Phenothiazines biological activity

Keywords Benz[c] acridines Benzo [a] phenothiazines Biological activity Phenothiazines QSAR Theoretical calculations... 

An interesting additional example of the interchangeability of the bridging atoms in the neuroleptic series comes from the finding that the biologic activity of the phenothiazines is maintained in a compound that contains an extra atom on the nitrogen... 

Isothiazoles have also been incorporated into a wide range of established drugs including phenothiazines,123 sulfones,121 sulfonamides,3,66,156 thiosemicarbazones,140,157 amidines,158 nitrohetero-cycles,159 and benzimidazoles,160 but this approach does not appear to have resulted in any major improvements. However, many isothiazoles not directly related to known drugs have biological activity, and representatives are listed in Table I, No attempt has been made to include the numerous patents which mention isothiazole derivatives as part of a series, but for which no special claims are made. 

The results of the present study suggest the applicability of theoretical calculations such as frontier molecular orbital, dipole moments and AAHf in the prediction of biological activity of phenothiazines, benzo[a]phenothiazines, and benz[c] acridines. 

Molnar J, Sakagami H, Motohashi N (1993) Diverse biological activities displayed by phenothiazines, benzo [a] phenothiazines and benz[c]acridines. Anticancer Res 13 1019-1026... 

In the second section of the volume, N-hclerocycles such as phenothiazines, phenoxazines, dihydropyridines, and related compounds are shown also to have interesting biological activity including antitumor activity, vermicide, antibacterial activity, and antischizophrenic activity (i.e. chlorpromazine of the phenothiazine family and its analogs). The activity of phenothiazine and compounds such as phenoxazines and related heterocycles, and also recent bioactive mesoionic heterocycles will be discussed. 

The last chapter, Theoretical Studies on Phenothiazines, Benzo[a]pheno-thiazines and Benz[c] acridines by Teruo Kurihara, Kazumi Shinohara, Hidet-sugu Wakabayashi, Noboru Motohashi, Hiroshi Sakagami, and Joseph Mol-nar, presents their quantitative structure-activity relationship (QSAR) analysis for minimum inhibitory concentration (MIC) of phenothiazines and benzo[a]phenothiazines. The MIC values of phenothiazines were well correlated to AAHf, HOMO energy, and /xG. QSAR may be applicable to predict the MIC of phenothiazines. This review could contribute to prediction of the relationship of structure to biological activity. 

A systematic survey of the influence exerted by the substituents upon the stability of semiquinone forms was undertaken by Tozer and Dallas Tuck, in order to investigate the effect of the substituent upon the biological activity of phenothiazine derivatives, an activity correlated by many authors with in vivo formation of radical species. If the disproportionation reaction shown in Eq. (3) (Section IV, B, 1) were to reach equilibrium, the value K defined in Eq. (5) would express the stability of substituted S+ species. 

It was mentioned in Section I,B that 3Z -phenothiazines are known only as derivatives in which both hydrogen atoms from position 3 are substituted. This class includes substances important as dyestuffs, which in some cases display useful biological activity. 

The remarkable photochemical, photophysical and physicochemical properties of the phenothiazine and benzo[a]phenothiazine substituted derivatives should also result in a variety of biological activities and a number of applications in medicine and related fields. 

Phenothiazine and many of its substituted derivatives possess important and various biological activities, and have been shown to present significant insecticidal, antifungal, antibacterial and anthelmintic properties. Unsubstituted phenothiazine has also been used for vermifugal application, which has earned this molecule a good place alongside penicillin and DDT for its great impact on mankind, as recently pointed out by Mitchell [111]. 

As part of the series Topics in Heterocyclic chemistry, this volume titled Bioactive Heterocycles II presents comprehensive and up-to-date reviews on selected topics concerning mainly the usefulness for human health of flavonoids and related compounds, Sophora flavonoids and their functions in Sophora species (Leguminosae), the relationship of biological activity with the diverse structures of heterocycles by quantum chemical calculation, advances in bioactive mesoionic heterocycles, and the spectroscopic properties and application of bioactive phenothiazines including also benzo[a]phenothiazines. 

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. 

The biological activity of calmodulin is strongly inhibited by antipsychotic drugs of the phenothiazine type. One of the most effective inhibitors is trifluoperazine (TFP)... 

---