Pyrimido[4,5-c]pyridazines. 1. Cyclizations with .alpha.-keto esters

Morrison, Robert W.; Mallory, W. Revill; Styles, Virgil L.

doi:10.1021/jo00419a028

Cited by 15 publications

(10 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The remaining compounds that were not commercially available were synthesized according to the following published procedures: 1 , 12, 16; 2 , 35; 4 . 17 Details of the preparation of 2 & 4 are provided in the supplementary data section (Scheme S1 and synthesis methods).…”

Section: Methodsmentioning

confidence: 99%

Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase

Hevener

Yun

et al. 2009

J. Med. Chem.

View full text Add to dashboard Cite

Dihydropteroate synthase (DHPS) is a key enzyme in bacterial folate synthesis and the target of the sulfonamide class of antibacterials. Resistance and toxicities associated with sulfonamides have led to a decrease in their clinical use. Compounds that bind to the pterin binding site of DHPS, as opposed to the p-amino benzoic acid (pABA) binding site targeted by the sulfonamide agents, are anticipated to bypass sulfonamide resistance. To identify such inhibitors and map the pterin binding pocket, we have performed virtual screening, synthetic, and structural studies using Bacillus anthracis DHPS. Several compounds with inhibitory activity have been identified, and crystal structures have been determined that show how the compounds engage the pterin site. The structural studies identify the key binding elements and have been used to generate a structure-activity based pharmacophore map that will facilitate the development of the next generation of DHPS inhibitors which specifically target the pterin site.

show abstract

Section: Methodsmentioning

confidence: 99%

Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase

Hevener

Yun

et al. 2009

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…[19, 20] However, subsequent improvement was not possible due to the lack of structural information on the complex. We subsequently determined the crystal structure of Bacillus anthracis DHPS ( Ba DHPS) in complex with this molecule 1 (Figure 1) and confirmed that it does engage the pterin pocket.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Design of Novel Pyrimido[4,5‐c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

et al. 2012

View full text Add to dashboard Cite

Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of the sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS has a high degree of conservation and is distinct from the sulfonamide binding site, and therefore represents an attractive alternative target for the design of novel antibacterial agents. Previously, we have structurally characterized a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise the binding. Using this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines was designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length were less apparent.

show abstract

“…Analogous results were obtained when dimethyl oxaloacetate was used [38]. The synthesis of pyrimido [4,5-c]pyridazines by the cyclization of α-keto esters with 6-(1-alkylhydrazino)isocytosines was described in [39]. Oxaloacetic ester was also used as α-keto ester.…”

Section: Production Of Condensed Heterocycles With Two or More Heteromentioning

confidence: 77%

Synthesis of heterocyclic compounds using oxaloacetic ester (review)

Yamashkin

Zhukova

2008

Chem Heterocycl Comp

View full text Add to dashboard Cite

Published data on the use of oxaloacetic ester in the synthesis of various heterocyclic systems are discussed.Scientists have been engaged in research on the reactions of oxaloacetic ester since the end of the nineteenth century. A large contribution to this field was made by Wislicenus, who extensively studied the chemical transformations of oxaloacetic ester [1]. The interest in oxaloacetic ester was prompted by the presence of four reaction centers in its molecule, making it possible the use it for the production of a large number of different compounds. In this review articles concerning the use of oxaloacetic ester in the synthesis of both monocyclic and condensed heterocyclic compounds are analyzed. OXALOACETIC ESTER IN THE SYNTHESIS OF MONOHETEROCYCLESThere are a large number of reactions in which oxaloacetic ester is used as starting compound in the synthesis of five-membered (furan and pyrrole derivatives) and six-membered (pyridine and pyrimidine derivatives) heterocycles.Thus, for example, oxaloacetic ester (1) undergoes intramolecular ester condensation, forming the dioxo derivative of furan 2 [2]. OEt OEt O O O OEt OH O O OEt O EtO O O 1 2 __________________________________________________________________________________________ M. E. Evsevyev

show abstract

Pyrimido[4,5-c]pyridazines. 1. Cyclizations with .alpha.-keto esters

Cited by 15 publications

References 4 publications

Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase

Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase

Structure‐Based Design of Novel Pyrimido[4,5‐c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

Synthesis of heterocyclic compounds using oxaloacetic ester (review)

Contact Info

Product

Resources

About