Design and synthesis of pyrazolo[3,4-d]pyridazine 5,6-dioxides as novel NO-donors

Recent advances in versatile pyridazine-cored materials: principles, applications, and challenges

“…With many great achievements in the past decades, there are mainly two typical synthetic strategies (strategies I and II, Scheme 7) in the construction of PDs, including the cyclization of pyridazine-ring (PD-ring) (strategy I) and the modification of PDring (strategy II) from various precursory chemicals. On the one hand, the cyclization of PD-ring (strategy I) could be achieved by several methods, such as the Schiff-base condensation between hydrazine and diketones 122 /anhydrides 73 /aromatic ortho-diesters, 6 oxidative N-N coupling cyclization between hydroxylamine and dinitrogen tetroxide (N 2 O 4 ), 123 or t-BuOCl and aromatic diamines, 78 Diels-Alder cycloaddition between tetrazines and substituted acetylenes [124][125][126] or ethylenes, 57,127 [3+n] cycloaddition from azomethine ylides, 128 diazo-based cycloaddition 48,104 or quarternizative cyclization, 102 and photoactivation of pyridazine-N-Oxides (PD-N-Oxides). 129 On the other hand, the modification of PD-ring (strategy II) could be achieved by a huge number of C-C or C-N coupling or cyclization methods, including Suzuki reaction, Stille reaction, nucleophilic substitution, Sonogashira reaction, Aldol condensation, C-H activated direct arylation, Minisci reaction, Ullmann reaction, Buchwald-Hartwig reaction, and aroylation via wet chemistry, thermochemistry, photochemistry, and/or electrochemistry, which have been significantly investigated and/or summarized.…”

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

“…A more convenient approach toward the formation of the pyridazine dioxide scaffold is based on an oxidative cyclization of 1,4-dioximes 68 . This method is more efficient and provides high yields of target heterocyclic NO-donors 69 including those comprised of a pyridazine dioxide motif fused with other heterocyclic rings (pyrazole [ 125 ], furazan [ 126 ], furoxan [ 127 , 128 ]) ( Scheme 35 ). Initially, PhI(OAc) 2 [ 129 ] or Pb(OAc) 4 [ 130 , 131 ] were used as oxidants, but later N 2 O 4 [ 125 , 126 , 128 ] or HNO 3 [ 127 ] were shown to provide higher yields and purity of pyridazine dioxides 69 .…”

“…Aryl substituted 2 H -pyrazolo [3,4- d ]pyridazine 5,6-dioxides produced low amounts of NO (4.2–10.5%), while those bicyclic derivatives comprising of NO-donor furoxan and pyridazine dioxide subunits demonstrated the highest NO-releasing ability (27.7–48.3%) [ 125 ]. Furthermore, 4,7-dimethyl-1,2,5-oxadiazolo[3,4- d ]pyridazine 1,5,6-trioxide was able to relax noradrenaline-precontracted aortic rings at concentrations less than 0.1 mM.…”

Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide–Olefin Cycloaddition

“…Moreover, biomedical applications of simple heterocyclic NO donors along with their hybridization with other pharmacophoric scaffolds were found to be promising for the creation of new medications to overcome the issue of multidrug resistance [15][16][17]. A variety of heterocyclic NO donors (furoxans [18][19][20][21][22], azasydnones [23,24], sydnone imines [25], triazole oxides [26] and pyridazine dioxides [27]) were synthesized and evaluated for their pharmacological potency so far (Figure 1).…”