Study of the Lipophilicity of Tetracyclic Anticancer Azaphenothiazines

Although chlorpromazine is primarily used in psychiatry, it has been shown since its introduction to influence the course of neoplastic diseases. According to the strategy of drug repurposing, chlorpromazine has been successfully tested for its potential antitumor effects on multiple cancer cell lines. This effect is consistent with the overlap of molecular pathways observed for years between schizophrenia and cancer. The main objective of this work was to evaluate the lipophilicity of 17 previously synthesized tetracyclic chlorpromazine analogues exhibiting diverse anticancer and antimicrobial activity using thin-layer chromatography and computational methods. For a compound to become an effective drug, it must have a favorable ADMET profile, which determines its pharmacokinetic properties as a drug candidate. Lipophilicity is one of the key parameters widely employed in designing new bioactive compounds as potential therapeutic agents. In this article, chromatographic plates precoated with silica gel 60 RP-18F₂₅₄ and a mixture of acetone and TRIS buffer were used as the mobile phase. The chromatographic parameter of lipophilicity (R_M0) of the investigated compounds determined by means of the Soczewinski-Wachtmeister formula was useful to obtain the values of the experimental lipophilicity parameter expressed as logP_TLC. The results of logP_TLC were compared with theoretical values of logP obtained using different algorithms (iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, and ClogP). Furthermore, the online platforms, such as SwissADME and pkCSM, allowed the determination of the remaining ADME parameters of the quinoline derivatives of chlorpromazine. The study of lipophilicity and ADME factors enabled confirmation that the tested compounds demonstrated favorable properties. Therefore, they can be considered as promising starting structures for further studies.