Synthesis of new quinoline analogs of selected neuroleptics

Introduction Neuroleptics are used as psychotropic medication for treatment of psychosis, schizophrenia, bipolar disorder, apathy and neurosis. The latest research on their biological activity shows their new activities including anticancer against brain, lung, breast, liver and colon cancer, antiviral against SARS-CoV and suppression of infections caused by dengue virus. Neuroleptics such as fluphenazine, triflupromazine and trifluoperazine were the research subject. The aim of the study was to synthesize new quinoline analogs of selected neuroleptics as new drugs’ candidates with more beneficial ADMET profiles.

Methods To synthesize new quinoline analogs, 6H-8-trifluoromethylquinobenzothiazine was synthesized by the reaction of 2-amino-4-trifluoromethylthiphenol with 3-bromo-2-chloroquinoline. After synthesizing 6H-8-trifluoromethylquinobenzothiazine its structure was confirmed by spectroscopic methods. Afterwards 6H-8-trifluoromethylquinobenzothiazine was used as a substrate to obtain new quinoline analogs with pharmacophore dialkylaminoalkyl substituents. The structure of each one of newly synthesized compounds was confirmed by the use of spectroscopic methods such as ¹H NMR, ¹³C NMR and ESI HR MS. All synthesized compounds were studied for anticancer activity against three human cancer cell lines: breast (MDA-MB-231), pancreatic (Mia-PaCa-2) and lung (A-549). Doxorubicin and cisplatin were used as reference drug. Human keratinocyte cell line (HaCaT) was used as healthy cells.

Results The research carried out allowed to synthesize 6H-8-trifluoromethylquinobenzothiazine and to obtain new quinoline analogs with pharmacophore dialkylaminoalkyl substituents. Currently, eleven new quinoline analogs were synthesized. The study for anticancer activity allowed to determine concentration of new compounds required for 50% inhibition of three human cancer cell lines.

Conclusions The method chosen to synthesize new quinoline analogs was effective and allowed eleven new compounds to be obtained. The study for anticancer activity against three human cancer cell lines concludes that there are three compounds that show the most promising anticancer activity (IC₅₀ < 5.5 μM).