Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses. A wide number of vascular diseases as well as various immune and neurodegenerative disorders were found to be directly associated with a disruption of NO production in living organisms. These issues justify a constant search of novel NO-donors with improved pharmacokinetic profiles and prolonged action. In a series of known structural classes capable of NO release, heterocyclic NO-donors are of special importance due to their increased hydrolytic stability and low toxicity. It is no wonder that synthetic and biochemical investigations of heterocyclic NO-donors have emerged significantly in recent years. In this review, we summarized recent advances in the synthesis, reactivity and biomedical applications of promising heterocyclic NO-donors (furoxans, sydnone imines, pyridazine dioxides, azasydnones). The synthetic potential of each heterocyclic system along with biochemical mechanisms of action are emphasized.     

Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines and Pyridazines

Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-triazolo[1,5-a]pyrazines and their benzo-fused quinoxaline and quinoxalinone-containing analogs. Recent applications detail the use of these heterocycles in medicinal chemistry (c-Met inhibition or GABA_A modulating activity) as fluorescent probes and as structural units of polymers.     

Facile synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives by a one-pot, three-component reactions

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl or aryl isocyanides and electron-deficient acetylenic esters with 3,6-dihydroxypyridazine, leads to a vinylisonitrilium cation, which undergoes an addition reaction with the conjugate base of the 3,6-dihydroxypyridazine to produce dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates in good yields at room temperature.     

A new method for the synthesis of 3-aryl-6-(2-pyrrolyl)pyridazines

A new method for the synthesis of 3-halo-6-(N-tosyl-2-pyrrolyl)pyridazine 7 was developed. Suzuki cross-coupling reactions of 7 with arylboronic acids and in situ de-tosylation gave a variety of novel 3-aryl-6-(2-pyrrolyl)pyridazines. It found that protection of the pyrrolyl moiety was necessary for efficient coupling reaction.     

Novel Synthesis of Thieno[2,3-c]Pyridazine and Pyrimido[4',5':4,5]thieno[2,3-c]pyridazine Derivatives

Abstract

Novel series of thieno[2,3-c]pyridazines and pyrimido[4′,5′:4,5] thieno-[2,3-c]pyridazines have been synthesized from the readily accessible 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3b.     

RECENT TRENDS IN THE CHEMISTRY OF THIENOPYRIDAZINES

This review describes the synthesis of thieno[2,3-c]pyridazine, thieno [3,2-c]pyridazine, thieno[2,3-d]pyridazine and thieno[3,4-d]pyridazine derivatives and their reactions.     

Synthesis of new annulated pyridazine derivatives and studying their antioxidant and antimicrobial activities

Benzil was reacted with cyanoacetohydrazide under microwave irradiation to give 3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile 1 which used as starting material for the synthesis of new heterocyclic compounds. Chlorination of pyridazinone 1 with POCl₃ afforded the chloro-pyridazine derivative 3, which then condensed with 2-aminothiazole or hydrazine hydrate to produce 3,4-diphenyl-5H-thiazolo[3′,2′:1,2]pyrimido[4,5-c]pyridazin-5-one 5 or 3-hydrazinyl-5,6-diphenylpyridazine-4-carbonitrile 6, respectively. New Schiff bases were obtained by condensation reactions of compound 6 with different aldehydes. On the other hand, compound 6 reacted with different carbon electrophiles naming acetyl acetone, diethyl malonate, and phenyl isothiocyanate producing new pyarazolo-pyridazine derivatives 11, 12, and 14, respectively. Chemical structures of all newly synthesized compounds were confirmed on the basis of spectral data and had been screened for antimicrobial and antioxidant activity.     

Novel Synthesis of Some New Pyridazine and Pyridazino[4,5-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a and b react with dimethylformamide dimethylacetal (DMFDMA) in refluxing toluene to afford the enaminones 2a and b respectively. Compounds 2a and 2b react with the hydrazine hydrate 3a and phenyl hydrazine 3b in refluxing ethanol to afford the pyridazine derivatives 5a–d, presumably via the intermediates 4. Compounds 5a–d, react with hydrazine hydrate 3a to afford the pyridazino[4,5-d]pyridazines 6a–d respectively. The pyridazines 5a and b and the pyridazino[4,5-d] pyridazines 6a and b could be oxidized into the full aromatic systems 7a and b and 8a and b respectively. Compounds 7a and b react also with hydrazine hydrate 3a to afford 8a and b respectively.

Heterocyclic Synthesis with Nitriles: Synthesis of Some New Thiophene,Pyridazine, Oxazine,Thiopyran, Pyrrole,and Pyrrolo[1,2‐b]pyridazine Derivatives

2‐Phenyl‐1,1,3‐tricyanopropene[α‐(cyanomethyl)benzylidene‐malononitrile] undergoes bromination with N‐bromosuccinimide (NBS) to afford 2‐phenyl‐1,1,3‐tricyano‐3‐bromopropene: [α(bromocyanomethyl)benzylidene malononitrile]. This bromo derivative undergoes reactions with sodium hydrogen sulfide, hydrazine hydrate, phenyl hydrazine, hydroxylamine hydrochloride, ethyl thioglycollate, urea derivatives, and cyanacetohydrazide to afford thiophene, 4H‐pyridazines, 4H‐oxazine and 4H‐thiopyran, N‐substituted pyrrole, and pyrrolo[1,2‐b]pyridazine derivatives respectively.     

Synthesis of highly refractive polyimides derived from 3,6‐bis(4‐aminophenylenesulfanyl)pyridazine and 4,6‐bis(4‐aminophenylenesulfanyl)pyrimidine

A series of aromatic polyimides (PIs) containing pyridazine or pyrimidine in their main chains has been developed. All of the PIs were prepared from newly synthesized diamines, 3,6‐bis(4‐aminophenylenesulfanyl)pyridazine (APP), 4,6‐bis(4‐aminophenylenesulfanyl)pyrimidine (APPM) and aromatic dianhydrides, 4,4′‐[p‐thiobis(phenylenesulfanyl)]diphthalic anhydride (3SDEA) and 4,4′‐oxydiphthalic anhydride (ODPA) via the conventional two‐step polycondensation. The PIs showed good thermal stability with 10% weight loss at temperatures above 450 °C and glass transition temperatures above 190 °C. Films with a 10‐μm thickness exhibited good optical transparency above 80% at 500 nm, high refractive indices ranging from 1.7218 to 1.7499, and low birefringence between 0.0066 and 0.0102. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4886–4984, 2009