In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound

Lucia Pintilie and Amalia Stefaniu

## Abstract

Quinolones are an important class of heterocyclic compounds that possess interesting biological activities like antimicrobial, antitubercular, and antitumor. The objective of this study is to evaluate in silico the antitumoral and antimycobacterial activity of some quinolone derivatives by using CLC Drug Discovery Workbench Software. Docking studies were carried out for all ligands, and the docking scores were compared with the scores of standard drugs, topotecan and levofloxacin. The docking studies have been carried out to predict the most possible type of interaction, the binding affinities, and the orientations of the docked ligands at the active site of the target protein.

Keywords: molecular docking, quinolones, antimicrobial activity, antitumoral activity, antimycobacterial activity

## 1. Introduction

In medical practice, many quinolone derivatives with antimicrobial activity are used; some of these being considered by pharmacists as the primary drugs in human and veterinary anti-infectious therapy. Quinolones have a broad spectrum and a strong antibacterial activity [1, 2]. They are characterized by pharmacokinetics that allows their use in all localized infections. Recently, pharmacological studies have shown that quinolones also possess other biological activities: antitumor activity [3–6], antimycobaterial activity [7], antiviral activity on herpes virus, inhibiting neurovegetative diseases and ischemic infections, and food product storage (due to bactericidal properties). First antitumoral quinolone is Voreloxin: (+)-1,4-dihydro-7- (3S4S)-3-hydroxy-4-amino-1-pyrrolidinyl-4-oxo-1-(2-thiazolyl)-1.8-naphthyridine-3-carboxylic acid (Figure 1) [3]. Some quinolone derivatives (e.g., Moxifloxacin: 1-cyclopropyl-6-fluoro-7-((4aS,7aS)-hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H) yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid-Figure 2) show activity against Mycobacterium tuberculosis, and these compounds are the first new antimycobacterial drugs to be available since the discovery of rifampin [8].

Lascufloxacin (AM-1977) (Figure 3) [9, 10] is a new 8-methoxy fluoroquinolone antibacterial agent with unique pharmacophores at the first and seventh positions of the quinolone rings. The oral and parenteral formulations have been developed for the treatment of community-acquired pneumonia and other respiratory tract infections in Japan. Lascufloxacin shows in vitro activity against various respiratory

Figure 1. Voreloxin.

Figure 2. Moxifloxacin.

The objective of this study is to evaluate "in silico" antitumoral and antimycobacterial activities of some quinolone derivatives by using CLC Drug Discovery Workbench Software [13]. Docking studies were conducted for all ligands, and the docking scores were compared with the scores of standard drugs, topotecan and

2.1 Structure and the synthesis pathway of the quinolone derivatives

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound

DOI: http://dx.doi.org/10.5772/intechopen.85970

antimicrobial activity [1, 2]. The results have revealed that the compounds

In previous papers, we presented the synthesis of quinolone derivatives with

represented in Figure 6 have showed weak antibacterial activities against the tested strains. For this reason, we have initiated in silico drug design and molecular docking studies to predict anticancer and antitubercular activities targeting DNAtopoisomerase I and topoisomerase IV from Klebsiella pneumoniae, respectively. We have performed molecular docking studies to see how the nature of substituents on the quinolone ring influences the anticancer and antitubercular activities targeting human DNA topoisomerase I and topoisomerase IV from Klebsiella pneumoniae, respectively. The studies have been realized with CLC Drug Discovery Workbench Software [13] in order to achieve accurate predictions on optimized conformations for both the quinolones (as ligands) and their target receptor pro-

The quinolone compounds have been synthesized by Gould-Jacobs cyclization process (Figure 7). Appropriate unsubstituted aniline (1) is reacted with diethyl

levofloxacin.

Figure 5.

Zabofloxacin D-aspartate.

Figure 4.

Nemonoxacin (Taigexyn).

2. Materials and methods

teins to form stable complexes.

21

#### Figure 3. Lascufloxacin.

pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, and Mycoplasma pneumoniae.

Quinolones, considered to be "privileged building blocks," are obtained through simple and flexible synthesis methods and allow design and development of large libraries of bioactive molecules. A 2011 study on 21 antibiotics launched since 2000 has highlighted that the discovery and development of new antibiotics obtained through chemical synthesis is still topical. Of the nine antibiotics obtained by chemical synthesis, launched between 2000 and 2011, eight antibiotics belong to the class of fluoroquinolones [11]. New drugs introduced into medical therapies each year are privileged structures for specific biological targets. These new chemical entities provide a perspective on molecular recognition, serving as a basis for designing future new drugs. In 2016, 19 chemically synthesized drugs were approved [12], with the two drugs having the quinolone structure: nemonoxacin (Figure 4) and zabofloxacin (Figure 5).

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound DOI: http://dx.doi.org/10.5772/intechopen.85970

Figure 4. Nemonoxacin (Taigexyn).

The objective of this study is to evaluate "in silico" antitumoral and antimycobacterial activities of some quinolone derivatives by using CLC Drug Discovery Workbench Software [13]. Docking studies were conducted for all ligands, and the docking scores were compared with the scores of standard drugs, topotecan and levofloxacin.
