Synthesis of new series of pyrimido[4,5-b][1,4] benzothiazines as 15-lipoxygenase inhibitors and study of their inhibitory mechanism

Nikpour, Mohsen; Mousavian, Mina; Davoodnejad, Mahdieh; Alimardani, Maliheh; Sadeghian, Hamid

doi:10.1007/s00044-013-0506-7

Cited by 19 publications

(16 citation statements)

References 16 publications

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“…Among the synthetic coumarins, O -allyl and O -isopentenyl derivatives ( a and b series) demonstrated no considerable lipoxygenase inhibition while O -geranyl and O -farnesyl derivatives ( c and d series) demonstrated potent inhibitory activity at IC 50 value below 11 μM compared to 4-MMPB (IC 50 = 16.8 μM) ( Table 1 ), as standard 15-LOX inhibitors [ 19 , 22 ]. In all, 5- O -prenylated coumarins: 4a , 4b , 4c and 4d , demonstrated the best inhibitory activity at IC 50 values of 93.5, 62.5, 4.8 and 0.74 μM, in contrast with their related isomers from each of the synthetic groups ( 4 , 8 , 12 and 18 ), respectively.…”

Section: Resultsmentioning

confidence: 99%

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O-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors

et al. 2017

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Allyloxy, Isopentenyloxy, geranyloxy and farnesyloxy derivatives of 3-carboxycoumarin, at position 5, 6, 7, and 8, were synthesized and their inhibitory potency against human 15-lipoxygenase-1 (human 15-LOX-1) were determined. Among the synthetic coumarins, O-allyl and O-isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition while O-geranyl and O-farnesyl derivatives demonstrated potent inhibitory activity. 5-farnesyloxy-3-carboxycoumarin demonstrated the most potent inhibitory activity by IC50 = 0.74 μM while 6-farnesyloxy-3-carboxycoumarin was the weakest inhibitor among farnesyl analogs (IC50 = 10.4 μM). Bonding affinity of the designed molecular structures toward 15-LOX-1 3D structure complexed with RS75091, as potent 15-LOX-1 inhibitor, was studied by utilizing docking analysis. There was a direct relationship between lipoxygenase inhibitory potency and prenyl length chain. The ability of the prenyl portion to fill the lipophilic pocket which is formed by Ile663, Ala404, Arg403, Ile400, Ile173 and Phe167 side chains can explain the observed relationship. Similarity rate between the docked models and complexed form of RS75091, from point of view of configuration and conformation, could explain inhibitory potency variation between each prenyloxy substitution of 3-carboxycoumarins.

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Section: Resultsmentioning

confidence: 99%

“…Ethanol was used as control solution. After 30 min at room temperature, the absorbance was read at 517 nm and the significant decrease in absorbance in comparison with the control was recorded [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

O-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors

et al. 2017

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“…The lipo‐oxygenase inhibitory activity of all the synthetic compounds against SLO (soybean 15‐lipo‐oxygenase) was determined using peroxide formation method reported in the previous literatures . In this method, the basis of the lipo‐oxygenase assay is the measurement of fatty acid peroxide concentration.…”

Section: Resultsmentioning

confidence: 99%

“…The absorbance at 598 nm was compared with the control test. The enzyme inhibition results are reported in Table …”

Section: Methodsmentioning

confidence: 99%

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2‐Prenylated m‐dimethoxybenzenes as potent inhibitors of 15‐lipo‐oxygenase: inhibitory mechanism and SAR studies

et al. 2016

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15-lipo-oxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. In this study, a series of allyl and prenyl dimethoxybenzenes were synthesized and their inhibitory potency against soybean 15-Lipo-oxygenase (L1; EC 1,13,11,12) was determined. Among the synthetic compounds, 2,6-dimethoxy-1-isopentenyl-4-methylbenzene, 2,6-dimethoxy-1-geranyl-4-methylbenzene, and 2,6-dimethoxy-1-farnesyl-4-methylbenzene showed the most potent inhibitory activity with IC50 values of 7.6, 5.3, and 0.52 μm, respectively. For some of the compounds, SAR studies showed acceptable relationship between inhibitory potency and enzyme-ligand interactions. Radical scavenging assessment results apart from the SAR studies indicate that electronic properties are the major factors for lipo-oxygenase inhibition potency of the mentioned compounds. Based on the theoretical studies, it was suggested that CH…O intramolecular hydrogen bond between ortho-methoxy oxygen and methine hydrogen atoms is one of the major factors in the stability of 2,6-dimethoxyallyl(or prenyl)benzenes radical via the planarity fixation between phenyl and allyl (or prenyl) pi orbitals.

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Iodine‐Catalyzed, Ethyl‐Lactate‐Mediated Synthesis of 1,4‐Benzothiazines via Metal‐Free Cascade Enaminone Transamination and C−H Sulfenylation

Wan

Cao

et al. 2018

Asian J Org Chem

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The reactions between N,N‐dimethyl enaminones and ortho‐aminothiophenols provide 1,4‐benzothiazines via cascade C−N bond transamination and C(sp2)−H sulfenylation. By employing biomass‐available ethyl lactate as a green medium, the present work offers a complementary metal‐free cross‐coupling‐based synthesis of 1,4‐benzothiazines to those known tandem reactions catalyzed by transition metals.

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Synthesis of new series of pyrimido[4,5-b][1,4] benzothiazines as 15-lipoxygenase inhibitors and study of their inhibitory mechanism

Cited by 19 publications

References 16 publications

O-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors

O-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors

2‐Prenylated m‐dimethoxybenzenes as potent inhibitors of 15‐lipo‐oxygenase: inhibitory mechanism and SAR studies

Iodine‐Catalyzed, Ethyl‐Lactate‐Mediated Synthesis of 1,4‐Benzothiazines via Metal‐Free Cascade Enaminone Transamination and C−H Sulfenylation

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