Towards Property Profiling: SYNTHESIS and SAR Probing of New Tetracyclic Diazaphenothiazine Analogues.
Anna Empel, Andrzej Bak, Violetta Kozik, Malgorzata Latocha, Alois Cizek, Josef Jampilek, Kinga Suwinska, Aleksander Sochanik, Andrzej Zieba
Author Information
Anna Empel: Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.
Andrzej Bak: Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland. ORCID
Violetta Kozik: Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland.
Malgorzata Latocha: Department of Cell Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jedności 9, 41-200 Sosnowiec, Poland.
Alois Cizek: Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Palackeho 1946/1, 61242 Brno, Czech Republic. ORCID
Josef Jampilek: Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 84215 Bratislava, Slovakia. ORCID
Kinga Suwinska: Faculty of Mathematics and Natural Sciences, Cardinal Stefan Wyszyński University, K. Woycickiego 1/3, 01-938 Warszawa, Poland. ORCID
Aleksander Sochanik: Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Wybrzeże AK 15, 44-101 Gliwice, Poland.
Andrzej Zieba: Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.
A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with the structure of 1-methyl-4-(3-pyridyl)aminoquinolinium-3-thiolate was related to the substituents in the 2- and 4-pyridine position. The structures of the compounds were analyzed using H, C NMR (COSY, HSQC, HMBC) and X-ray analysis, respectively. Moreover, the antiproliferative activity against tumor cells (A549, T47D, SNB-19) and a normal cell line (NHDF) was tested. The antibacterial screening of all the compounds was conducted against the reference and quality control strain ATCC 29213, three clinical isolates of methicillin-resistant (MRSA). In silico computation of the intermolecular similarity was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of structure/property-related descriptors calculated for the novel tetracyclic diazaphenothiazine derivatives. The distance-oriented property evaluation was correlated with the experimental anticancer activities and empirical lipophilicity as well. The quantitative shape-based comparison was conducted using the CoMSA method in order to indicate the potentially valid steric, electronic and lipophilic properties. Finally, the numerical sampling of similarity-related activity landscape (SALI) provided a subtle picture of the SAR trends.
