Synthesis and evaluation of 2-aryl-4H-3,1-benzoxazin-4-ones as C1r serine protease inhibitors

Gilmore, John L.; Hays, Samuel P.; Caprathe, Bradley W.; Lee, Chitase; Emmerling, Mark R.; Michael, Walter; Jaén, Juan C.

doi:10.1016/0960-894x(96)00094-7

Cited by 43 publications

(19 citation statements)

References 5 publications

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“…They are indeed useful intermediates in organic synthesis affording through reaction with nitrogen nucleophiles 4(3H)quinazolinones. With the aim of extending information on the reactivity of 4H-3,1-benzoxazinones and also synthesizing from them new heterocyclic systems, potentially with biological activity [8][9][10][11][12] and in continuation of our work on the behaviour of stable benzoxazinones 13 towards nitrogen and carbon nucleophiles, other derivatives were obtained via the interaction of acetic anhydride and/or isobutyroyl chloride with anthranilic acid derivatives. The electronically unsaturated character of unstable benzoxazinones which are (4H)-3,1-benzoxazinones bearing saturated substituents such as CH 3 , CH 2 COCH 3 , CH 2 CN and CH 2 CH 2 CO 2 H at position 2 [14][15][16][17] renders their synthesis difficult because they are not satisfactorily stable rings.…”

Section: Introductionmentioning

confidence: 99%

Reactivity of 4H-3,1-benzoxazin-4-ones towards nitrogen and carbon nucleophilic reagents: applications to the synthesis of new Heterocycles

Madkour¹

2004

Arkivoc

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6,8-Dibromo-(4H)-3,1-benzoxazinone 1a was synthesized and allowed to react with some nitrogen nucleophiles namely, hydroxylamine hydrochloride, 4-aminoacetophenone, ophenylenediamine, sulfanilamide, sulfamethoxazole, semicarbazide hydrochloride and ethanolamine to afford 3-substituted-4(3H)-quinazolinones 2-8, 10-12 and triazolo[2,3-c]quinazoline 9. 6-Bromo(4H)-3,1-benzoxazin-4-one 1b was also synthesized and converted into 3-amino-4(3H) quinazolinone 13 by reaction with hydrazine hydrate. The latter product was utilized to construct new heterocyclic systems namely, triazino[2,3-c] quinazoline 14 and the thiazole derivative 16. An interesting heterocyclic transformation occurred on treatment of benzoxazinone 1a with malononitrile in presence of sodium ethoxide to give quinoline derivative 18 which reacted with phenyl isocyanate to yield oxazinoquinoline 19. The reaction of benzoxazinone 1a with Grignard' reagents afforded unexpected products 20 and 21 whereas Friedel-Crafts reaction of the same oxazinone with some aromatic hydrocarbons namely, benzene, ethylbenzene, m-and p-xylenes afforded either two benzophenone derivatives 20 and 22 or 23 and 24 in case of less bulky hydrocarbons i.e., benzene and ethylbenzene or only one product 25 and 26 in case of more bulky m-and p-xylenes. Oxazinone ring cleavage occurred when barbituric and/or thiobarbituric acid reacted with benzoxazinone 1a in refluxing pyridine to give the corresponding 5-arylidene derivatives 27a,b.

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Section: Introductionmentioning

confidence: 99%

Reactivity of 4H-3,1-benzoxazin-4-ones towards nitrogen and carbon nucleophilic reagents: applications to the synthesis of new Heterocycles

Madkour¹

2004

Arkivoc

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“…This chemotype (2-aryl-3,1-benzoxazin-4-ones) was originally reported by Gilmore and co-workers in 1996. The best compound was 2-(2′-iodophenyl)-3,1-benzoxazin-4-one (CID296008, IC 50 = 1.25 μM) [47]. Later the previously cited HTS campaign identified two further hit compounds [11], and one of them was applied as a lead compound (seed #10; see Supplementary Materials) in the 2D similarity search.…”

Section: Discussionmentioning

confidence: 99%

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Szilágyi¹,

Hajdú

Flachner³

et al. 2019

Molecules

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The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively.

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“…6), inhibitors of C1r serine protease, is to treat the AA with a benzoyl chloride in pyridine [246]. Similar compounds have been isolated from oats (Avena sativum) [133].…”

Section: Benzoxazinesmentioning

confidence: 97%

The Chemistry of Anthranilic Acid

Wiklund¹,

Bergman

2006

COS

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Synthesis and evaluation of 2-aryl-4H-3,1-benzoxazin-4-ones as C1r serine protease inhibitors

Cited by 43 publications

References 5 publications

Reactivity of 4H-3,1-benzoxazin-4-ones towards nitrogen and carbon nucleophilic reagents: applications to the synthesis of new Heterocycles

Reactivity of 4H-3,1-benzoxazin-4-ones towards nitrogen and carbon nucleophilic reagents: applications to the synthesis of new Heterocycles

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

The Chemistry of Anthranilic Acid

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