Novel ciprofloxacin and norfloxacin-tetrazole hybrids as potential antibacterial and antiviral agents: Targeting S. aureus topoisomerase and SARS-CoV-2-MPro

Abstract

This study was designed to synthesize hybridizing molecules from ciprofloxacin and norfloxacin by enhancing their biological activity with tetrazoles. The synthesized compounds were investigated in the interaction with the target enzyme of fluoroquinolones (DNA gyrase) and COVID-19 main protease using molecular similarity, molecular docking, and QSAR studies. A QSAR study was carried out to explore the antibacterial activity of our compounds over Staphylococcus aureus a QSAR study, using descriptors obtained from the docking with DNA gyrase, in combination with steric type descriptors, was done obtaining suitable statistical parameters ( $R^2=87.00$ , $Q_{LMO}^2=71.67$ , and $Q_{EXT}^2=73.49$ ) to support our results. The binding interaction of our compounds with CoV-2-Mpro was done by molecular docking and were compared with different covalent and non-covalent inhibitors of this enzyme. For the docking studies we used several crystallographic structures of the CoV-2-Mpro. The interaction energy values and binding mode with several key residues, by our compounds, support the capability of them to be CoV-2-Mpro inhibitors. The characterization of the compounds was completed using FT-IR, ¹H-NMR, ¹³C-NMR, ¹⁹F-NMR and HRMS spectroscopic methods. The results showed that compounds 1, 4, 5, 10 and 12 had the potential to be further studied as new antibacterial and antiviral compounds.

Keywords: Covid-19 Main protease; DNA gyrase; Hybrid tetrazole-fluoroquinolone; Molecular docking; Multicomponent reaction; QSAR.

Graphical abstract

Fig. 1

Molecular structures of the synthesized quinolones.

Fig. 2

Commercial bactericidal fluoroquinolone drugs were used as references in this study.

Fig. 3

2D representation of the quinolone-tetrazole derivatives synthesized by K. Chauhan et al. .

Fig. 4

3D structure representation of the complex formed by the fluoroquinolone-DNA-gyrase. 2D schematic representations of compounds 1, 4, 7, 10 and 12, displaying the most relevant interactions. Dotted lines = hydrogen bonds; dashed pink = π–π interactions; grey dotted bonds = hydrophobic interactions.

Fig. 5

3D structure representation of the complex formed by the fluoroquinolone-DNA-gyrase. 2D schematic representation of 5, 6 and 9, displaying the most relevant interactions. Dotted lines = hydrogen bonds; pink dashed = π–π interactions.

Fig. 6

3D structure representation of the complex formed by the fluoroquinolone-DNA-gyrase of compounds 13 to 19. Only the (R) isomers of the fluoroquinolones are displayed, with the nitrogen of tetrazole in light green and the carboxylate oxygens in red.

Fig. 7

Template structure of quinolone derivatives. An equation to obtain $\Delta V$. $V_{\mathrm{x}}$ and $V_0$ state for the molecular volume of compound X+ and the molecular volume of the scaffold structure, respectively.

Fig. 8

Linear correlation of Y_predvs Y of four experiments. Blue colored points represent the molecules of the training set and yellow-colored points represent the external set. The R², $R_{adj}^2$, $Q_{LMO}^2$, and $Q_{EXT}^2$ values are indicated.

Fig. 9

Structural alignment of CoV-2-MPro crystals: 6lu7 (yellow), 6m2n (blue), 6w63 (cyan) and 7l0d (grey). Leu27, His41, Met49, Cys145, His164, Met165, Arg188, Gln189 and Gln 192 are shown in stick representation.

Fig. 10

Non-covalent interactions of different inhibitors with CoV-2-Mpro. A) 6lu7, b) 7l0d, c) 6m2n, and d) 6w63. Surface plots of amino acid lipophilicity, the Kyte-Doolittle scale.

Fig. 11

Molecular docking and non-covalent interactions of CFX and NFX with different crystal structures of CoV-2-Mpro. a) 6lu7, b) 7l0d, c) 6m2n, and d) 6w63. Surface plots of amino acid lipophilicity on the Kyte-Doolittle scale.

Fig. 12

Molecular docking and non-covalent interactions of 8 with different crystal structures of CoV-2-Mpro. A) 6lu7, b) 7l0d, c) 6m2n, and d) 6w63. Hydrogen bond interactions are shown as cyan dashed lines. Surface plots of amino acid lipophilicity, the Kyte-Doolittle scale.

Fig. 13

Molecular docking and non-covalent interactions of 5 with different crystal structures of CoV-2-Mpro. A) 6lu7, b) 7l0d, c) 6m2n, and d) 6w63. Hydrogen bond interactions are shown as cyan dashed lines. Surface plots of amino acid lipophilicity, the Kyte-Doolittle scale.

Fig. 14

Molecules are used as inhibitors of CoV-2-Mpro , , , , , . Similar molecular fragments are highlighted in red color.

Fig. 15

General procedure for synthesis of fluoroquinolone-tetrazole hybrids.