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Synthesis, Antiphospholipase A?, Antiprotease, Antibacterial Evaluation and Molecular Docking Analysis of Certain Novel Hydrazones.

ABSTRACT: Some novel hydrazone derivatives 6a-o were synthesized from the key intermediate 4-Chloro-N-(2-hydrazinocarbonyl-phenyl)-benzamide 5 and characterized using IR, ¹H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. The inhibitory potential against two secretory phospholipase A? (sPLA?), three protease enzymes and eleven bacterial strains were evaluated. The results revealed that all compounds showed preferential inhibition towards hGIIA isoform of sPLA? rather than DrG-IB with compounds 6l and 6e being the most active. The tested compounds exhibited excellent antiprotease activity against proteinase K and protease from Bacillus sp. with compound 6l being the most active against both enzymes. Furthermore, the maximum zones of inhibition against bacterial growth were exhibited by compounds; 6a, 6m, and 6o against P. aeruginosa; 6a, 6b, 6d, 6f, 6l, 6m, 6n, and 6o against Serratia; 6k against S. mutans; and compounds 6a, 6d, 6e, 6m, and 6n against E. feacalis. The docking simulations of hydrazones 6a-o with GIIA sPLA?, proteinase K and hydrazones 6a-e with glutamine-fructose-6-phosphate transaminase were performed to obtain information regarding the mechanism of action.

SUBMITTER: El-Sayed NN

PROVIDER: S-EPMC6272960 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundQuinolines 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.Methods2-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.ResultsNine 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.ConclusionCompounds 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.

Project description:Emergence of antimicrobial resistance to standard commercial drugs has become a critical public health concern worldwide. Hence, novel antimicrobials with improved biological activities are urgently needed. In this regard, a series of quinoline-stilbene derivatives were synthesized from substituted quinoline and benzyltriphenylphosphonium chloride using Wittig reaction. Furthermore, a novel pinacol of quinoline was synthesized by pinacolinazation of 2-methoxyquinoline-3-carbaldehyde which was achieved by aluminum powder-potassium hydroxide reagent combination at ambient temperature in methanol. The structures of the synthesized compounds were established based on their spectral data. The antibacterial activities of the synthesized compounds were evaluated in vitro by the paper disc diffusion method against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Salmonella typhimurium). The best activity was displayed by compound 19 against E. coli with an inhibition zone of 16.0 ± 0.82 mm and 14.67 ± 0.94 mm at 500 and 250 μg/mL, respectively. This is close to ciprofloxacin which is used as a positive control. The results of in silico molecular docking evaluation of the compounds against E. coli DNA gyraseB were in good agreement with the in vitro antibacterial analysis. Compounds 19 (-6.9 kcal/mol) and 24 (-7.1 kcal/mol) showed the maximum binding affinity close to ciprofloxacin (-7.3 kcal/mol) used as positive control. Therefore, the antibacterial activity displayed by these compounds is encouraging for further investigation to improve the activities of quinoline-stilbenes by incorporating various bioisosteric groups in one or more positions of the phenyl nuclei for their potential pharmacological use. Findings of the DPPH radical scavenging assay indicated that some of the quinolone stilbenes and pinacol possess moderate antioxidant properties compared to ascorbic acid used as a natural antioxidant.

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Synthesis, Antiphospholipase A?, Antiprotease, Antibacterial Evaluation and Molecular Docking Analysis of Certain Novel Hydrazones.

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