New Straightforward Synthesis and Characterization of a Unique 1β-Methylcarbapenem Antibiotic Biapenem Bearing a σ-Symmetric Bicyclotriazoliumthio Group as the Pendant Moiety

Kumagai, Toshio; Tamai, Satoshi; Abé, Takao; Matsunaga, Hiroshi; Hayashi, Kazuhiko; Kishi, Ikuo; Shiro, Motoo; Nagao, Yoshimitsu

doi:10.1021/jo980462j

Cited by 26 publications

(25 citation statements)

References 15 publications

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“…Tandem saponification and cyclization16 of 15 using 3M NaOH (aq) in MeOH afforded the bicyclic compound 2S-824 ( 16 ) in 26% yield. Oxidation of 16 with m CPBA17 in CH 2 Cl 2 furnished both 2SO-824 ( 17 ; 26%) and 2SO 2 -824 ( 18 ; 59%).…”

Section: Chemistrymentioning

confidence: 99%

Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

et al. 2009

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The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogs. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple 4-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles.

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Section: Chemistrymentioning

confidence: 99%

Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

et al. 2009

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confidence: 99%

“…interactions have been observed in a large number of organosulfur compounds controlling the conformation of small and large molecules. [1][2][3][4][5][6][7][8][9][10][11][12] Some of these compounds showed the strong bioactivity, and we suggested that the intramolecular nonbonded S · · · X interactions play an important role on the mechanism of several biological effects.1,2,6-12) For example, the clear S · · · O close contact in the complex crystalline structure of carbonic anhydrase I and acetazolamide was recognized.12) The same nonbonded interaction was observed in the crystalline structure of acyliminothiadiazoline, which has potent angiotensin II receptor antagonistic activity. 6,11) It is estimated that the ring structure consisted of the intramolecular nonbonded S · · · X interactions was more flexible than that of covalent bonding, and this flexibility increased the binding affinity of the active compound to the flexible pocket of the enzyme or the receptor.…”

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confidence: 99%

Intramolecular Nonbonded S...N Interaction in Rabeprazole

Hayashi

Ogawa

Sano

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Intramolecular nonbonded S · · · X (XϭS, O, N, etc.) interactions have been observed in a large number of organosulfur compounds controlling the conformation of small and large molecules. [1][2][3][4][5][6][7][8][9][10][11][12] Some of these compounds showed the strong bioactivity, and we suggested that the intramolecular nonbonded S · · · X interactions play an important role on the mechanism of several biological effects.1,2,6-12) For example, the clear S · · · O close contact in the complex crystalline structure of carbonic anhydrase I and acetazolamide was recognized.12) The same nonbonded interaction was observed in the crystalline structure of acyliminothiadiazoline, which has potent angiotensin II receptor antagonistic activity. 6,11) It is estimated that the ring structure consisted of the intramolecular nonbonded S · · · X interactions was more flexible than that of covalent bonding, and this flexibility increased the binding affinity of the active compound to the flexible pocket of the enzyme or the receptor. These results prompted us to disclose the new roles of intramolecular nonbonded S · · · X interactions in other drugs. Herein, we focus on rabeprazole, [13][14][15][16] and discuss the intramolecular nonbonded S · · · N interaction in rabeprazole and its role.Sodium rabeprazole (1) is one of the inhibitors of the gas-13,14) As a result of the investigations on the mechanism of action of these inhibitors, it has been expected that 1 will be activated by protonation in the parietal cell (intermediate 2), converted into the sulfenamide 5 via the spiro sulfoxide 3 and sulfenic acid 4, and the active principle 5 can react with the accessible cysteines of the gastric (H ϩ -K ϩ )-ATPase followed by the inhibition of the enzyme (compound 6), as shown in Chart 1. 14,[17][18][19][20] In this reaction cascade, the key step is the formation of the putative spiro sulfoxide 3 arising from nucleophilic attack of the pyridine nitrogen on the activated 2-position of the benzimidazole moiety.18) The fact that the nucleophilic attack of the pyridine nitrogen smoothly proceeds despite the week nucleophilicity is very interest, and made us guess that the intramoleculer nonbonded S · · · N interaction influenced this step. Because, if such intramoleculer nonbonded S · · · N interaction is possible in rabeplazole, the 4-membered quasiring in 2 containing the rabeplazole structure would be formed and bring the nitrogen atom of pyridine close to the electrophilic position of benzimidazole moiety, as shown in Fig. 1. Therefore, in order to make clear the presence of the intramoleculer nonbonded S · · · N interaction in 1, we characterized the crystal structures of derivatives of 1 at first, since 1 itself could hardly be crystallized. 21)The reactions of 1 with various electrophiles in the presence of amines gave the corresponding derivatives of 1 in 36-92% yields, as shown in Chart 2. The resultant derivatives 7a-d were recrystallized from suitable solvents to obtain the corresponding crystals available for X-ray crystal...

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“…Carbapenems are well recognized to have broad antibacterial activities, and most of the carbapenem compounds have been developed for parenteral use such as imipenem [1], panipenem [2], meropenem [3], biapenem [4,5], ertapenem [6] and doripenem [7]. The development of oral carbapenems is now expected in the clinical realm because oral administration is advantageous for patients.…”

Section: Introductionmentioning

confidence: 99%

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

et al. 2006

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New Straightforward Synthesis and Characterization of a Unique 1β-Methylcarbapenem Antibiotic Biapenem Bearing a σ-Symmetric Bicyclotriazoliumthio Group as the Pendant Moiety

Cited by 26 publications

References 15 publications

Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

Intramolecular Nonbonded S...N Interaction in Rabeprazole

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

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