Cargando…

Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit

Nitrogen-containing heterocycles have shown pharmacological properties against various diseases. Herein, in our study, flavoHB enzyme is a highly promising well-validated target for identification of antibacterial inhibitors using in silico and in vitro techniques. To identify a new class of antimic...

Descripción completa

Detalles Bibliográficos
Autores principales: Hussein, Abdel Haleem M., El-Adasy, Abu-Bakr A., El-Saghier, Ahmed M., Olish, M., Abdelmonsef, Aboubakr H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9041306/
https://www.ncbi.nlm.nih.gov/pubmed/35496342
http://dx.doi.org/10.1039/d2ra01794f
_version_ 1784694518210101248
author Hussein, Abdel Haleem M.
El-Adasy, Abu-Bakr A.
El-Saghier, Ahmed M.
Olish, M.
Abdelmonsef, Aboubakr H.
author_facet Hussein, Abdel Haleem M.
El-Adasy, Abu-Bakr A.
El-Saghier, Ahmed M.
Olish, M.
Abdelmonsef, Aboubakr H.
author_sort Hussein, Abdel Haleem M.
collection PubMed
description Nitrogen-containing heterocycles have shown pharmacological properties against various diseases. Herein, in our study, flavoHB enzyme is a highly promising well-validated target for identification of antibacterial inhibitors using in silico and in vitro techniques. To identify a new class of antimicrobial agents, N-(4-hydroxyphenyl)-3-oxobutanamide was utilized as a precursor in the synthesis of several nitrogen-based heterocycles (pyridine, pyrimidine, and pyrazole) attached to p-phenolic substrates 2–8. Treatment of 3-oxobutanimide 1 with malononitrile and/or ethyl cyanoacetate in ethanolic piperidine afforded the pyridinone analogues 2a,b. On the other hand, treatment of 1 with arylidene cyanothioacetamide furnished the pyridinthione derivative 3. The reaction of starting material 1 with salicylaldehyde and/or dimethyl formamide dimethyl acetal (DMF-DMA) yielded the pyridinones 4 and 5, respectively. Reaction of 1 with terephthalaldehyde and urea or thiourea gave bis structures 6a,b. The reaction of compound 1 with ethyl isothiocyanate and hydrazine hydrate afforded pyrimidine and pyrazole derivatives 7 and 8, respectively. The structures of newly prepared compounds 2–8 were elucidated using elemental data and spectral analyses such as IR, (1)H NMR, (13)C NMR, and MS. In addition, an in-house nitrogen-containing heterocycle analogues library 2–8 was examined and screened in vitro for their antibacterial effects against Gram-negative bacteria, Escherichia coli and Gram-positive bacteria, Staphylococcus haemolyticus, Kocuria kristinae, Enterococcus casseliflavus, and Bacillus cereus. Compounds 6a and 6b have also shown the highest antibacterial activity against all types of bacteria strains tested except Kocuria kristinae. Further, the molecular docking study of the newly prepared compounds with the target enzyme flavohemoglobin (flavoHB) was undertaken to explore their potential inhibitory activities. The results of the docking study indicated that compounds 6a and 6b have exerted the highest docking scores against the active site of flavoHB. As a result, the in vitro and molecular docking study findings suggested that the compounds 6a and 6b (with pyrimidine moiety, amide linkage, and phenolic substrate) might be potent bacterial flavohemoglobin (flavoHB) inhibitors and they could set a promising starting point for future design of antibacterial agents.
format Online
Article
Text
id pubmed-9041306
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher The Royal Society of Chemistry
record_format MEDLINE/PubMed
spelling pubmed-90413062022-04-28 Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit Hussein, Abdel Haleem M. El-Adasy, Abu-Bakr A. El-Saghier, Ahmed M. Olish, M. Abdelmonsef, Aboubakr H. RSC Adv Chemistry Nitrogen-containing heterocycles have shown pharmacological properties against various diseases. Herein, in our study, flavoHB enzyme is a highly promising well-validated target for identification of antibacterial inhibitors using in silico and in vitro techniques. To identify a new class of antimicrobial agents, N-(4-hydroxyphenyl)-3-oxobutanamide was utilized as a precursor in the synthesis of several nitrogen-based heterocycles (pyridine, pyrimidine, and pyrazole) attached to p-phenolic substrates 2–8. Treatment of 3-oxobutanimide 1 with malononitrile and/or ethyl cyanoacetate in ethanolic piperidine afforded the pyridinone analogues 2a,b. On the other hand, treatment of 1 with arylidene cyanothioacetamide furnished the pyridinthione derivative 3. The reaction of starting material 1 with salicylaldehyde and/or dimethyl formamide dimethyl acetal (DMF-DMA) yielded the pyridinones 4 and 5, respectively. Reaction of 1 with terephthalaldehyde and urea or thiourea gave bis structures 6a,b. The reaction of compound 1 with ethyl isothiocyanate and hydrazine hydrate afforded pyrimidine and pyrazole derivatives 7 and 8, respectively. The structures of newly prepared compounds 2–8 were elucidated using elemental data and spectral analyses such as IR, (1)H NMR, (13)C NMR, and MS. In addition, an in-house nitrogen-containing heterocycle analogues library 2–8 was examined and screened in vitro for their antibacterial effects against Gram-negative bacteria, Escherichia coli and Gram-positive bacteria, Staphylococcus haemolyticus, Kocuria kristinae, Enterococcus casseliflavus, and Bacillus cereus. Compounds 6a and 6b have also shown the highest antibacterial activity against all types of bacteria strains tested except Kocuria kristinae. Further, the molecular docking study of the newly prepared compounds with the target enzyme flavohemoglobin (flavoHB) was undertaken to explore their potential inhibitory activities. The results of the docking study indicated that compounds 6a and 6b have exerted the highest docking scores against the active site of flavoHB. As a result, the in vitro and molecular docking study findings suggested that the compounds 6a and 6b (with pyrimidine moiety, amide linkage, and phenolic substrate) might be potent bacterial flavohemoglobin (flavoHB) inhibitors and they could set a promising starting point for future design of antibacterial agents. The Royal Society of Chemistry 2022-04-26 /pmc/articles/PMC9041306/ /pubmed/35496342 http://dx.doi.org/10.1039/d2ra01794f Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Hussein, Abdel Haleem M.
El-Adasy, Abu-Bakr A.
El-Saghier, Ahmed M.
Olish, M.
Abdelmonsef, Aboubakr H.
Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit
title Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit
title_full Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit
title_fullStr Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit
title_full_unstemmed Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit
title_short Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit
title_sort synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9041306/
https://www.ncbi.nlm.nih.gov/pubmed/35496342
http://dx.doi.org/10.1039/d2ra01794f
work_keys_str_mv AT husseinabdelhaleemm synthesischaracterizationinsilicomoleculardockingandantibacterialactivitiesofsomenewnitrogenheterocyclicanaloguesbasedonapphenolicunit
AT eladasyabubakra synthesischaracterizationinsilicomoleculardockingandantibacterialactivitiesofsomenewnitrogenheterocyclicanaloguesbasedonapphenolicunit
AT elsaghierahmedm synthesischaracterizationinsilicomoleculardockingandantibacterialactivitiesofsomenewnitrogenheterocyclicanaloguesbasedonapphenolicunit
AT olishm synthesischaracterizationinsilicomoleculardockingandantibacterialactivitiesofsomenewnitrogenheterocyclicanaloguesbasedonapphenolicunit
AT abdelmonsefaboubakrh synthesischaracterizationinsilicomoleculardockingandantibacterialactivitiesofsomenewnitrogenheterocyclicanaloguesbasedonapphenolicunit