandor, Timari Geza, KoczkaIstvan, Herecz Isavan. Synthesis and biological evaluation of N-(1-Aziridino)-6-(FQ)s. Bioorg Med Chem Lett 1996;13:1507-10.
  35. Hong Chang Hong, Kim Young Kwan, Chang Jay Hyok, Kim Se Ho, Choi Hoon, Nam Hyun Do, et al. Noval(FQ) antibacterial agents containing oxime-substituted (Aminomethyl) pyrrolidines: synthesis and antibacterial activity of 7-(4-(Aminomethyl)-3-(Methoxyimino)Pyrrolidin-1-Yl)-1Cyclopropyl-6-Fluoro-4-Oxo-1,4 -Dihydro[1,8]Naphthyridine-3-Carboxylic Acid. J Med Chem 1997;40:3584-93.
  36. Neito MJ, Alovero FDL, Manzo RH, Mazzieri MR. A new class of (FQ)s: Benzenesulfonamide (FQ)s antibacterial activity and SAR studies. Eur J Med Chem 1999;34,209-14.
  37. Kuo-Chang Fang, Yeh-Long Chen, Jia-Yuh Sheu, Tai-Chi Wang, Cherng-Chyi Tzeng. Synthesis, Antibacterial, and cytotoxic evaluation of certain 7-Substituted norfloxacin derivatives. J Med Chem 2000;43:3809-12.
  38. Chen YL, Fang KC, Sheu JY, Hsu SL, Tzeng CC. Synthesis and antibacterial evaluation of certain quinolone derivatives. J Med Chem 2001;44:2374-7.
  39. F Alovero, A Barnes, M Nieto, MR Mazzieri, RH Manzo. Comparative study of new benzenesulfonamide (FQ)s structurally related to ciprofloxacin against selected ciprofloxacin-susceptible and–resistant Gram-positive cocci. J Antimicrob Chemother 2001;48:709-12.
  40. Natesh Rameshkumar, Mohan, Ekambaram Harihara, Ilavarasan Raju, Sridhar Seshaiah Krishnan. Synthesis of 6-Fluoro-1,4-Dihydro-4-Oxo-Quinoline-3-carboxylic acid derivatives as potential antimicrobial agents. Eur J Med Chem 2003;38:1001-4.
  41. HU Guo-Qiang, Zhang Zhong Quan, Huang Wen Long, Zhang Hui Bin, Huang Sheng Tang. Synthesis and antibacterial activity of new tetracyclic triazolothiadiazino (FQ)s. Chin Chem Lett 2004;1:23-5.
  42. Liu Bo, Yang Chun-Hao, XuGuang-Yu, Zhu Yong-Hong, Cui Jing-Rong, Wu Xi-Han. Syntheses of quinolone hydrochloride enantiomers from synthons (R)-and (S)-2-methylpiperazine. Bioorg Med Chem Lett 2005;13:2451-8.
  43. Yue-Ling Zhao, Yeh-Long Chen, Jia-YuhSheu, I-Li Chen, Tai-Chi Wangc, Cherng-Chyi Tzenga. Synthesis and antimycobacterial evaluation of certain (FQ) derivatives. Bioorg Med Chem Lett 2005;13:3921-6.
  44. Foroumadi Alireza, Ghodsi Shahram, Emami, Najjari Somayyeh, Samadi Nasrin, Faramarzi Mohammad Ali, et al. Synthesis and antibacterial activity of new (FQ)s containing a substituted N-(Phenethyl) piperazine moiety. Bioorg Med Chem Lett 2006;16:3450-4.
  45. Talah AK, Gadad. Synthesis, Antibacterial and antitubercular activities of some 7-[4-(5-Amino-[1,3,4]Thiadiazole-2-Sulfonyl )-Piperazin-1-Yl] fluoroquinolonic derivatives. Eur J Med Chem 2006;41:918-24.
  46. Prabodh Chander Sharma, Sandeep Jainb. Synthesis and in-vitro antibacterial activity of some novel n-nicotinoyl-1-ethyl-6-fluoro-1,4-dihydro-7-piperazin-1-yl-4 -oxoquinoline-3-carboxylates. Acta Poloniae Pharm Drug Res 2008;65:551-7.
  47. Pokrovskaya Varvara, Belakhov Valery, Hainrichson Mariana, Yaron Sima, Baasov Timor. Design, Synthesis, and evaluation of noval (FQ)-Aminoglycoside hybrid antibiotics. J Med Chem 2009;52:2243-54.
  48. Lucia Pintilie, Catalina Negut, C Oniscu, MT Caproiu, M Nechifor, Luminitaiancu, et al. Synthesis and antibacterial activity of some novel quinolones. Rom Biotechnol Lett 2009;14:4756-67.
  49. Raed A, Al-Qawasmeh, Jalal A Zahra, Franca Zani, Paola Vicini, Roland Boese, et al. Synthesis and antibacterial activity of 9-cyclopropyl-4-fluoro-6-oxo-6,9-dihydro-[1,2,5]thiadiazolo [3,4-h]quinoline-7-carboxylic acid and its ethyl ester. ARKIVOC 2009;12:322-36.
  50. Akhiles Roy, SM Sardar, BU Salve, DD Rishi Pathak. Studies on synthesis and biological evaluation of some substituted (FQ)s. Int J Chem Tech Res 2009;1:34-45.
  51. Ghodsi Shahram, Fouladi Shahrbanoo, Safari Hamze Ali, Ganji Masood Taghi. Synthesis and characterization of new (FQ)s containing an n substituted piperazine. Asian J Org Chem 2009;21:3037-40.
  52. Shaikh Anwar R, Giridhar Rajani, Megraud Francis, Yadav Mange Ram. Metalloantibiotics: synthesis, characterization and antimicrobial evaluation of bismuth-fluroquinolone complex against helicobacter pyroli. Acta Pharm 2009;59:259-71.
  53. Taghi-Ganji Karim Masood. Synthesis and characterization of new derivative of norfloxacin-containing an n substituted piperazine moiety. Asian J Org Chem 2009;21:3851-4.
  54. Vincenet T, Andriole. The Quinolones. 4th ed. California: ACADIMIC PRESS; 2000.
  55. Shanmugam Srinivasan, Shweta Gupta, Ruchi Marwah, P Manisankar, Rupesh Kumar. Synthesis, Characterization and in vitro biological studies of novel N-Aryl piperazinyl (FQ)s. Res J Pharm Biol Chem Sci 2010;1:208-19.
  56. Om Prakash, Prabodh Chander, Sharma Sandeep Jain. Synthesis and antibacterial evaluation of novel (FQ) derivatives. Int Proc Chem Biol Environ Eng 2011;5:1-5.
  57. Rajnish Kumar, Ashwani Kumar, Sandip Jain, Darpan Kaushik. Synthesis, antibacterial evaluation and QSAR studies of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolone derivatives. Eur J Med Chem 2011;46:3543-50.
  58. Najma Sultana, Muhammad Saeed Arayne, Syeda Bushra Shakeb Rizvi, Urooj Haroon. Synthesis, Characterization, and biological evaluation of ciprofloxacin carboxamide analogues. Bull Korean Chem Soc 2011;32:483-8.
  59. Negar Mohammad hosseini, Zahra Alipanahi, Eskandar Alipour, Saeed Emami, Mohammad Ali Faramarzi, Nasrin Samadi, et al. Synthesis and antibacterial activity of novel levofloxacin derivatives containing a substituted thienylethyl moiety. Daru J Pharm Sci 2012;20:1-6.
  60. SN Pandeya, Ranjana, Meena K Yadav. Synthesis and antimicrobial activity of ciprofloxacin schiff and mannich bases. Int J Pharm Tech Res 2012;4:778-85.
  61. Jubie, R Kalirajan, Pavan Kumar Yadav. Design, Synthesis and docking studies of a novel ciprofloxacin analogue as an antimicrobial AGENT. EJ Chem 2012;9:980-7.
  62. Sahu Susanta Kumar, Pandeya Surendra Nath, Pathak Ashish Kumar. In-silico identification and molecular docking studies of quinolone resistance determining region (QRDR) of E. coli DNA Gyrase-A with ofloxacin schiff bases. Int J Pharm Tech Res 2013;5:1791-9.
  63. Saeed Emami, Ebrahim Ghafouri, Mohammad Ali Faramarzi, Nasrin Samadi, Hamid Irannejad, et al. Mannich bases of 7-piperazinylquinolones and kojic acid derivatives: synthesis, in vitro antibacterial activity and in silico study. Eur J Med Chem 2013;68:181-7.
  64. M Jeyanthi, BR Venkatraman. Synthesis and biological evaluation of novel 7-mercaptobenzimidazolyl (FQ)s. Int J Chem Tech Res 2014;6:1246-50.
  65. Mehul M Patel, Laxman J Patel. Design, Synthesis, Molecular docking, and antibacterial evaluation of some novel fluoroquinolone derivatives as potent antibacterial agent. Sci World J 2014. org/10.1155/2014/897187. [Article in Press]
  66. ACD/Chem Sketch Freeware, version 10. 00, Advanced Chemistry Development, Inc. Toronto, ON, Canada; 2012.
  67. Open Babel Freeware. Available from: www.vcclab.org/ lab/babel/start.html last view. [Last accessed on 01 May 2015].
  68. 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 Delivery Rev 2001;46:23–6.
  69. Edward H Kerns, Li Di. Drug-like properties: concepts, Structure design and methods: from ADME to toxicity optimization. 1st ed. Academic Press; 2008. p. 120-6.
  70. Molinspiration cheminformatics. Molinspiration; 2010. Available from: http://www.molinspiration.com/cgi-bin/ properties. [Last accessed on 26 Mar 2015].
  71. Christopher A. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 200;46:23-6.
  72. Kai-Cheng Hsu, Yen-Fu Chen, Shen-Rong Lin, Jinn-Moon Yang. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis, BMC Bioinf 2011;12:1-11.
  73. Jinn-Moon Yang. Graphical-automatic drug design system for docking, screening and post-analysis. Department of Biological Science and Technology & Institute of Bioinformatics National Chiao Tung University; 2008. p. 1-69.
  74. Balavignesh V, Srinivasan E, Ramesh Babu NG. Molecular docking study ON NS5B polymerase of hepatitis virus by screening of volatile compounds from Acacia concinna and ADMET prediction. Int J Pharm Life Sci 2013;4:2548-58.
  75. D Gnanslin Sheeba, V Subha, K Suseela Gomathi, T Citarasu. Virtual docking studies of flavonoid compound against cell wall proteins of mycobacterium tuberculosis. Asian J Pharm Res Dev 2013;1:88-97.
  76. Malik Mohammed, Adil Mustufa, Shubhra Chandra, Saima Wajid. Homology modeling and molecular docking analysis of human RAC-alpha serine/threonine protein kinase. Int J Pharma Bio Sci 2014;5:1033-42.
  77. Rini Abraham, Nisha NC, George K Varghese, Sreekumar S. Molecular docking of terminalia cuneata on cholesteryl-esteras. Int J Computational Bioinf In Silico Modeling 2014;3:324-9.