Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents

Various literature sources have documented that sydnones are important bioactive molecules with a wide spectrum of activities involving the anti-proliferative and anti-inflammatory actions. Phenyl styrylketones and their derivatives as members of the chalcone family have also been reported as signif...

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Main Authors:	Nik Yusoff, Nik Mohd. Idris, Ridzwan, Irna Elina, Bakhtiar, Muhammad Taher, Abdualkader, Abdualrahman Mohammed
Format:	Monograph
Language:	English
Published:	2018
Subjects:	RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry
Online Access:	http://irep.iium.edu.my/64122/ http://irep.iium.edu.my/64122/3/64122%20Profile%20Final%20report%20FRGS%20Dr%20Nik.pdf

id	iium-64122
recordtype	eprints
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English
topic	RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry
spellingShingle	RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry Nik Yusoff, Nik Mohd. Idris Ridzwan, Irna Elina Bakhtiar, Muhammad Taher Abdualkader, Abdualrahman Mohammed Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents
description	Various literature sources have documented that sydnones are important bioactive molecules with a wide spectrum of activities involving the anti-proliferative and anti-inflammatory actions. Phenyl styrylketones and their derivatives as members of the chalcone family have also been reported as significant biological agents. The current study was initiated to evaluate in vitro cytotoxic and anti-inflammatory activity of sydnone-based compounds including some novel sydnone-styrylketone hybrids. The classical cyclodehydration of N-nitroso amino acids was applied in the preparation of the sydnone ring. Aldol condensation was utilized to join two sydnone rings by a styrylketone linker. Compounds identity was confirmed using FTIR, NMR and MS spectroscopy. MTT assay was used to evaluate the cytotoxicity of the synthesized compound. ELISA test was performed to investigate the COX-1/COX-2 inhibitory activity. The binding of sydnones with COX enzymes was examined by Glide docking and the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA). The drug-likeness scores and membrane permeability of the compounds were also in silico predicted. Twenty-five sydnone-containing compounds were synthesized. Compounds 46-48 and 56-58 were reported as new sydnone derivatives. Compounds 61-63 were synthesized as novel structures containing two sydnone rings linked via α,β-unsaturated ketone. The structure of the synthesized compounds was confirmed by FTIR, 1H NMR, 13C NMR and ToF-MS analyses. All compounds exhibited low cytotoxicity especially against normal cell lines (IC50 in the range of mM). Only compound 45 had a significant antiproliferative activity against prostate (IC50 = 42 μM) and breast (IC50 = 63 μM) cancer cell lines. The in vitro COX inhibition assay showed varied activity. Compounds 47, 51, 58 and 63 showed the most potent COX inhibitory effect at a concentration of 200 μM. Selectivity index showed that only compound 63 was a selective COX-2 inhibitor. Acetylation of the sydnone ring at C4 was detrimental to the cytotoxic activity while prolific for the anti-inflammatory effects (COX inhibition). Docking analysis showed that COX-2 selectivity was due to a favorable positive charged interaction between the sydnone ring of 63 and Arg513 in the catalytic region of COX-2. Compound 51 was hydrogen bonded to the guanidinium group of Arg513. The low inhibitory effect of 63 against COX-1 was due to an unfavorable polar interaction with His513 in the binding pocket of COX-1. Drug-likeness prediction disclosed that the compounds comply with Lipinski’s rule and CMC-like rule. Similarity search delineated that sydnone-styrylketone hybrids had common structural features with known anti-inflammatory agents. Prediction of permeability through the physiological membrane revealed a good pharmacokinetic profile with intestinal absorption more than 80% and a potential BBB penetration. In conclusion, the compounds were successfully synthesized and characterized. However, only two compounds 59 and 60 were not successfully prepared. The structure of 3-(4-chloro-3-nitrophenyl)sydnone 45 could be a lead molecule in designing potent chemotherapeutic agents. Compound 63 shared architecture and pharmacophoric characters with known selective COX-2 inhibitors (coxib family) making it a good candidate for designing selective and safe NSAID.
format	Monograph
author	Nik Yusoff, Nik Mohd. Idris Ridzwan, Irna Elina Bakhtiar, Muhammad Taher Abdualkader, Abdualrahman Mohammed
author_facet	Nik Yusoff, Nik Mohd. Idris Ridzwan, Irna Elina Bakhtiar, Muhammad Taher Abdualkader, Abdualrahman Mohammed
author_sort	Nik Yusoff, Nik Mohd. Idris
title	Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents
title_short	Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents
title_full	Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents
title_fullStr	Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents
title_full_unstemmed	Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents
title_sort	synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents
publishDate	2018
url	http://irep.iium.edu.my/64122/ http://irep.iium.edu.my/64122/3/64122%20Profile%20Final%20report%20FRGS%20Dr%20Nik.pdf
first_indexed	2023-09-18T21:30:56Z
last_indexed	2023-09-18T21:30:56Z
_version_	1777412505759383552
spelling	iium-641222018-12-13T04:44:01Z http://irep.iium.edu.my/64122/ Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents Nik Yusoff, Nik Mohd. Idris Ridzwan, Irna Elina Bakhtiar, Muhammad Taher Abdualkader, Abdualrahman Mohammed RS Pharmacy and materia medica RS403 Materia Medica-Pharmaceutical Chemistry Various literature sources have documented that sydnones are important bioactive molecules with a wide spectrum of activities involving the anti-proliferative and anti-inflammatory actions. Phenyl styrylketones and their derivatives as members of the chalcone family have also been reported as significant biological agents. The current study was initiated to evaluate in vitro cytotoxic and anti-inflammatory activity of sydnone-based compounds including some novel sydnone-styrylketone hybrids. The classical cyclodehydration of N-nitroso amino acids was applied in the preparation of the sydnone ring. Aldol condensation was utilized to join two sydnone rings by a styrylketone linker. Compounds identity was confirmed using FTIR, NMR and MS spectroscopy. MTT assay was used to evaluate the cytotoxicity of the synthesized compound. ELISA test was performed to investigate the COX-1/COX-2 inhibitory activity. The binding of sydnones with COX enzymes was examined by Glide docking and the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA). The drug-likeness scores and membrane permeability of the compounds were also in silico predicted. Twenty-five sydnone-containing compounds were synthesized. Compounds 46-48 and 56-58 were reported as new sydnone derivatives. Compounds 61-63 were synthesized as novel structures containing two sydnone rings linked via α,β-unsaturated ketone. The structure of the synthesized compounds was confirmed by FTIR, 1H NMR, 13C NMR and ToF-MS analyses. All compounds exhibited low cytotoxicity especially against normal cell lines (IC50 in the range of mM). Only compound 45 had a significant antiproliferative activity against prostate (IC50 = 42 μM) and breast (IC50 = 63 μM) cancer cell lines. The in vitro COX inhibition assay showed varied activity. Compounds 47, 51, 58 and 63 showed the most potent COX inhibitory effect at a concentration of 200 μM. Selectivity index showed that only compound 63 was a selective COX-2 inhibitor. Acetylation of the sydnone ring at C4 was detrimental to the cytotoxic activity while prolific for the anti-inflammatory effects (COX inhibition). Docking analysis showed that COX-2 selectivity was due to a favorable positive charged interaction between the sydnone ring of 63 and Arg513 in the catalytic region of COX-2. Compound 51 was hydrogen bonded to the guanidinium group of Arg513. The low inhibitory effect of 63 against COX-1 was due to an unfavorable polar interaction with His513 in the binding pocket of COX-1. Drug-likeness prediction disclosed that the compounds comply with Lipinski’s rule and CMC-like rule. Similarity search delineated that sydnone-styrylketone hybrids had common structural features with known anti-inflammatory agents. Prediction of permeability through the physiological membrane revealed a good pharmacokinetic profile with intestinal absorption more than 80% and a potential BBB penetration. In conclusion, the compounds were successfully synthesized and characterized. However, only two compounds 59 and 60 were not successfully prepared. The structure of 3-(4-chloro-3-nitrophenyl)sydnone 45 could be a lead molecule in designing potent chemotherapeutic agents. Compound 63 shared architecture and pharmacophoric characters with known selective COX-2 inhibitors (coxib family) making it a good candidate for designing selective and safe NSAID. 2018 Monograph NonPeerReviewed application/pdf en http://irep.iium.edu.my/64122/3/64122%20Profile%20Final%20report%20FRGS%20Dr%20Nik.pdf Nik Yusoff, Nik Mohd. Idris and Ridzwan, Irna Elina and Bakhtiar, Muhammad Taher and Abdualkader, Abdualrahman Mohammed (2018) Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents. Research Report. UNSPECIFIED. (Unpublished)

Synthesis, mechanistic and biological evalution of novel bis-sydnone styrylketone as antiproliferative and antioxidant agents

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