Triazolobenzo- and triazolothienodiazepines as potent antagonists of platelet activating factor

Walser, A.; Flynn, Thomas; Mason, C.; Crowley, Herman J.; Maresca, Catherine; Yaremko, Bob; O’Donnell, Margaret

doi:10.1021/jm00107a048

Cited by 51 publications

(24 citation statements)

References 4 publications

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“…Thus, reaction of 17 with NaBH 4 in EtOH [26] followed by treatment with NaOH afforded the hydroxy compound 25 in 66 % yield (Scheme 4). Interestingly, if after performing the reduction of compound 17 with NaBH 4 , the reaction was quenched by addition of MeOH, the corresponding methoxy derivative 26 was isolated.…”

Section: Chemistrymentioning

confidence: 99%

“…Interestingly, if after performing the reduction of compound 17 with NaBH 4 , the reaction was quenched by addition of MeOH, the corresponding methoxy derivative 26 was isolated. Further reduction of the hydroxy compound 25 with NaBH 4 in trifluoroacetic acid [26] led to 27 in 93 % yield. As will be discussed later, compound 27 was found to be equipotent to the parent naphthalimide derivative 17.…”

Section: Chemistrymentioning

confidence: 99%

“…Concerning the modifications at the distal substituent, the initial set of compounds (25)(26)(27) kept the inhibitory potency against the dTMP phosphorylation catalyzed by TMPKmt, as shown in Table 1. In particular, compound 27 (K i = 1.4 mm) was equipotent to the parent naphthalimide derivative 17, indicating that at least one of the carbonyl groups of the naphthalimide substituent was not required for interaction with the target enzyme.…”

Section: Enzymatic Assaysmentioning

confidence: 99%

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Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

et al. 2008

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In the search for novel inhibitors of the enzyme thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt), an attractive target for novel antituberculosis agents, we report herein the discovery of the first acyclic nucleoside analogues that potently and selectively inhibit TMPKmt. The most potent compounds in this series are (Z)‐butenylthymines carrying a naphtholactam or naphthosultam moiety at position 4, which display Ki values of 0.42 and 0.27 μM, respectively. Docking studies followed by molecular dynamics simulations performed to rationalize the interaction of this new family of inhibitors with the target enzyme revealed a key interaction between the distal substituent and Arg 95 in the target enzyme. The fact that these inhibitors are more easily synthesizable than previously identified TMPKmt inhibitors, together with their potency against the target enzyme, makes them attractive lead compounds for further optimization.

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Enzymatic Assaysmentioning

confidence: 99%

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Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

et al. 2008

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“…Among tricyclic benzodiazepine derivatives, triazolobenzodiazepines are one of the most important families due to their pharmaceutical interest [1][2][3][4][5]. Several triazolobenzodiazepines, e.g.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 1,3,3a,5‐tetraaryl‐3a,4,5,6‐tetrahydro‐3H‐1,2,4‐triazolo[4,3‐a] [1,5]benzodiazepines

Wang

Zhang

2001

Heteroatom Chemistry

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A series of 3a,5‐diaryl‐1,3‐diphenyl‐3a,4,5,6‐tetrahydro‐3H‐1,2,4‐triazolo[4,3‐a][1,5]benzo‐diazepines was synthesized by the cycloaddition reactions of 2,4‐diaryl‐2,3‐dihydro‐1H‐1,5‐benzo‐diazepines and N‐phenylbenzonitrileimine generated from N‐phenylbenzenecarbohydrazonic chloride in the presence of triethylamine in anhydrous tetrahydrofuran. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:557–559, 2001

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“…The quinazolinones were investigated in several research laboratories, as potent antagonists of platelet activating factor [2]. They were also used as alpha-1-adrenergic receptor antagonists [3] and as agonists on human ORL1 (nociceptin) receptor [4].…”

mentioning

confidence: 99%

Synthesis of 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone from 1-(3,4-dimethoxyphenyl)-urea and benzoic acid in polyphosphoric acid

Ivanov

2006

Molbank

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The quinazoline skeleton, when selectively functionalized, is a building block for the preparation of numerous alkaloids and substances capable of exhibiting a wide variety of biological activity [1]. The quinazolinones were investigated in several research laboratories, as potent antagonists of platelet activating factor [2]. They were also used as alpha-1-adrenergic receptor antagonists [3] and as agonists on human ORL1 (nociceptin) receptor [4]. There have been few reports about the synthesis of quinazolinones. R. Conley et al. [5] were used direct metalation starting with 3,4-dimethoxyanilin with n-butillithium, then treating with potassium cyanate and followed cyclization in PPA [5,6]. Recently, J. Vicente et al. reports the first ortho-palladated arylurea complexes, obtained by oxidative addition reactions, and has studied their reactivity toward different reagents to prepare quinazolinone derivatives [7]. The Friedel-Crafts acylation of activated benzene rings in the presence of polyphosphoric acid is a very convenient method for direct synthesis of aromatic ketones [8]. The newly synthesized compound 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone was obtained from 1-(3,4-dimethoxy-phenyl)-3-phenyl-urea. 1-(3,4-dimethoxyphenyl)-3-phenylurea (1) (0.544 g, 2 mmol) and benzoic acid (2) (0.366 g, 3 mmol) were dissolved in CH 2 Cl 2 (3-5 mL) in an open flask and polyphosphoric acid (10 g) was added. The mixture was stirred at 80°C for 6 h, then poured on crushed ice. The solution was alkalized with 25% ammonia, then extracted with CH 2 Cl 2 (3 x 20 mL) and the combined extracts were dried (Na 2 SO 4 ) and concentrated. To crude product 6,7-dimethoxy-3,4-diphenyl-3H-quinazolinone 3 in 15 mL methanol, NaBH 4 (4 mmol, 0,18 g) was added portionwise. The solution was stirred 30 min at room temperature, than the solvent was removed under vacuum. Water (30 mL) was added to the residue and the solution was extracted with CH 2 Cl 2 (3 x 20 mL), then the combined extracts were dried (Na 2 SO 4 ) and filtered. The products were filtered through a short column with neutral Al 2 O 3 and then were purified by recrystallization from ether or n-hexane/ether=1:1 (yield 59%).Melting Point: 210-211°C

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Triazolobenzo- and triazolothienodiazepines as potent antagonists of platelet activating factor

Cited by 51 publications

References 4 publications

Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

Synthesis of 1,3,3a,5‐tetraaryl‐3a,4,5,6‐tetrahydro‐3H‐1,2,4‐triazolo[4,3‐a] [1,5]benzodiazepines

Synthesis of 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone from 1-(3,4-dimethoxyphenyl)-urea and benzoic acid in polyphosphoric acid

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