Design, Synthesis, Analysis, and Cytotoxicity of Novel Heteroaryl Derivatives of Dipyridothiazines

Heterocyclic compounds have enormous pharmacological potential and therefore play a key role in the design of new drugs. Dipyridothiazines, both heterocyclic compounds and phenothiazine derivatives, exhibit promising anticancer, immunostimulatory, and antioxidant activities. The aim of this study was to design, synthesize, and evaluate the cytotoxicity of new 10-heteroaryl dipyridothiazines based on 2,7- and 3,6-diazaphenothiazine cores. The structural characterization of the new compounds was confirmed by spectroscopic methods. Cytotoxicity analysis was performed using the MTT assay against human keratinocytes (HaCaT) and two types of cancer cell lines: breast cancer (MDA-MB-231), lung carcer (A-549). The reference drugs used in the study were doxorubicin and cisplatin. The group of derivatives studied included active compounds as well as inactive derivatives. In order to explain differences in an activity level, molecular modelling supported by molecular dynamics was performed on histone deacetylase 6 (HDAC6), a known therapeutic target associated with oncogenic transformation and cancer metastasis. Molecular docking indicated that the derivative formed on the 2,7-diazaphenothiazine core is a more potent HDAC6 inhibitor, characterized by more stable binding and more favourable complex energy, despite minimal structural differences compared to the compound formed on the 3,6-diazaphenothiazine core. A preliminary SAR analysis was performed.