10-(Prop-2-yn-1-yl)-2,7-diaza­phenothia­zine1

In the title mol­ecule [systematic name: 10-(prop-2-yn-1-yl)dipyrido[3,4-b:3′,4′-e][1,4]thia­zine], C13H9N3S, the dihedral angle between the two pyridine rings is 146.33 (7)° and the angle between two halves of the thia­zine ring is 138.84 (8)°, resulting in a butterfly shape for the tricyclic system. The central thia­zine ring adopts a boat conformation, with the 2-propynyl substituent at the thia­zine N atom located in a pseudo-equatorial position and oriented to the concave side of the diaza­phenothia­zine system. In the crystal, mol­ecules are arranged via π–π inter­actions between the pyridine rings [centroid–centroid distances = 3.838 (1) and 3.845 (1) Å] into stacks extending along [001]. There are C—H⋯C and C—H⋯N inter­actions between mol­ecules of neighbouring stacks

Dual action of dipyridothiazine and quinobenzothiazine derivatives : anticancer and cholinesterase-inhibiting activity

The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with $IC_{50}$ values from 0.78 to 19.32 $\mu$M, while their $IC_{50}$ values against eqBuChE ranged from 0.46 to 10.38 $\mu$M. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an $IC_{50}$ value of 0.46 $\mu$M. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives

Evaluation of the Lipophilicity of New Anticancer 1,2,3-Triazole-Dipyridothiazine Hybrids Using RP TLC and Different Computational Methods

Two new anticancer-active 1,2,3-triazole-dipyridothiazine hybrids were evaluated for their lipophilicity using thin-layer chromatography (TLC) and computational methods. The experimental lipophilicity was evaluated with mobile phases (mixtures of TRIS buffer and acetone), exploiting a linear correlation between the retention parameter (RM) and the volume of acetone. The relative lipophilicity parameter (RM0) was obtained by extrapolation to 0% acetone concentration. This parameter was intercorrelated with a specific hydrophobic surface area (b) revealing two congeneric subgroups: hybrids of 1,2,3-triazole-2,7-diazaphenothiazines and 1,2,3-triazole-3,6-diazaphenothiazines. The parameter RM0 was converted into the absolute lipophilicity parameter logPTLC using a calibration curve prepared on the basis of compounds of known logP values. Triazole–dipyridothiazine hybrids turned out to be medium lipophilic with logPTLC values of 1.232–2.979. The chromatographically established parameter logPTLC was compared to the calculated lipophilic parameter logPcalcd obtained with various algorithms. The lipophilicity was correlated with molecular descriptors and ADME properties. The new triazole–dipyridothiazine hybrids followed Lipinski’s rule of five. The lipophilicity of these hybrids was dependent on the substituents attached to the triazole ring and the location of the azine nitrogen atoms

Lipophilicity and Pharmacokinetic Properties of New Anticancer Dipyridothiazine with 1,2,3-Triazole Substituents

The lipophilicity parameters (logPcalcd, RM0 and logPTLC) of 10 new active anticancer dipirydothiazines with a 1,2,3-triazole ring were determined theoretically using computational methods and experimentally by reversed-phase TLC. Experimental lipophilicity was assessed using mobile phases (a mixture of TRIS buffer and acetone) using a linear correlation between the RM retention parameter and the volume of acetone. The RM0 parameter was correlated with the specific hydrophobic surface b, revealing two congenerative subgroups: 1,2,3-triazole-1,6-diazaphenothiazines and 1,2,3-triazole-1,8-diazaphenothiazines hybrids. The RM0 parameter was converted into the logPTLC lipophilicity parameter using a calibration curve. The investigated compounds appeared to be moderately lipophilic. Lipophilicity has been compared with molecular descriptors and ADME properties. The new derivatives followed Lipinski’s, Ghose’s and Veber’s rules

Lipophilicity and Pharmacokinetic Properties of New Anticancer Dipyridothiazine with 1,2,3-Triazole Substituents

The lipophilicity parameters (logPcalcd, RM0 and logPTLC) of 10 new active anticancer dipirydothiazines with a 1,2,3-triazole ring were determined theoretically using computational methods and experimentally by reversed-phase TLC. Experimental lipophilicity was assessed using mobile phases (a mixture of TRIS buffer and acetone) using a linear correlation between the RM retention parameter and the volume of acetone. The RM0 parameter was correlated with the specific hydrophobic surface b, revealing two congenerative subgroups: 1,2,3-triazole-1,6-diazaphenothiazines and 1,2,3-triazole-1,8-diazaphenothiazines hybrids. The RM0 parameter was converted into the logPTLC lipophilicity parameter using a calibration curve. The investigated compounds appeared to be moderately lipophilic. Lipophilicity has been compared with molecular descriptors and ADME properties. The new derivatives followed Lipinski’s, Ghose’s and Veber’s rules

Phenothiazines Modified with the Pyridine Ring as Promising Anticancer Agents

Azaphenothiazines are the largest and most perspective group of modified phenothiazines, and they exhibit variety of biological activities. The review sums up the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, which are modified azaphenothiazines with one and two pyridine rings, respectively, against 10 types of cancer cell lines. Some 10-substituted dipyridothiazines and even 10-unsubstituted parent compounds, such as 10H-1,9-diazaphenothiazine and 10H-3,6-diazaphenothiazine, exhibited very potent action with the IC50 values less than 1 µg/mL and 1 µM against selected cancer cell lines. The strength of the anticancer action depends both on the tricyclic ring scaffolds and the substituents at the thiazine nitrogen atom. The review discusses the kind of the substituents, nature of tricyclic ring scaffolds with the location of the azine nitrogen atoms, the types of the cancer cell lines, and the mechanism of action

Anticancer activities of tetra-, penta-, and hexacyclic phenothiazines modified with quinoline moiety.

The quinoline molecule is a chemical motif showing a highly promising pharmacological potential. Its numerous derivatives introduced into medicine revolutionized in the treatment of many entities of disease. The presence of the quinoline system in the structure of phenothiazines made it possible to obtain new aza- and diazaphenothiazine derivatives that show promising anticancer potential. The aza-analogs of the phenothiazines are structurally modified phenothiazines by the substitution of one or both benzene rings in the phenothiazine ring system with various azine rings. This approach to the strategy of obtaining new substances with biological potential can be classified as molecular hybridization methods consisting of the combination of two or more pharmacophores to develop compounds with improved properties. Recently, valuable reviews on phenothiazines have appeared in the scientific literature, but they focus on dibenzothiazines. This review summarises the knowledge on the anticancer activity of isomeric quinobenzothiazines, diqinothiazines, and quinobenzothiazinum salts, which are modified phenothiazines with one and two quinoline rings, respectively, against different types of cancer cell lines. Hybridization of these two leading structures, phenothiazines and quinoline, both very important in medicinal chemistry, resulted in obtaining a very large group of compounds with diverse structures and a diverse anticancer activity

Tri- and Pentacyclic Azaphenothiazine as Pro-Apoptotic Agents in Lung Carcinoma with a Protective Potential to Healthy Cell Lines

The phenothiazine derivatives, tricyclic 10H-3,6-diazaphenothiazine (DPT-1) and pentacyclic 7-(3′-dimethylaminopropyl)diquinothiazine (DPT-2), have recently been shown to exhibit promising anticancer activities in vitro. In this report, we demonstrated that DPT-1 and DPT-2 could be pro-apoptotic agents in lung carcinoma, the human lung carcinoma A549 and non-small lung carcinoma H1299, in the range of IC50 = 1.52–12.89 µM, with a protective potential to healthy cell lines BEAS-2B and NHDF. The compounds showed higher activity in the range of the tested concentrations and low cytotoxicity in relation to normal healthy cells than doxorubicin, used as the reference drug. The cytostatic potential of DPT-1 and DPT-2 was demonstrated with the use of MTT assay. Cell cycle analysis via flow cytometry using Annexin-V assay showed the pro-apoptotic and pro-necrotic role of the studied diazaphenothiazines in the cell cycle. DPT-1 and DPT-2 initiated a biological response in the investigated cancer models with a different mechanism and at a different rate. Based on these findings, it can be concluded that DPT-1 and DPT-2 have potential as chemotherapeutic agents