مقالات پذیرفته شده در هفتمین کنگره بین المللی زیست پزشکی
Synthesis, Antimicrobial activity and Molecular Docking study of Novel 4-anilinoquinazoline derivatives.
Synthesis, Antimicrobial activity and Molecular Docking study of Novel 4-anilinoquinazoline derivatives.
Rezvan Rezaeinasab,1,*
1. Department of Medicinal Chemistry, Faculty of Pharmacy, Lorestan University of Medical Sciences, Khorramabad, Iran.
Introduction: Nowadays, antibacterial resistance is recognized as a significant threat to health worldwide. Therefore, the search for new antibacterial drug compounds is an attractive goal for medicinal chemists . Quinazoline heterocycles are functional bioactive scaffolds in medicinal chemistry. The simple and condensed quinazoline derivatives possess diverse pharmacological activities, including anticancer , antihistaminic , antinociceptive , antithrombotic , anticonvulsant , and anti-inflammatory . Quinazolines are well known to play a significant role as inhibitors. An example is the 4-anilinoquinazoline used as an epidermal growth factor receptor (EGFR)inhibitor. Gefitinib (ZD-1839, Iressa) and erlotinib (OSI-774, Tarceva) are used as dual EGFR- human epidermal growth factor receptor 2 (HER2) inhibitors, which are used in the clinic(scheme1) . Among various pharmacological activities, quinazoline derivatives have significant antimicrobial properties. DNA gyrase is one of the interesting targets in Escherichia coli that catalyze changes in the topology of DNA and induces the formation of negative supercoils . Due to its vital role in the survival of bacterial cells and the lack of its existence in higher eukaryotes, bacterial DNA gyrase has been used as an antibacterial target. Molecular docking is used to predict the interactions between a ligand and a receptor molecule to predict ligand conformation and orientation within a targeted binding site . In the present work, we have synthesized some new derivatives of N,2-diphenylquinazolin-4-amine containing phenyl group at position 2, and various aniline derivatives at the 4th position of the quinazoline ring (Scheme 2). In addition, the antimicrobial activities of all synthesized N,2-diphenylquinazolin-4-amine derivatives were evaluated against both Gram-positive and Gram-negative bacteria as well as fungal strains. Among the compounds tested, some of N,2-diphenylquinazolin-4-amine were found to be superior in inhibiting the growth of all the bacterial and fungal strains. The synthesized derivatives were docked into the binding pocket of DNA gyrase protein, and their binding energies were calculated.
Methods: The designed compounds were prepared through the nucleophilic substitution reaction of substituted anilines with 4-chloro-2-phenylquinazoline (1) and characterized by spectroscopic methods.
The antimicrobial effect of the synthesized compounds against E. coli, P. aeruginosa, S. aureus, B. subtilis, L. rhamnosus, and C. albicans was assessed by the microdilution method.
Docking experiments were performed using AutoDock 4.2. Software.
Results: The designed compounds were synthesized through the SNAr reaction of substituted anilines with 4-chloro-2-phenylquinazoline (1) as presented in Scheme 2. The reaction was done by the nucleophilic attack of NH2 to the fourth position of the quinazoline ring to displace the chlorine moiety.
To explore the binding modes of the newly synthesized N,2-diphenylquinazolin-4-amine derivatives (3a-g) with the active site of E. coli DNA gyrase, a molecular docking simulation was accomplished using AutoDock 4.2. software. Firstly, chlorobiocin (the original co-crystallized ligand) was re-docked in the active site of E. coli DNA gyrase B kinase (PDB code: 1KZN) , which revealed a score energy of -6.48 kcal/mol (Table 1 and Figure 1). As shown in Fig. 1-5 and Table1, some compounds (3a, 3d, 3e, and 3f) can create a strong hydrogen bond with Asn46, Asp73, and Thr165 at a distance of 3.91 Å - 6.31 Å, which is consistent with the decomposition analysis of the electrostatic interaction.
In the biological assay, the activity of the target compounds against the Gram-positive strains was more potent than their activity against the Gram-negative strains. In turn, N-(3-chlorophenyl)-2-phenylquinazolin-4-amine 3e showed potent activity against S. aureus (MIC = 0.0039 mg/mL), equal to that of the reference drug. The 1-phenyl-2-(2-phenylquinazolin-4-yl) hydrazine 3g also revealed potent activity against P. aeruginosa at 0.0625 mg/mL concentration. It seems that lipophilicity could improve the antibacterial activity of the newly synthesized N,2-diphenylquinazolin-4-amine derivatives (3a-g).
Conclusion: In this study, synthesis, molecular docking, and evaluation of the antimicrobial activity of seven novel N,2-diphenylquinazolin-4-amine derivatives were reported. All compounds showed moderate to good antibacterial activity, while remarkable antifungal activities were observed for these compounds. Computational studies were performed by automated docking of ligands to the binding sites of DNA gyrase. The results revealed that compound 3c showed minimum binding energy (-6.13 kJ/mol) and so, indicated a strong binding affinity towards DNA gyrase.