Phenothiazines molecular structure

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. 

Tsakovska [194] used methods of molecular modeling to investigate a group of 25 phenothiazines and structurally related compounds. The role of hydrophobicity of modulators and hydrogen-bond acceptor interactions in MDR reversal were revealed. The piperazine moiety with a tertiary nitrogen was identified as the most favorable type of side chain for effective MDR modulators. 

Debye-ScherrerX-ray diffraction photographs of phenothiazine and of some phenothiazine drugs were taken for analytical purposes by the Colleter group " and others. An exact knowledge of the molecular structure of phenothiazines may be useful to the under-... 

The pharmacological activity as well as the side effects of phenothiazine derivatives have been shown to often depend on the nature and position of substituents [4]. Since there is also a correlation between the molecular structure and the photophysical properties of these compounds, it is worthwhile to thoroughly examine their first excited singlet- and triplet-state characteristics. 

A comparative molecular analysis study based on three-dimensional quantum structure-activity relationships was performed by Pajeva and Wiese [159] on 40 phenothiazines and structurally related drugs to predict their MDR modification. More than 350 theoretical models were derived and evaluated using steric, electrostatic and hydrophobic fields alone and in combination. All examined fields were found to contribute to MDR reversing activity, and their hydrophobic fields improved the correlative and predictive power of the models in all cases. The results point out the role of hydropho-bicity as a space-directed molecular property to explain the differences in anti-MDR activity of the drugs under study. 

Fig. 13 Molecular structure of phenothiazine derivative of perfluorosubphthalocyamnato boron(lll) 195b (CCDC 798231) [108]...

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). 

Contrary to the results of most quantitative structure-activity relationship (QSAR) studies on phenothiazine type modulators, Dearden et al. [195] found that molecular size, polarity, or polarizability better than other structural features of the compounds correlated with MDR reversing ability, P-gp associated ATPase activity, and inhibition of drug efflux from the blood-brain barrier. They did not find evidence that hydrogen bonding or hydrophobicity played a role in MDR reversal. 

Recently, Michalak et al. [156] presented a review on the interactions of phenothiazines with lipid bilayers and their role in MDR reversal. The drug partition between water and the lipid phase was discussed. The molecular size and polarizability of phenothiazines were found to correlate satisfactorily with the reduction of MDR. The most important structural features required for a high anti-MDR activity of phenothiazines seem to be their hydrophobic ring system, the type of substituent located at the 2-position, the presence of... 

A pharmacophore does not represent a real molecule or a real association of functional groups but is a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds toward their target structure. The pharmacophore can be considered to be the largest common denominator shared by a set of active molecules. This definition discards a misuse often found in the MEDICINAL CHEMISTRY literature, which consists of naming as pharmacophores simple chemical functionalities such as guanidines, sulfonamides, or dihydroimidazoles (formerly imidazolines), or typical structural skeletons such as flavones, phenothiazines, prostaglandins, or steroids. 

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 resistance. Molecular Pharmacology, 35, 105—115. 

In the phenothiazine area, it has been amply demonstrated that structural changes, in addition to producing expected quantitative changes in tranquilizing activity, also produce unexpected qualitative changes in biological activity. As a result antipruritic, antispasmodic, anticonvulsant, antibacterial, antiemetic, antimotion sickness, anthelmintic, and antidepressant compounds have been developed by molecular modification of the phenothiazines. 

A highly useful source for finding novel lead compounds constitute the compound collections of synthetic small-molecular-weight compounds that have been accumulated over the past decades in industrial companies and academic institutions. Since these compound collections are usually derived from a limited amount of so-called priviledged core structures such as benzodiazepines, dihydropyrimidines, phenothiazines and others, they exhibit a more limited chemical and structural diversity than natural products. Due to their ususally simpler structure a given hit or lead can be subsequently optimised in a quite efficient manner resulting in low manufacturing and development costs. 

Figure 7 Structure and function of the photochemically driven molecular shuttle, (a) Intramolecular translation mechanism in rotaxane composed of Ru(II)polypyridinium complex (P +), dimethyl bipyridinium (A2), and bipyridinium (Ai) with crown ether ring (R). (b) Shuttling assisted by electron relay using phenothiazine (PTZ). (Reproduced with permission from Ref. 114, V. Balzani, M. Clemente-Leon, A. Credi, B. Ferrer, M. Venturi, A. H. Flood, J. F. Stoddart, Proc. Natl. Acad. Sci. U. S. A. 2006,103, 1178-1183. Copyright (2006) National Academy of Sciences, U.S.A.)...

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