¹³C nuclear magnetic resonance and reactivity of 4H-3,1-benzoxazin-4-ones

Abstract

Can. J. Chem. 66, 4 16 (1988). Complete carbon-13 nuclear magnetic resonance assignments have been made for 22 4H-3,l -benzoxazin-4-ones. These compounds are alternate substrate inhibitors of human leukocyte elastase, a serine protease involved in tissue degradation. Correlations between the carbon chemical shifts and rates of alkaline hydrolysis are consistent with hydrolysis via attack at C4, and are also useful in the selection of parameters for structure-activity analysis. VALERIE J. ROBINSON et ROBIN W. SPENCER. Can. J . Chem. 66, 416 (1988). On a fait des attributions compl&tes des spectres en rksonance magnCtique nuclkaire du I3C de 22 4H-benzoxazine-3,l ones-4. Ces composCs sont des inhibiteurs de substrats d'elastase leucocytaire humaine, une protease de la skrine impliquee dans la degradation des tissus. Des corrClations entre les deplacements chimiques des carbones et les taux d'hydrolyse alcaline sont en accord avec un mecanisme d'hydrolyse impliquant une attaque en C4; de plus, ces corrClations sont utiles dans la selection des parametres necessaires pour une analyse structure-activitk.[Traduit par la revue] Introduction 4H-3,l-Benzoxazin-4-ones are potent inhibitors of serine proteases (1-6) with clinical potential in a number of degradative diseases (7). It is well established that benzoxazinones inhibit by acting as alternate substrates, acylating the target protease via attack of serine 195 at C4, and then slowly deacylating (2-6) (Scheme I).

2-Amino- and 2-Alkylthio-4H-3,1-benzothiazin-4-ones: Synthesis, Interconversion and Enzyme Inhibitory Activities

“…The corresponding chemical shifts of the benzoxazinones were observed at 154/160 ppm ( 8h ) and 164/159 ppm ( 9i ). These values were in accordance with literature data for 4 H -3,1-benzoxazin-4-ones [ 14 , 32 , 37 , 38 , 39 ]. A similar influence of the sulphur-oxygen exchange on the chemical shift of the C-4 carbon was observed for pairs of 2-thien-2-yl and 2-cyano substituted 4 H -3,1-benzothiazin(oxazin)-4-ones [ 32 , 40 ].…”

2-(Diethylamino)thieno[1,3]oxazin-4-ones as Stable Inhibitors of Human Leukocyte Elastase

“…As described for compound 58 , aqueous alkaline hydrolysis of the thieno[1,3]oxazinones 7 and 50 − 57 was assumed to proceed by hydroxide attack at C-4 to produce the corresponding ureidothiophenecarboxylic acids. An analogous hydrolytic ring opening for 3,1-benzoxazin-4-ones is well established. ,,, Both the alkaline hydrolysis of fused 1,3-oxazin-4-ones and the process by which they inhibit HLE involve attack of a nucleophilic oxygen upon the lactone carbonyl carbon. Therefore, recognition of structural features promoting enzyme inhibition over chemical reactivity is crucial in the design of such mechanism-based inhibitors.…”

“…An analogous hydrolytic ring opening for 3,1-benzoxazin-4-ones is well established. 19,33,37,43 Both the alkaline hydrolysis of fused 1,3oxazin-4-ones and the process by which they inhibit HLE involve attack of a nucleophilic oxygen upon the lactone carbonyl carbon. Therefore, recognition of structural features promoting enzyme inhibition over chemical reactivity is crucial in the design of such mechanismbased inhibitors.…”

Synthesis of derivatives of thiophene using methyl 2‐isothiocyanatobenzoate

“…Table 1 contains the C-13 nmr spectroscopic data for all of the compounds mentioned above. Use of HMQC and HMBC along with literature data of model compounds [18][19][20][21][22] allowed the assignments of signals to specific carbon atoms of these compounds.…”