Synthesis, in silico molecular docking analysis, pharmacokinetic properties and evaluation of antibacterial and antioxidant activities of fluoroquinolines

Abstract

Background Quinolines have demonstrated various biological activities such as antimalarial, antibacterial and anticancer. Hence, compounds with such scaffold have been used as lead in drug development. This project is, therefore, aimed to synthesis and evaluates some biological activities of quinoline analogs. Methods 2-Chloro-7-fluoroquinoline-3-carbaldehydes were synthesized by the application of Vilsmeier–Haack reaction. The chlorine in the fluoroquinoline-3-carbaldehyde was replaced with various nucleophiles. The aldehyde functional group was also converted to carboxylic acid and imine groups using oxidizing agent and various amines, respectively. The structures of the compounds synthesized were characterized by spectroscopic methods. Disc diffusion and DPPH assays were used to evaluate the antibacterial and antioxidant activities, respectively. The in silico molecular docking analysis of the synthesized compounds were done using AutoDock Vina against E. coli DNA Gyrase B and human topoisomerase IIα. The drug likeness properties were assessed using SwissADME and PreADMET. Results Nine novel quinoline derivatives were synthesized in good yields. The in vitro antibacterial activity of the synthesized compounds was beyond 9.3 mm inhibition zone (IZ). Compounds 4, 5, 6, 7, 8, 10, 15, and 16 exhibited activity against E. coli, P. aeruginosa, S. aureus and S. pyogenes with IZ ranging from 7.3 ± 0.67 to 15.3 ± 0.33 mm at 200 μg/mL. Compound 9 displayed IZ against three of the bacterial strains except S. aureus. The IC50 for the radical scavenging activity of the synthesized compounds were from 5.31 to 16.71 μg/mL. The binding affinities of the synthesized compounds were from − 6.1 to − 7.2 kcal/mol against E. coli DNA gyrase B and − 6.8 to − 7.4 kcal/mol against human topoisomerase IIα. All of the synthesized compounds obeyed Lipinski’s rule of five without violation. Conclusion Compounds 4, 5, 6, 7, 8, 10, 15, and 16 displayed activity against Gram positive and Gram negative bacterial strains indicating that these compounds might be used as broad spectrum bactericidal activity. Compound 8 (13.6 ± 0.22 mm) showed better IZ against P. aeruginosa compared with ciprofloxacin (10.0 ± 0.45 mm) demonstrating the potential of this compound as antibacterial agent against this strain. Compounds 5, 6, 7, 8, 9 and 10 showed comparable binding affinities in their in silico molecular docking analysis against E. coli DNA gyrase B. All of the synthesized compounds also obeyed Lipinski’s rule of five without violation which suggests these compounds as antibacterial agents for further study. Compounds 7 and 8 were proved to be a very potent radical scavenger with IC50 values of 5.31 and 5.41 μg/mL, respectively. Compound 5, 6, 8, 10 and 16 had comparable binding affinity against human topoisomerase IIα suggesting these compounds as a possible candidate for anticancer drugs.

Synthesis, Characterization, Biological Properties, ADMET and Drug-likeness Analysis of Mn (II) complexes with Schiff Bases Derived from Sulphathiazole and 4-diethylaminosalicyaldehyde/Salicyaldehyde

“…Only L 2 and MnL2 can have AMES Toxicity. All other results of the toxicity predictions (Table 9) showed that these compounds are less toxic [37].…”

“…Interaction of molecules with cytochrome P450 (CYP) enzymes is essential because these isoenzymes may result in unwanted adverse side effects by lowering the solubility and the accumulation of the drug or its metabolites. Predictions revealed that STZ exhibits non-inhibitor for all the enzymes, L1 inhibits only CPY1A2, CYP2C9, and CYP3A4, L2 inhibits CYP2C19, CYP2C9, CYP2D6, and CYP2D6, MnL1 inhibit only CYP2C9, ciprofloxacin act as non-inhibitor whereas fluconazole inhibits CYP2C19 [37]. Druglikeness is a prediction that determines whether a particular pharmacological agent has properties consistent with being an orally active drug or not, in which this prediction is based on the Lipinski rule of five, Ghose filter, Veber's rule, Egan, Muegge and Bioavailability score.…”

In Silico Identification of New Anti-SARS-CoV-2 Main Protease (Mpro) Molecules with Pharmacokinetic Properties from Natural Sources Using Molecular Dynamics (MD) Simulations and Hierarchical Virtual Screening

“…Geronikaki et al [ 39 ] used SwissADME to examine the drugability of various bioactive compounds in their study. Fekadu et al [ 40 ] also acknowledged the significance of SwissADME as an in silico tool by using it to assess the drug-like properties of different compounds in their study. Even with all the 16 molecules satisfying the requirements of the SwissADME drug-likeness filters, their success as drug candidates against COVID 19 depended on their binding affinities to SARS-CoV-2 M pro as well; hence, they were docked to the viral main protease using Pyrx software.…”

Evaluation of novel compounds as anti-bacterial or anti-virulence agents

“…Molecular docking studies were also carried out to verify and rationalize anti-bacterial properties of some synthesized compounds with promising MIC and MBC values indicating on possible structural modification for achieving better anti-bacterial activity. Some examples include molecular docking studies of synthesized pterostilbene derivatives against DNA polymerase ( Tang et al., 2019 ), fluoroquinolones derivatives against E. coli DNA gyrase B ( Fekadu et al., 2022 ), quinoline derivatives against S. aureus tyrosyl-tRNA synthetase ( Bouzian et al., 2020 ), diclofenac derivatives against DNA gyrase ( Hamed et al., 2023 ).…”