Cargando…

Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase

In the current study, a novel compound, bis(3-(2H-benzo[d][1,2,3]triazol-2-yl)-2-(prop-2-yn-1-yloxy)-5-(2,4,4-trimethylpentan-2-yl)phenyl)methane (TAJ1), has been synthesized by the reaction of 6,6′-methylenebis(2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-(2,4,4-trimethylpentan-2-yl)phenol) (1), propargyl...

Descripción completa

Detalles Bibliográficos
Autores principales: Qadri, Tahir, Aziz, Mubashir, Channar, Pervaiz Ali, Ejaz, Syeda Abida, Hussain, Mumtaz, Attaullah, Hafiz Muhammad, Ujan, Rabail, Hussain, Zahid, Zehra, Tasneem, Saeed, Aamer, Shah, M. R., Ogaly, Hanan A., Al-Zahrani, Fatimah A. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655664/
https://www.ncbi.nlm.nih.gov/pubmed/38020022
http://dx.doi.org/10.1039/d3ra06149c
_version_ 1785147972356407296
author Qadri, Tahir
Aziz, Mubashir
Channar, Pervaiz Ali
Ejaz, Syeda Abida
Hussain, Mumtaz
Attaullah, Hafiz Muhammad
Ujan, Rabail
Hussain, Zahid
Zehra, Tasneem
Saeed, Aamer
Shah, M. R.
Ogaly, Hanan A.
Al-Zahrani, Fatimah A. M.
author_facet Qadri, Tahir
Aziz, Mubashir
Channar, Pervaiz Ali
Ejaz, Syeda Abida
Hussain, Mumtaz
Attaullah, Hafiz Muhammad
Ujan, Rabail
Hussain, Zahid
Zehra, Tasneem
Saeed, Aamer
Shah, M. R.
Ogaly, Hanan A.
Al-Zahrani, Fatimah A. M.
author_sort Qadri, Tahir
collection PubMed
description In the current study, a novel compound, bis(3-(2H-benzo[d][1,2,3]triazol-2-yl)-2-(prop-2-yn-1-yloxy)-5-(2,4,4-trimethylpentan-2-yl)phenyl)methane (TAJ1), has been synthesized by the reaction of 6,6′-methylenebis(2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-(2,4,4-trimethylpentan-2-yl)phenol) (1), propargyl bromide (2) and potassium carbonate. Spectroscopic (FTIR, (1)H-NMR, (13)C-NMR) and single-crystal assays proved the structure of the synthesized sample. XRD analysis confirmed the structure of the synthesized compound, showing that it possesses two aromatic parts linked via a –CH(2) carbon with a bond angle of 108.40°. The cell line activity reported a percent growth reduction for different cell types (HeLa cells, MCF-7 cells, and Vero cells) under various treatment conditions (TAJ1, cisplatin, and doxorubicin) after 24 hours and 48 hours. The percent growth reduction represents a decrease in cell growth compared to a control condition. Furthermore, density functional theory (DFT) calculations were utilized to examine the frontier molecular orbitals (FMOs) and overall chemical reactivity descriptors of TAJ1. The molecule's chemical reactivity and stability were assessed by determining the HOMO–LUMO energy gap. TAJ1 displayed a HOMO energy level of −0.224 eV, a LUMO energy level of −0.065 eV, and a HOMO–LUMO gap of 0.159 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of TAJ1 with various proteins. The compound TAJ1 showed potent interactions with NEK2, exhibiting −10.5 kcal mol(−1) binding energy. Although TAJ1 has demonstrated interactions with NEK7, NEK9, TP53, NF-KAPPA-B, and caspase-3 proteins, suggesting its potential as a therapeutic agent, it is important to evaluate the conformational stability of the protein–ligand complex. Hence, molecular dynamics simulations were conducted to assess this stability. To analyze the complex, root mean square deviation (RMSD) and root mean square fluctuation analyses were performed. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective NEK2 inhibitors. Therefore, further investigation of the inhibitory potential of these identified compounds using in vitro and in vivo approaches is recommended.
format Online
Article
Text
id pubmed-10655664
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher The Royal Society of Chemistry
record_format MEDLINE/PubMed
spelling pubmed-106556642023-11-17 Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase Qadri, Tahir Aziz, Mubashir Channar, Pervaiz Ali Ejaz, Syeda Abida Hussain, Mumtaz Attaullah, Hafiz Muhammad Ujan, Rabail Hussain, Zahid Zehra, Tasneem Saeed, Aamer Shah, M. R. Ogaly, Hanan A. Al-Zahrani, Fatimah A. M. RSC Adv Chemistry In the current study, a novel compound, bis(3-(2H-benzo[d][1,2,3]triazol-2-yl)-2-(prop-2-yn-1-yloxy)-5-(2,4,4-trimethylpentan-2-yl)phenyl)methane (TAJ1), has been synthesized by the reaction of 6,6′-methylenebis(2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-(2,4,4-trimethylpentan-2-yl)phenol) (1), propargyl bromide (2) and potassium carbonate. Spectroscopic (FTIR, (1)H-NMR, (13)C-NMR) and single-crystal assays proved the structure of the synthesized sample. XRD analysis confirmed the structure of the synthesized compound, showing that it possesses two aromatic parts linked via a –CH(2) carbon with a bond angle of 108.40°. The cell line activity reported a percent growth reduction for different cell types (HeLa cells, MCF-7 cells, and Vero cells) under various treatment conditions (TAJ1, cisplatin, and doxorubicin) after 24 hours and 48 hours. The percent growth reduction represents a decrease in cell growth compared to a control condition. Furthermore, density functional theory (DFT) calculations were utilized to examine the frontier molecular orbitals (FMOs) and overall chemical reactivity descriptors of TAJ1. The molecule's chemical reactivity and stability were assessed by determining the HOMO–LUMO energy gap. TAJ1 displayed a HOMO energy level of −0.224 eV, a LUMO energy level of −0.065 eV, and a HOMO–LUMO gap of 0.159 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of TAJ1 with various proteins. The compound TAJ1 showed potent interactions with NEK2, exhibiting −10.5 kcal mol(−1) binding energy. Although TAJ1 has demonstrated interactions with NEK7, NEK9, TP53, NF-KAPPA-B, and caspase-3 proteins, suggesting its potential as a therapeutic agent, it is important to evaluate the conformational stability of the protein–ligand complex. Hence, molecular dynamics simulations were conducted to assess this stability. To analyze the complex, root mean square deviation (RMSD) and root mean square fluctuation analyses were performed. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective NEK2 inhibitors. Therefore, further investigation of the inhibitory potential of these identified compounds using in vitro and in vivo approaches is recommended. The Royal Society of Chemistry 2023-11-17 /pmc/articles/PMC10655664/ /pubmed/38020022 http://dx.doi.org/10.1039/d3ra06149c Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Qadri, Tahir
Aziz, Mubashir
Channar, Pervaiz Ali
Ejaz, Syeda Abida
Hussain, Mumtaz
Attaullah, Hafiz Muhammad
Ujan, Rabail
Hussain, Zahid
Zehra, Tasneem
Saeed, Aamer
Shah, M. R.
Ogaly, Hanan A.
Al-Zahrani, Fatimah A. M.
Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase
title Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase
title_full Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase
title_fullStr Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase
title_full_unstemmed Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase
title_short Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase
title_sort synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of nima related kinase
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655664/
https://www.ncbi.nlm.nih.gov/pubmed/38020022
http://dx.doi.org/10.1039/d3ra06149c
work_keys_str_mv AT qadritahir synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT azizmubashir synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT channarpervaizali synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT ejazsyedaabida synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT hussainmumtaz synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT attaullahhafizmuhammad synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT ujanrabail synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT hussainzahid synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT zehratasneem synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT saeedaamer synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT shahmr synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT ogalyhanana synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase
AT alzahranifatimaham synthesisbiologicalevaluationandinsilicoinvestigationsofbenzotriazolederivativesaspotentialinhibitorsofnimarelatedkinase