Phenothiazines structure

In this chapter, we will give a review of the most significant and recent literature data on the physicochemical, biomedical and biological properties of simple phenothiazines and fused benzo[a]phenothiazines (structures in Figs. 1-4). The first section will be concerned with the spectroscopic, pho-... 

The phenothiazine structure is found in a number of pharmaceuticals used as antihistamines, antipsychotics, sedatives and antiemetics. Examples are the neuroleptic chlorpromazin 38 and the sedative promethazine 39 ... 

A phenothiazine structural analogue, very intimately related to chlorpromazine, and exhibits extremely potent analgesie aetivity. Importantly, it is devoid of any dependence liability, besides it does not produee respiratory depression. It is specifically of some extent of advantage in such patients for whom addiction as well as respiratory depression are serious problems. 

Incorporation of the aromatic rings of the ethyienediamines into the tricyciic phenothiazine structure produced compounds (e.g., promethazine) with good antihistaminic action and relatively strong sedative properties (see Chapter 37). At first, these compounds were found to be useful as antihistamines, but their very strong sedative properties aiso iead to their use as potentiating agents for anesthesia (25). Further deveiopment to increase the sedative properties of the phenothiazines resulted in the development of chlorpromazine in 1950 (26). 

Interest in the synthesis, reactions, and properties of fused-ring systems incorporating the phenothiazine structure is continuing, and further compounds... 

Oxidation of P-nicotinamide adenine dinucleotide (NADH) to NAD+ has attracted much interest from the viewpoint of its role in biosensors reactions. It has been reported that several quinone derivatives and polymerized redox dyes, such as phenoxazine and phenothiazine derivatives, possess catalytic activities for the oxidation of NADH and have been used for dehydrogenase biosensors development [1, 2]. Flavins (contain in chemical structure isoalloxazine ring) are the prosthetic groups responsible for NAD+/NADH conversion in the active sites of some dehydrogenase enzymes. Upon the electropolymerization of flavin derivatives, the effective catalysts of NAD+/NADH regeneration, which mimic the NADH-dehydrogenase activity, would be synthesized [3]. 

Replacement of the methyl group of the piperazine-substituted phenothiazines by some more polar group such as hydroxyethyl fragment leads to a further small increase in potency. It should be noted at this point that all phenothiazines manifest a series of side effects. The given set of these varies, however, with the side chains. The availability of the great variety of such structural variations makes it more likely that some drug will be found that a given individual will tolerate. 

The phenothiazine duoperone (5) combines structural elements found in phenothiazine and buty-rophenone antipsychotic agents. Alkylation of substituted piperidine 1 with 3-chloropropanol affords the intermediate 2 treatment of this with thionyl chloride converts the terminal hydroxyl to chloride. Alkylation of the phenothiazine 4 with halide 3 affords the antipsychotic agent duoperone (5) [1]. 

Chemical Name 2-methoxy-N,N,(3-trimethyl-10H-phenothiazine-10-propanamine Common Name Levomepromazine Structural Formula ... 

Chemical Name N,N,O -trimethyl-10H-phenothiazine-10-ethanamine hydrochloride Common Name Proazamine hydrochloride Structural Formula CH3... 

Therapeutic Function Antihistaminic Chemical Name 10-[2-(1-PyrrolidinyDethyl] phenothiazine Common Name Parathiazine Structural Formula ... 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

The phenothiazines, chlorpromazine and promethazine, have been described as inhibitors of CCU-induced lipid peroxidation at relatively high concentrations in rat liver microsomes (Slater, 1968). Structural modifications of chlorpromazine were undertaken to try to increase antioxidant activity and maintain molecular lipophilicity. The 2-N-N-dimethyl ethanamine methanesulphonate-substituted phenothiazine (3) was found to be a potent inhibitor of iron-dependent lipid peroxidation. It was also found to block Cu -catalysed oxidation of LDL more effectively than probucol and to protect primary cultures of rat hippocampal neurons against hydrogen peroxide-induced toxicity in vitro (Yu et al., 1992). 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

Fig. 1 Chemical structures of pyrene conjugated at the 5 -end (5 -Py) and the 2 sugar position of uridine (PyU), and phenothiazine conjugated at the 5 -end of ODN (5 -Ptz)...

Chlorpromazine is technically described as a phenothiazine, as are thioridazine and fluphenazine. Together with their structural analogues the thioxanthenes (e.g., clopenthixol) and the butyrophenones (e.g., haloperidol), the phenothiazines comprise the three major families of typical neuroleptics. They were developed in the late 1950s and early 1960s (Table 11.3). All these drugs block dopamine receptors, principally the D2 subtypes, with an affinity that correlates highly (r = +0.90) with their clinical... 

Although substituted phenols (e.g., para-iodophenol, para-phenylphenol, firefly luciferin, coumaric acid) are popular enhancers, in both luminol and acridan ester oxidation, enhancers with other functional groups [24], e.g., phe-nylboronic acids [25-28], phenothiazines [29], are also useful. As an example the structure of the phenothiazine enhancer used in the Supersignal substrate family is shown in Figure 6. 

Ford, J.M., Prozialeck, W.C. and Hait, W. N. (1989) Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug... 

It is interesting to compare the biphenylamine substituted compounds with the corresponding carbazoles, phenoxazines, and phenothiazines. For the triaryla-mino-based structures, the carbazole 24 has the highest oxidation potential (0.69 V vs. Ag/0.01 Ag+) [102], followed by the phenoxazine 25a (0.46 V vs. Ag/0.01 Ag+) [166]. A similar observation was made for the corresponding derivatives of 36a the phenothiazine (0.27 V vs. Fc/Fc+) and the phenoxazine (0.29 V vs. Fc/Fc+) have higher oxidation potentials than the parent compound. The carbazole 37 has an even higher oxidation potential, but in this case the oxidation is not reversible [234]. The redox properties of carbazoles are not fully understood yet. In some devices, a carbazole such as CBP (10) was used as an interface layer on the cathode side, suggesting a lower barrier for electron injection [50]. 

Typical Antipsychotics. The earliest antipsychotics were all structurally similar and belonged to the phenothiazine class. However, over the years, many medications with many different strnctnres have been fonnd to work in essentially the same manner. 

Phenothiazine derivatives. Comparison of the structures in Scheme 1.37 can lead to a prediction that hexa(anisyl)-l,3,5-triaminobenzene is more similar to 10,10 -(l,3-phenylene) diphenothiazine than to 10,10 -(l,4-phenylene)diphenothiazine. Nevertheless, on one-electron oxidation, these two isomeric diphenothiazines give dication-diradicals (Okada et al. 1996, Sun et al. 2004). As shown, m-phenylenediphenothaizine has a singlet state, and p-phenylenediphenothiazine has a triplet state. Both diphenothiazine dication-diradicals... 

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