A1 Refereed original research article in a scientific journal
Evaluation of Ethylated Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as 15-Lipoxygenase Inhibitors Together with Cytotoxic, ADME and Molecular Modeling Studies
Authors: Muzaffar Saima, Shahid Wardah, Saleem Muhammad, Ashraf Muhammad, Aziz-ur-Rehman, Bashir Bushra, Ali Mudassar, Al-Rashida Mariya, Baral Bikash, Bhattarai Keshab, Riaz Naheed
Publisher: WILEY-V C H VERLAG GMBH
Publication year: 2020
Journal: ChemistrySelect
Journal name in source: CHEMISTRYSELECT
Journal acronym: CHEMISTRYSELECT
Volume: 5
Issue: 44
First page : 14210
Last page: 14216
Number of pages: 7
ISSN: 2365-6549
eISSN: 2365-6549
DOI: https://doi.org/10.1002/slct.202003704
Abstract
Searching the organic compound as anti-inflammatory agent is a fruitful effort to treat inflammatory disorders such as asthma, arthritis, psoriasis, and especially cancer. These disorders can be cured by lipoxygenase (LOX) inhibitors, which have the ability to stop the development and progression of inflammation. The present research described the synthesis of fifteen new N-alkyl/aralkyl/aryl derivatives (7 a-o) of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide by the continuous conversions of ethyl piperidine-4-carboxylate (a) into phenylcarbamoyl derivative (1) hydrazide (2), semicarbazide (3) and finally the N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The target molecules (7 a-o) were formed by the reaction of 4 with various electrophiles (6 a-o), in methanolic potassium hydroxide. These synthetic analogues were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. The compounds 7 a-o were screened for their inhibitory potential against 15-lipoxygenase. Compounds 7 b, 7 e, 7 c and 7 g displayed the potent inhibitory potential (IC50 17.52 +/- 0.67, 35.61 +/- 0.81, 36.24 +/- 0.83 & 36.52 +/- 0.58 μM, respectively), whereas, moderate inhibition was shown by 7 h, 7 a, 7 d with IC50 values between 42.95 +/- 0.73 to 45.67 +/- 0.75 μM, respectively. Some compounds exhibited drug-like characteristics due to their lower cytotoxic and good ADME profiles and supported by molecular modeling studies where one of the NH groups was found engaged through hydrogen bonding with Ala672. The carbonyl group amide and Asn554 were connected by a hydrogen bond, whereas the second NH group was also linked through hydrogen bonds with Gln363.
Searching the organic compound as anti-inflammatory agent is a fruitful effort to treat inflammatory disorders such as asthma, arthritis, psoriasis, and especially cancer. These disorders can be cured by lipoxygenase (LOX) inhibitors, which have the ability to stop the development and progression of inflammation. The present research described the synthesis of fifteen new N-alkyl/aralkyl/aryl derivatives (7 a-o) of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide by the continuous conversions of ethyl piperidine-4-carboxylate (a) into phenylcarbamoyl derivative (1) hydrazide (2), semicarbazide (3) and finally the N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The target molecules (7 a-o) were formed by the reaction of 4 with various electrophiles (6 a-o), in methanolic potassium hydroxide. These synthetic analogues were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. The compounds 7 a-o were screened for their inhibitory potential against 15-lipoxygenase. Compounds 7 b, 7 e, 7 c and 7 g displayed the potent inhibitory potential (IC50 17.52 +/- 0.67, 35.61 +/- 0.81, 36.24 +/- 0.83 & 36.52 +/- 0.58 μM, respectively), whereas, moderate inhibition was shown by 7 h, 7 a, 7 d with IC50 values between 42.95 +/- 0.73 to 45.67 +/- 0.75 μM, respectively. Some compounds exhibited drug-like characteristics due to their lower cytotoxic and good ADME profiles and supported by molecular modeling studies where one of the NH groups was found engaged through hydrogen bonding with Ala672. The carbonyl group amide and Asn554 were connected by a hydrogen bond, whereas the second NH group was also linked through hydrogen bonds with Gln363.
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