Substitution and solvent effects on the photophysical properties of several series of 10-alkylated phenothiazine derivatives.

The photophysical properties of several 2-substituted, 10-alkylated phenothiazines were measured in several solvents to investigate the relevance of the molecular structure in their photophysics and consequent photochemistry. Because the interaction modes of each drug and its corresponding species strongly depend on the variety of microenvironments in the cells, the properties of each one of these species must also be determined separately to understand fully the mechanism of action of the drug and the mechanism of its side effects. Information on the chemical interactions of the different species at the cellular level can be inferred from the corresponding electronic properties. In this work, we present absorption, steady-state, and time-resolved emission, laser flash photolysis, and quantum theoretical results for the ground state, the first excited singlet and triplet states, and the cation radical of promazine hydrochloride (PZ), 2-chlorpromazine hydrochloride (CPZ), 2-trifluoromethylpromazine hydrochloride (TFMPZ), 2-trifluoromethylperazine dihydrochloride (TFMP), 2-thiomethylpromazine (TMPZ), and thioridazine hydrochloride (TR). The corresponding nonalkylated phenothiazines are included as references. The photophysical properties of this drug family depend more on the solvent and the 2-substituents than on the dialkylaminopropyl chain. The largest effect was found for the triplet state of the 2-halogenated derivatives in phosphate buffer (PBS). Both the quantum yield and the lifetime of this intermediate drop to less than 5% of the corresponding value in organic solvents. The triplet state of halogenated promazines is efficiently quenched by a proton-transfer mechanism, and the rate of this quenching correlates very well with the phototoxicity of the promazine drugs. Therefore, we postulate that this species is directly related to the phototoxic side effect of neuroleptic drugs.