Fluorinated dual antithrombotic compounds based on 1,4-benzoxazine scaffold

Ilić, Miloš; Kikelj, D.; Ilaš, Janez

doi:10.1016/j.ejmech.2012.01.059

Cited by 11 publications

(4 citation statements)

References 17 publications

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“…In 21 , the direction of spacer is inverted. Compounds 13 – 21 bear different residues, either at the 6 or 7 position, with fluorinated aryl groups as a typical substructure present in 13 – 18 [ 39 , 40 , 41 ]. These compounds have also been evaluated towards thrombin, trypsin, factor Xa and at the fibrinogen receptor.…”

Section: Resultsmentioning

confidence: 99%

“…Except for 14 , the fluorinated derivatives showed a strong thrombin inhibition and, moreover, 13 , 15 and 16 inhibited thrombin better than trypsin and factor Xa. [ 39 , 41 ]. Compound 18 was also characterized with respect radical scavenging activity, lipid peroxidation of linoleic acid and lipoxygenase inhibition [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

“…However, thrombin inhibition is not always accompanied by matriptase-2 inhibition. For example, 13 was inactive at matriptase-2, but highly active at thrombin [ 39 ]. Among the 3,4-dihydro-2 H -1,4-benzoxazines with a methyl group at 4-position ( 13 – 21 ), several members inhibited matriptase-2 with IC 50 values of less than 30 µM.…”

Section: Resultsmentioning

confidence: 99%

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3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

et al. 2016

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The liver enzyme matriptase-2 is a multi-domain, transmembrane serine protease with an extracellular, C-terminal catalytic domain. Synthetic low-molecular weight inhibitors of matriptase-2 have potential as therapeutics to treat iron overload syndromes, in particular in patients with β-thalassemia. A sub-library of 64 compounds was screened for matriptase-2 inhibition and several active compounds were identified. (S)-Ethyl 2-(benzyl(3-((4-carbamidoylphenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-oxoacetate ((S)-12) showed an IC50 value of less than 10 µM. Structure-activity relationships were discussed and proposals to design new matriptase-2 inhibitors were made.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

et al. 2016

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“…In order to study the effect of fluorine substituent(s) on anticoagulant and GP IIb/IIIa antagonistic activity, in 2012, Ilić et al [48] synthesized dual antithrombotic compounds based on a 1,4-benzoxazine scaffold by preparing their 3-fluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl and 3,5-difluorobenzyl analogues, bearing a substituent on the position 6 or 7 of the 1,4-benzoxazine scaffold, and found compound 22 (Figure 5) was the most potent compound with balanced dual inhibitory activity ( K i(Thr) = 0.33 ± 0.07 µM, IC 50(GP IIb/IIIa) = 1.1 ± 0.6 µM).…”

Section: Orally Active Thrombin Inhibitorsmentioning

confidence: 99%

Development of Orally Active Thrombin Inhibitors for the Treatment of Thrombotic Disorder Diseases

Dai

2015

Molecules

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Thrombotic disorders represent the major share of the various cardiovascular diseases, and significant progress has been made in the development of synthetic thrombin inhibitors as new anticoagulants. In addition to the development of highly potent and selective inhibitors with improved safety and suitable half-life, several allosteric inhibitors have been designed and synthesized, that did not fully nullify the procoagulant signal and thus could result in reduced bleeding complications. Furthermore, natural products with thrombin inhibitory activity have been isolated, and some natural products have been modified in order to improve their inhibitory activity and metabolic stability. This review summarizes the development of orally active thrombin inhibitors for the treatment of thrombotic disorder diseases, which could serve as a reference for the interested researchers.

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Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate

et al. 2021

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Racemic ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate is a key synthon for the design of promising therapeutic drugs. It is mainly synthesized from racemic ethyl 2,3-dibromopropionate and 2-aminophenol in presence of K 2 CO 3 in refluxed acetone. Unfortunately, synthesis of (R)-and (S)enantiomers using the enantioselective version of this reaction, which should normally be performed with a double S N 2 mechanism, is unsuitable due to a racemization process involving the dehydrobromination of enantiopure ethyl 2,3-dibromopropionate into ethyl 2-bromoacrylate. For the first time, the enantioselective version is studied (ee ≈ 55-66%), and the percentage of racemization process has estimated to around 34-46% after determination of the optimal experimental conditions for analytical HPLC enantioseparation of racemate. The influence of the experimental and purification conditions on

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Fluorinated dual antithrombotic compounds based on 1,4-benzoxazine scaffold

Cited by 11 publications

References 17 publications

3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

Development of Orally Active Thrombin Inhibitors for the Treatment of Thrombotic Disorder Diseases

Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate

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