The NO-releasing Heterocycles

Gasco A, Schoenafinger K (2005) The NO-releasing heterocycles. In Wang PG, Cai TB, TaniguchiN (eds) Nitric oxide donors. Wiley-VCH, Weinheim, pp 131-175... 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Sterically hindered amino substituents or amino substituents with electron-with-drawing groups in the 3-position of the sydnonimine ring, as in Marsidomine 88, C89-4095 89 or C4144 90, have little impact on the stability of the heterocyclic system toward ring opening, but are able to slow down the process of oxidative NO-release from the nitroso intermediates [107]. 

This review has attempted to highlight the bio active mesoionic compounds and stimulate further development in this field. Mesoionic compounds are still considered as exotic structures even within the field of heterocyclic chemistry. Much attention has been directed toward the syd-nones (2), sydnonimines (3), l,2,3,4-oxatriazolium-5-aminates (9), and 1,3,4-thiadiazolium-2-aminates (7). In particular, their properties as NO-releasing compounds have been of interest. 

Nitrogen can be incorporated as an oxime into a different kind of ene reaction that has been explored by Grigg and his group. The ene component now bears no resemblance to a diene one pair of electrons comes from the lone pair on nitrogen and the other from the OH bond of the oxime 140. The enophile is a more conventional enone and the initial product is a nitrone 141. No nitrogen heterocycle is formed in this step, but, if the enophile contains a second alkene, a 1,3-dipolar cycloaddition gives a bicyclic structure. The simplest reagent for this job is the rather unstable divinyl ketone (penta-l,4-dien-3-one, 143). Fortunately this can be released from the dichloroketone 142 with base and distilled with the solvent THF into the reaction mixture.24... 

Pyridine Woxide chemistry, which clearly has no parallel in benzenoid chemistry, is an extremely important and useful aspect of the chemistry of heterocycles of the pyridine series. The structure of these derivatives means that they are both more susceptible to electrophilic substitution and react more easily with nucleophiles - an extraordinary concept when first encountered. On the one hand, the formally negatively charged oxygen can release electrons to stabilise an intermediate from electrophilic attack and, on the other, the positively charged ring nitrogen can act as an electron sink to encourage nucleophilic addition. 

In many cases, however, the ortho isomer is the predominant product, and it is the meta para ratio which is close to the statistical value, in reactions both on benzenoid compounds and on pyri-dine. " There has been no satisfactory explanation of this feature of the reaction. One theory, which lacks verification, is that the radical first forms a complex with the aromatic compound at the position of greatest electron density that this is invariably cither the substituent or the position ortho to the substituent, depending on whether the substituent is electron-attracting or -releasing and that when the preliminary complex collapses to the tr-complex, the new bond is most likely to be formed at the ortho position.For heterocyclic compounds such as pyridine it is possible that the phenyl radical complexes with the nitrogen atom and that a simple electronic reorganization forms the tj-complex at the 2-position. 

Other heterocyclic N-oxides have been found to display biological activities that may depend on their proven or hypothesised ability to release NO these include 4/ /-pyrazol-4-oTie 1,2-dioxides 71, 2H-1,2,3-triazole 1-oxides 72, benzotetrazine 1,3-dioxides 73 and 1,2,3-benzotriazine 3-oxides 74. These systems have been less extensively studied than the furoxan and 1,2-diazetine dioxide systems discussed above. 

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