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Communication

Anticancer Efficacy of Antibacterial Quinobenzothiazines

by
Ewa Kisiel-Nawrot
1,
Malgorzata Latocha
2,
Andrzej Bak
3,
Violetta Kozik
3,
Josef Jampilek
4,5,* and
Andrzej Zieba
1,*
1
Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Jagiellonska 4, 41-200 Sosnowiec, Poland
2
Department of Cell Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Jednosci 9, 41-200 Sosnowiec, Poland
3
Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland
4
Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
5
Department of Chemical Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 783 71 Olomouc, Czech Republic
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2023, 13(5), 2886; https://doi.org/10.3390/app13052886
Submission received: 16 January 2023 / Revised: 20 February 2023 / Accepted: 22 February 2023 / Published: 23 February 2023
(This article belongs to the Special Issue Biomaterial Synthesis and Application)
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Versions Notes

Abstract

:
The antitumor potency of a series of designed and prepared antibacterial quinobenzothiazines was evaluated against different types of human cancer cell lines, such as glioblastoma SNB-19, lung adenocarcinoma A549 and breast cancer T47D, and the activities of the compounds were compared to cisplatin and doxorubicin. 9-Propoxy-5-methyl-12H-quino[3,4-b][1,4]benzo- thiazinium chloride (4a), 9-allyloxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (4d) and 11-benzyloxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (4l) were the most active compounds; their IC50 values against all three cell lines ranged from 5.3 to 9.3 µM. The effective derivatives showed no cytotoxic effect up to 100 µM on normal human dermal fibroblasts (NHDFs). To explore the structure–activity relationship, the effect of the type/nature and position of the substituents on the tetracyclic quinobenzothiazine system on the anticancer activity was investigated. Additionally, the receptor-dependent approach was used to specify the mutual ligand–enzyme (bio)compositions that might be potentially valid for the antitumor characteristics of new quinobenzothiazine derivatives. In particular, the molecular docking procedure was applied for the most potent agents against the human breast cancer line T47D in order to obtain comprehensive knowledge about the aromatase–inhibitor binding mode. The docking study revealed that some regularities in the spatial atomic distribution and nonbonding interactions (e.g., hydrophobic patterns) can be observed for the most active molecules. The surface of the electron-rich aromatic rings of 4d and 4l molecules could also contribute to π–π stacking interactions with protoporphyrin IX (HEM) as well as to the formation of π–cation interactions with the adjacent iron cofactor.

1. Introduction

The cancerous growth of various tissues has become one of the most frequent causes of illness and death. According to the statistics of the World Health Organization, breast, lung, colon, rectal and prostate cancers are in the first place. It can be stated that, in total, cancer caused almost 10 million deaths in 2020: i.e., every sixth patient died of cancer [1]. For example, in 2008, cancer was the cause of 7.5 million deaths, which was approximately 13% of all deaths [2]. These data show a trend of cancer incidence growth in spite of better diagnostics and treatment. It is important to mention that these diagnoses and their occurrence are highly correlated with the income of the population in different regions of the world. Areas with high incomes also have higher rates of cancer than areas with low incomes. On the one hand, about one-third of cancer deaths are due to high body weight, the heavy consumption of alcohol and tobacco products, a diet low in fruit and vegetables, little physical activity and high levels of stress [1,2]. On the other hand, infections causing cancer, e.g., hepatitis and human papillomavirus, cause about 30% of cancer cases in low- and middle-income regions. Another group, which is more or less unaffected by income, represents the hereditary burden, such as in the case of breast cancer [1,2].
Worldwide, great attention is paid to the discovery and development of various anticancer drugs. A wide variety of compounds with different antiproliferative mechanisms of action are currently in use. In general, antineoplastics can be classified into alkylating agents, antimetabolites, cytotoxic antibiotics, alkaloids and plant medicines, complexing compounds from the group of platinum cytostatics, protein kinase inhibitors and monoclonal antibodies [3,4,5,6,7,8]. A different drug is suitable for each type of tumor growth. It can be stated that the resistance of tumor cells represents a major problem that combined therapy tries to overcome. Currently, the eyes of the professional and lay public are focused on the therapeutic use of nanoparticles/nanoformulated antineoplastics and a wide range of drug delivery nanosystems [5,9,10,11].
Apoptosis, as programmed, self-automated cell death, is critical for body homeostasis and cellular integrity. Moreover, the impairment of apoptotic process execution can lead to the appearance of various diseases, including breast cancer [12]. Hence, targeting apoptosis regulators and/or inducers in cancer cells is an appealing strategy for the treatment of hormone-sensitive breast cancer. According to the apoptogenic hypothesis, the suppression of estrogen biosynthesis by aromatase inhibition can induce and stimulate apoptotic signaling pathways, reducing the risk of hormone-dependent breast cancer progression [13]. As a matter of fact, aromatase can be competitively inhibited by a diverse range of steroidal and nonsteroidal agents (e.g., phenothiazine derivatives carrying a benzenesulfonamide moiety); however, novel aromatase inhibitors (AIs) are urgently needed due to side-effect issues (e.g., drug resistance) [14].
Due to their structures, heterocyclic compounds have the ability to interact with a wide variety of biological targets [15,16,17,18] and undoubtedly play an essential role in the design of antineoplastics [19,20,21,22,23,24]. Notable heterocyclic structures are phenothiazine and quinoline scaffolds, which are included in many drugs. Phenothiazines are used as antipsychotics/neuroleptics, antihistamines, antiemetics, antipruritics, analgesics and anthelmintics [3,25,26,27]. Quinolines can be found in anti-invasive, analgesic, anticonvulsant, anti-Alzheimer, and antioxidant drugs or in drugs affecting the cardiovascular system and smooth muscles [3,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43].
The fusion of the two scaffolds results in a tetracyclic platform of quinobenzothiazines showing primarily anticancer and antibacterial activities [44,45,46,47,48,49]. Subsequent studies resulted in the design of angularly fused quino[3,4-b][1,4]benzothiazines, which demonstrated significant in vitro anticancer activity against a spectrum of human cancer cell lines [50,51,52]. In an earlier work, a unique, original method for the synthesis of azaphenothiazine derivatives was presented [53], which allows the formation of derivatives containing specific substituents at different positions of the tetracyclic quinobenzothiazinium system. The method involves the reaction of thioquinanthrenediinium bis-chloride (1) with substituted isomeric hydroxyanilines (2). The intermediate product of these reactions is a betaine system with the structure of 1-methyl-4-(phenylamino)quinoline-3-thiolate (3), the cyclization of which leads to the formation of a thiazine ring. The control of the parameters of the cyclization reaction enables its selective course and allows the unique introduction of various types of substituents in the 9, 10 and 11 positions of the quino[3,4-b][1,4]benzothiazine scaffold (see Scheme 1). Using this method of synthesis, a series of propoxy, allyloxy, propargyloxy and benzyloxy derivatives were obtained (see Table 1).
Recently, antimicrobial activity against Gram-positive bacteria and mycobacteria has also been reported [53]. From the point of view of the treatment of oncological patients in whom anticancer therapy causes general immunosuppression, in addition to resistant nosocomial pathogens, common infections or opportunistic pathogens pose a great threat to life for these patients, it is advantageous if the compounds show anticancer and antimicrobial activities [54,55,56]. This fact led us to the goal of this study, namely, to perform a primary in vitro anticancer screening of active antimicrobial agents investigated recently [53]. Furthermore, the molecular docking approach was used for the most potent agents against the human breast cancer line T47D in order to gain insight into the aromatase–inhibitor binding mode, which might be potentially valid for the antitumor characteristics of new quinobenzothiazine derivatives.

2. Materials and Methods

2.1. Chemistry

The detailed synthesis of alkoxy 5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chlorides 4a–l and the characterization of all compounds were described recently [53].

2.2. In Vitro Cell Viability Analysis

Human glioblastoma SNB-19, lung adenocarcinoma A549 and breast T47D cancer cell lines were employed for in vitro antiproliferative assays. Normal human dermal fibroblasts (NHDFs) were used as a control for the cytotoxic effect on human noncancer cells. The in vitro cell viability effects of the compounds were evaluated using the Cell Proliferation Reagent WST-1 assay (Roche Molecular Biochemicals Mannheim, Germany). Detailed conditions and implementation were described by Empel et al. [52] and by Kisiel-Nawrot et al. [53]. The in vitro cell viability of individual human cell lines was expressed as the IC50 [µM] value. The results are shown in Table 1.

2.3. Molecular Docking Study

CACTVS/csed and CORINA editors were used to generate 3-dimensional molecular models of the 4a–l ligand population. The data format conversion was conducted using the OpenBabel (inter)change file format converter. The Sybyl-X 2.0/Certara package installed on a DELL workstation with Ubuntu 20.10 operating system was employed to perform the molecular modeling simulations. The Sybyl-X MAXMIN2 module was used to initially optimize the compound spatial geometry with the standard Tripos force field (POWELL conjugate gradient algorithm) with a 0.01 kcal/mol energy gradient convergence criterion. The crystal structure of human placental aromatase cytochrome P450 in complex with androstenedione at 2.90 Å resolution was downloaded from the PDB repository (PDB code: 3eqm) [57]. Apart from protoporphyrin IX containing an iron ion (C34H32FeN4O4), all remaining heteroatoms, including the 4-androstene-3-17-dione (ASD) molecule, were eradicated from the AC2 binding site prior to docking in the AutoDock Vina 1.2.0 program [58]. Initially, the ligand/enzyme structures were prepared in the pdbqt file format with the calculated Gasteiger charges. The grid box (size 15 × 15 × 15 Å) was centered on the central atom of the ASD analog. In AutoDock Vina, docking simulations of different poses (default nine) were generated progressively from a single conformer (an energy-optimized molecule). The resulting molecular conformations and orientations (poses) with the preferred torsion angles and rotatable bonds were then evaluated by the united-atom (UA) scoring function. Schrödinger Maestro graphical viewers and Protein-Ligand Interaction Profiler (PLIP) were employed to illustrate the foreseen 2D/3D binding modes, respectively.

3. Results and Discussion

All recently described target alkoxyquinolinobenzothiazinium chlorides 4a–l [53] were evaluated against human glioblastoma SNB-19, lung adenocarcinoma A549 and breast T47D cancer cell lines; i.e., cancer cells representing completely different cancers with different sensitivities were used. The abilities of compounds 4a–l to inhibit the viability of human cancer cells were compared with those of cisplatin and doxorubicin and expressed as IC50 values. Normal human dermal fibroblasts (NHDFs) were used as a control for the cytotoxic effect on human noncancer cells. All results are shown in Table 1.
9-Propoxy derivative 4a against SNB-19 and A549 cells, 9-allyloxy derivative 4d against A549 and T47D cells and 11-benzyloxy derivative 4l against SNB-19 and T47D cells were the most active compounds. On the other hand, 11-propargyloxy (4i), 11-allyloxy (4f) and 11-propoxy (4c) derivatives were the least active. These facts show the overall disadvantage of substitution at the C(11) position with a nonaromatic substituent. It should be noted that active derivatives did not exhibit cytotoxic effects up to 100 µM on NHDF cells. Only 4j, 4i and 4b demonstrated cytotoxicity, with IC50 values of 37.7, 47.5 and 65.5 µM, respectively, against NHDF cells.
The results in Table 1 show that anticancer activity is influenced by the type/nature of substitution and the position of individual substituents. From the activity against SNB-19 cells, it can be observed that the presence of a multiple bond and the number of unsaturated bonds (up to the formation of an aromatic ring) shift the efficacy within the trio of positional isomers from position C(9) (compound 4a) through C(10) (compounds 4e and 4h) to C(11) (compound 4l). The initially inactive derivatives 4c,f,i substituted at C(11) with an aliphatic chain turned into one of the most active compounds after benzyloxy substitution (compound 4l). For activity against A544 cells, substitution at the C(9) position with propoxy and allyloxy (compounds 4a, 4d) appears to be the most favorable. All three benzyloxy-substituted positional isomers 4j–l showed similar moderate activity. In the case of the T47D cell line, it can only be stated that derivatives substituted with a propoxy chain showed the worst activity; on the contrary, the presence of a chain with a multiple bond (allyloxy and propargyloxy) in position C(9)/C(10) and/or substitution with a benzyloxy moiety in position C(11) is advantageous.
Thus, it can be inferred that substitutions of C(9) with propoxy or allyloxy and C(11) with benzyloxy moieties seem to be the most advantageous for anticancer activity. This finding is consistent with previously published results [52], where the most significant antiproliferative activity was associated with substitution at the C(9) position with a simple small substituent, such as -OCH3, -F, -Cl or -Br. Unfortunately, this activity was against both cancer lines and noncancer NHDF cells [52]. High anticancer activity was also associated with substitution at the C(9) position with piperazine or the C(10) position with an N-pyrrolidinylethoxy chain. On the other hand, the substitution at the C(9) position of 5-methyl-12(H)-quino[3,4-b][1,4]benzothiazinium chloride with a phenyl ring caused a decrease in activity [51].
The published mechanisms of the antiproliferative effects of both derivatives substituted on the nitrogen atom of thiazine and similar derivatives substituted at the C(9) or C(10) positions of quino[3,4-b][1,4]benzothiazine indicate the binding of these compounds to cellular DNA [50,51]. The investigated angular quinobenzothiazinium salts are composed of two planar structural fragments mutually arranged in an L-shape [53], so it could be hypothesized that they are able to intercalate into the DNA helix, similar to, e.g., cytostatic anthracyclines [59]. Therefore, it can be assumed that propoxy/allyloxy substitution at the C(9) position or benzyloxy substitution at the C(11) position of 5-methyl-12(H)-quino[3,4-b][1,4]benzothiazinium chloride increases the stability of the DNA–agent complex by forming hydrogen bonds with purine and pyrimidine bases and results in the inhibition of cell proliferation.
In addition, the most potent anticancer agents, 4d and 4l (with in vitro antiproliferative activity against T47D breast cancer cell lines comparable to cisplatin), were docked into the AC2 active site of aromatase chain A in order to collate the binding pattern of alkoxyquinolinobenzothiazinium chlorides with the 4-androstene-3-17-dione (ASD) interacting mode. In spite of the noticeable structural variations between ASD and quinobenzothiazine derivatives 4d and 4l, some regularities in the spatial atomic distribution and nonbonding interactions (e.g., hydrophobic patterns) can be observed, as shown in Figure 1. On the whole, the resulting binding geometries specified for the most active molecules, 4d and 4l, resemble that of reference androstenedione (ASD). Notably, in the most energetically favorable poses of compounds 4d and 4l, the oxygen atoms of the allyloxy substituent (4d) and benzyloxy moiety (4l) are oriented similarly to the 3-keto oxygen of the six-membered ASD ring that is positioned near the Asp309 amino acid residue (see Figure 1a–c). The 17-keto oxygen of the ASD substrate forms hydrogen bonds (HBs) with Met374 and has a weaker interaction with NH1 of Arg115 [57], as presented in the spatial (3D) ligand–aromatase interaction diagram in Figure 2a. Interestingly, the faces of the electron-rich aromatic rings of 4d and 4l molecules could contribute to π–π stacking interactions with protoporphyrin IX (HEM) as well as form π–cation interactions with the adjacent iron cofactor, as illustrated in Figure 2b,c.

4. Conclusions

A series of antibacterially active quinobenzothiazines have been synthesized by the recently described method and tested in vitro for their anticancer activity against human glioblastoma SNB-19, lung adenocarcinoma A549 and breast cancer T47D cell lines. Three of the tested compounds showed remarkable activity on cancer lines, namely, 9-propoxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (4a), 9-allyloxy- 5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (4d) and 11-benzyloxy-5-methyl- 12H-quino[3,4-b][1,4]benzothiazinium chloride (4l), which had IC50 values against all three cell lines ranging from 5.3 to 9.3 µM. At the same time, the compounds showed no cytotoxic effect on normal human dermal fibroblasts (NHDFs). Based on the observed influence of the type/nature of substitution and the position of individual substituents on activity, it can be concluded that substitutions of C(9) with propoxy and/or allyloxy tails or C(11) with a benzyloxy moiety are crucial for anticancer activity. The least favorable is a propargyl group in all positions, as well as substitution with a benzyloxy moiety in the C(9) and C(10) positions. An intercalation mechanism of action can probably be assumed; however, all three compounds deserve the attention of further detailed investigation.
Hence, the molecular docking approach was employed for the most potent agents against the human breast cancer line T47D in order to gain a comprehensive insight into the aromatase–inhibitor binding mode, which might be potentially valid for the antitumor characteristics of new quinobenzothiazines. Despite some structural variations between androstenedione (ASD) and quinobenzothiazine derivatives 4d and 4l, some regularities in the spatial atomic distribution and nonbonding interactions (e.g., hydrophobic patterns) can be observed. Basically, the resulting binding geometries determined for the most active molecules, 4d and 4l, resemble that of the reference ASD compound. Evidently, the oxygen atoms of the allyloxy substituent (4d) and benzyloxy moiety (4l) are oriented similarly to the 3-keto oxygen of the six-membered ASD ring, which is positioned near the Asp309 amino acid residue. Interestingly, the faces of the electron-rich aromatic rings of 4d and 4l molecules could contribute to π–π stacking interactions with protoporphyrin IX (HEM) as well as form π–cation interactions with the adjacent iron cofactor.
The observation of anticancer activity is partially consistent with our recent findings on antimicrobial activity, where substitution at the C(9) position with a propoxy or allyloxy moiety was favorable in terms of antibacterial activity. Thus, compounds 4a and 4h can be considered interesting anti-invasive agents with dual (anticancer and antibacterial) activity, while compound 4l is the most interesting purely anticancer agent.

Author Contributions

Conceptualization, A.Z. and J.J.; methodology, A.Z. and M.L.; investigation, E.K.-N., M.L., V.K. and A.B.; writing—original draft preparation, A.Z. and J.J.; writing—review and editing, J.J. and A.B.; funding acquisition, A.Z. and J.J. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Medical University of Silesia in Katowice, Grant No. PCN-1-039/K/2/F. The study was also supported by the Operation Program of Integrated Infrastructure for the project UpScale of Comenius University Capacities and Competence in Research, Development and Innovation, ITMS2014+: 313021BUZ3, co-financed by the European Regional Development Fund.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. WHO—Cancer. 2022. Available online: https://www.who.int/news-room/fact-sheets/detail/cancer (accessed on 20 December 2022).
  2. WHO—Global Health Observatory. Cancer Mortality and Morbidity. Available online: http://www.who.int/gho/ncd/mortality_morbidity/cancer_text/en/index.html (accessed on 20 December 2022).
  3. Roche, V.F.; Zito, S.W.; Lemke, T.; Williams, D.A. Foye’s Principles of Medicinal Chemistry, 8th ed.; Wolters Kluwer: Baltimore, MD, USA, 2019. [Google Scholar]
  4. Roskoski, R. A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol. Res. 2015, 100, 1–23. [Google Scholar] [CrossRef] [PubMed]
  5. Jampilek, J.; Kralova, K. Insights into lipid-based delivery nanosystems of protein-tyrosine kinase inhibitors for cancer therapy. Pharmaceutics 2022, 14, 2706. [Google Scholar] [CrossRef] [PubMed]
  6. Pottier, C.; Fresnais, M.; Gilon, M.; Jerusalem, G.; Longuespee, R.; Sounni, N.E. Tyrosine kinase inhibitors in cancer: Breakthrough and challenges of targeted therapy. Cancers 2020, 12, 731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Zahavi, D.; Weiner, L. Monoclonal antibodies in cancer therapy. Antibodies 2020, 9, 34. [Google Scholar] [CrossRef]
  8. Jin, S.; Sun, Y.; Liang, X.; Gu, X.; Ning, J.; Xu, Y.; Chen, S.; Pan, L. Emerging new therapeutic antibody derivatives for cancer treatment. Sig. Transduct. Target Ther. 2022, 7, 39. [Google Scholar] [CrossRef]
  9. Jampilek, J.; Kralova, K. Advances in drug delivery nanosystems using graphene-based materials and carbon nanotubes. Materials 2021, 14, 1059. [Google Scholar] [CrossRef]
  10. Jampilek, J.; Kralova, K. Anticancer applications of essential oils formulated into lipid-based delivery nanosystems. Pharmaceutics 2022, 14, 2681. [Google Scholar] [CrossRef]
  11. Yang, T.; Zhai, J.; Hu, D.; Yang, R.; Wang, G.; Li, Y.; Liang, G. “Targeting design” of nanoparticles in tumor therapy. Pharmaceutics 2022, 14, 1919. [Google Scholar] [CrossRef]
  12. Ding, X.L.; Zhang, H.Y.; Qi, L.; Zhao, B.X.; Lian, S.; Lv, H.S.; Miao, J.Y. Synthesis of novel pyrazole carboxamide derivatives and discovery of modulators for apoptosis or autophagy in A549 lung cancer cells. Bioorg. Med. Chem. Lett. 2009, 19, 5325–5328. [Google Scholar] [CrossRef]
  13. Fayed, E.A.; Eissa, S.I.; Bayoumi, A.H.; Gohar, N.A.; Mehany, A.B.M.; Ammar, Y.A. Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents. Mol. Divers. 2019, 23, 165–181. [Google Scholar] [CrossRef]
  14. Alam, M.J.; Alam, O.; Naim, M.J.; Nawaz, F.; Manaithiya, A.; Imran, M.; Thabet, H.K.; Alshehri, S.; Ghoneim, M.M.; Alam, P.; et al. Recent advancement in drug design and discovery of pyrazole biomolecules as cancer and inflammation therapeutics. Molecules 2022, 27, 8708. [Google Scholar] [CrossRef] [PubMed]
  15. Vinsova, J.; Cermakova, K.; Tomeckova, A.; Ceckova, M.; Jampilek, J.; Cermak, P.; Kunes, J.; Dolezal, M.; Staud, F. Synthesis and antimicrobial evaluation of new 2-substituted 5,7-di-tert-butylbenzoxazoles. Bioorg. Med. Chem. 2006, 14, 5850–5865. [Google Scholar] [CrossRef] [PubMed]
  16. Fajkusova, D.; Pesko, M.; Keltosova, S.; Guo, J.; Oktabec, Z.; Vejsova, M.; Kollar, P.; Coffey, A.; Csollei, J.; Kralova, K.; et al. Anti-infective and herbicidal activity of N-substituted 2-aminobenzothiazoles. Bioorg. Med. Chem. 2012, 20, 7059–7068. [Google Scholar] [CrossRef] [PubMed]
  17. Imramovsky, A.; Pejchal, V.; Stepankova, S.; Vorcakova, K.; Jampilek, J.; Vanco, J.; Simunek, P.; Kralovec, K.; Bruckova, L.; Mandikova, J.; et al. Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]thiazoles as cholinesterase inhibitors. Bioorg. Med. Chem. 2013, 21, 1735–1748. [Google Scholar] [CrossRef] [PubMed]
  18. Taylor, A.P.; Robinson, R.P.; Fobian, Y.M.; Blakemore, D.C.; Jones, L.H.; Fadeyi, O. Modern advances in heterocyclic chemistry in drug discovery. Org. Biomol. Chem. 2016, 14, 6611–6637. [Google Scholar] [CrossRef]
  19. Drug Discovery World: The Importance of Heterocyclic Compounds in Anti-Cancer Drug Design. Available online: https://www.ddw-online.com/the-importance-of-heterocyclic-compounds-in-anti-cancer-drug-design-1106-201708/ (accessed on 10 February 2023).
  20. Ali, I.; Lone, M.N.; Al-Othman, Z.A.; Al-Warthan, A.; Sanagi, M.M. Heterocyclic scaffolds: Centrality in anticancer drug development. Curr. Drug Targets 2015, 16, 711–734. [Google Scholar] [CrossRef]
  21. Lang, D.K.; Kaur, R.; Arora, R.; Saini, B.; Arora, S. Nitrogen-containing heterocycles as anticancer agents: An overview. Anticancer Agents Med. Chem. 2020, 20, 2150–2168. [Google Scholar] [CrossRef]
  22. Amewu, R.K.; Sakyi, P.O.; Osei-Safo, D.; Addae-Mensah, I. Synthetic and naturally occurring heterocyclic anticancer compounds with multiple biological targets. Molecules 2021, 26, 7134. [Google Scholar] [CrossRef]
  23. Martins, P.; Jesus, J.; Santos, S.; Raposo, L.R.; Roma-Rodrigues, C.; Baptista, P.V.; Fernandes, A.R. Heterocyclic anticancer compounds: Recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules 2015, 20, 16852–16891. [Google Scholar] [CrossRef]
  24. Banik, B.K.; Banerjee, B. Heterocyclic Anticancer Agents; De Gruyter: Berlin, Germany, 2022. [Google Scholar]
  25. Mosnaim, A.D.; Ranade, V.V.; Wolf, M.E.; Puente, J.; Valenzuela, M.A. Phenothiazine molecule provides the basic chemical structure for various classes of pharmacotherapeuticagents. Am. J. Therapeut. 2006, 13, 261–273. [Google Scholar] [CrossRef]
  26. Pluta, K.; Morak-Mlodawska, B.; Jelen, M. Recent progress in biological activities of synthesized phenothiazines. Eur. J. Med. Chem. 2011, 46, 3179–3189. [Google Scholar] [CrossRef] [PubMed]
  27. Hashizume, M.; Takashima, A.; Ono, C.; Okamoto, T.; Iwasaki, M. Phenothiazines inhibit SARS-CoV-2 cell entry via a blockade of spike protein binding to neuropilin-1. Antiviral. Res. 2022, 209, 105481. [Google Scholar] [CrossRef] [PubMed]
  28. Rajesh, Y.B.R.D. Quinoline heterocycles: Synthesis and bioactivity. In Heterocycles; Nandeshwarappa, B.P., Sadashiv, S.O., Eds.; IntechOpen: Rijeka, Croatia, 2018; Available online: https://www.intechopen.com/chapters/64434 (accessed on 11 January 2023).
  29. Ajani, O.O.; Iyaye, K.T.; Ademosun, O.T. Recent advances in chemistry and therapeutic potential of functionalized quinoline motifs—A review. RSC Adv. 2022, 12, 18594–18614. [Google Scholar] [CrossRef] [PubMed]
  30. Matada, B.S.; Pattanashettar, R.; Yernale, N.G. A comprehensive review on the biological interest of quinoline and its derivatives. Bioorg. Med. Chem. 2021, 32, 115973. [Google Scholar] [CrossRef] [PubMed]
  31. Mrozek-Wilczkiewicz, A.; Kalinowski, D.S.; Musiol, R.; Finster, J.; Szurko, A.; Serafin, K.; Knas, M.; Kamalapuram, S.K.; Kovacevic, Z.; Jampilek, J.; et al. Investigating the anti-proliferative activity of styrylazanaphthalenes and azanaphthalenediones. Bioorg. Med. Chem. 2010, 18, 2664–2671. [Google Scholar] [CrossRef] [PubMed]
  32. Musiol, R.; Jampilek, J.; Nycz, J.E.; Pesko, M.; Carroll, J.; Kralova, K.; Vejsova, M.; O’Mahony, J.; Coffey, A.; Mrozek, A.; et al. Investigating the activity spectrum for ring-substituted 8-hydroxyquinolines. Molecules 2010, 15, 288–304. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Kos, J.; Zadrazilova, I.; Nevin, E.; Soral, M.; Gonec, T.; Kollar, P.; Oravec, M.; Coffey, A.; O’Mahony, J.; Liptaj, T.; et al. Ring-substituted 8-hydroxyquinoline-2-carboxanilides as potential antimycobacterial agents. Bioorg. Med. Chem. 2015, 23, 4188–4196. [Google Scholar] [CrossRef]
  34. Pavic, K.; Perkovic, I.; Pospisilova, S.; Machado, M.; Fontinha, D.; Prudencio, M.; Jampilek, J.; Coffey, A.; Endersen, L.; Rimac, H.; et al. Primaquine hybrids as promising antimycobacterial and antimalarial agents. Eur. J. Med. Chem. 2018, 143, 769–779. [Google Scholar] [CrossRef]
  35. Kushkevych, I.; Vitezova, M.; Kos, J.; Kollar, P.; Jampilek, J. Effect of selected 8-hydroxyquinoline-2-carboxanilides on viability and sulfate metabolism of Desulfovibrio piger. J. Appl. Biomed. 2018, 16, 241–246. [Google Scholar] [CrossRef]
  36. Kos, J.; Ku, C.F.; Kapustikova, I.; Oravec, M.; Zhang, H.J.; Jampilek, J. 8-Hydroxyquinoline-2-carboxanilides as antiviral agents against avian influenza virus. ChemistrySelect 2019, 4, 4582–4587. [Google Scholar] [CrossRef]
  37. Luchi, R.J.; Conn, H.L.; Helwig, J. Cardiovascular effects of a quinidine-related compound, 4-hydroxymethyl-6-methoxyquinoline. Am. J. Card. 1962, 10, 252–260. [Google Scholar] [CrossRef]
  38. Terron, J.A.; Hong, E.; Villalon, C.M. Pharmacological screening of some quinoline derivatives in canine vascular smooth muscle. Arch. Med. Res. 1994, 25, 435–440. [Google Scholar] [PubMed]
  39. Moor, L.F.E.; Vasconcelos, T.R.A.; da Reis, R.; Pinto, L.S.S.; da Costa, T.M. Quinoline: An attractive scaffold in drug design. Mini Rev. Med. Chem. 2021, 21, 2209–2226. [Google Scholar] [CrossRef]
  40. Dib, M.; Ouchetto, H.; Ouchetto, K.; Hafid, A.; Khouili, M. Recent developments of quinoline derivatives and their potential biological activities. Curr. Org. Synth. 2021, 18, 248–269. [Google Scholar] [CrossRef] [PubMed]
  41. Yadav, P.; Shah, K. Quinolines, a perpetual, multipurpose scaffold in medicinal chemistry. Bioorg. Chem. 2021, 109, 104639. [Google Scholar] [CrossRef]
  42. Balaji, S.; Neupane, R.; Malla, S.; Khupse, R.; Amawi, H.; Kumari, S.; Tukaramrao, D.B.; Chattopadhyay, S.; Ashby, C.R.; Boddu, S.H.S.; et al. IND-2, a quinoline derivative, inhibits the proliferation of prostate cancer cells by inducing oxidative stress, apoptosis and inhibiting topoisomerase II. Life 2022, 12, 1879. [Google Scholar] [CrossRef]
  43. Sharma, S.; Singh, A.; Sharma, S.; Sharma, R.; Singh, J.; Kinarivala, N.; Nepali, K.; Liou, J.P. Tailored quinolines demonstrate flexibility to exert antitumor effects through varied mechanisms-a medicinal perspective. Anticancer Agents Med. Chem. 2021, 21, 288–315. [Google Scholar] [CrossRef]
  44. Zieba, A.; Sochanik, A.; Szurko, A.; Rams, M.; Mrozek, A.; Cmoch, P. Synthesis and in vitro antiproliferative activity of 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts. Eur. J. Med. Chem. 2010, 45, 4733–4739. [Google Scholar] [CrossRef]
  45. Zieba, A.; Czuba, Z.P.; Krol, W. In vitro antimicrobial activity of novel azaphenothiazine derivatives. Acta Pol. Pharm. 2012, 69, 1149–1152. [Google Scholar]
  46. Zieba, A.; Latocha, M.; Sochanik, A. Synthesis and in vitro antiproliferative activity of novel 12(H)-quino[3,4-b][1,4]benzothiazine derivatives. Med. Chem. Res. 2013, 22, 4158–4163. [Google Scholar] [CrossRef] [Green Version]
  47. Jonczyk, J.; Godyn, J.; Stawarska, E.; Morak-Mlodawska, B.; Jelen, M.; Pluta, K.; Malawska, B. Dual action of dipyridothiazine and quinobenzothiazine derivatives—Anticancer and cholinesterase-inhibiting activity. Molecules 2020, 25, 2604. [Google Scholar] [CrossRef] [PubMed]
  48. Owczarzy, A.; Zieba, A.; Pozycka, J.; Kulig, K.; Rogoz, W.; Szkudlarek, A.; Maciazek-Jurczyk, M. Spectroscopic studies of quinobenzothiazine derivative in terms of the in vitro interaction with selected human plasma proteins. Part 1. Molecules 2021, 26, 4776. [Google Scholar] [CrossRef] [PubMed]
  49. Skonieczna, M.; Kasprzycka, A.; Jelen, M.; Morak-Mlodawska, B. Tri- and pentacyclic azaphenothiazine as pro-apoptotic agents in lung carcinoma with a protective potential to healthy cell lines. Molecules 2022, 27, 5255. [Google Scholar] [CrossRef]
  50. Pluta, K.; Szmielew, M.; Suwinska, K.; Latocha, M. Synthesis, spectroscopic structure identification, X-ray study and anticancer activities of new angularly fused quinobenzothiazines. J. Mol. Struct. 2016, 1122, 62–71. [Google Scholar] [CrossRef]
  51. Zieba, A.; Latocha, M.; Sochanik, A.; Nycz, A.; Kusmierz, D. Synthesis and in vitro antiproliferative activity of novel phenyl ring-substituted 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazine derivatives. Molecules 2016, 21, 1455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Empel, A.; Bak, A.; Kozik, V.; Latocha, M.; Cizek, A.; Jampilek, J.; Suwinska, K.; Sochanik, A.; Zieba, A. Towards property profiling: Synthesis and SAR probing of new tetracyclic diazaphenothiazineanalogues. Int. J. Mol. Sci. 2021, 22, 12826. [Google Scholar] [CrossRef] [PubMed]
  53. Kisiel-Nawrot, E.; Pindjakova, D.; Latocha, M.; Bak, A.; Kozik, V.; Suwinska, K.; Sochanik, A.; Cizek, A.; Jampilek, J.; Zieba, A. Design, synthesis and antimicrobial properties of new tetracyclic quinobenzothiazine derivatives. Int. J. Mol. Sci. 2022, 23, 15078. [Google Scholar] [CrossRef]
  54. Diaconu, D.; Antoci, V.; Mangalagiu, V.; Amariucai-Mantu, D.; Mangalagiu, I.I. Quinoline–imidazole/benzimidazole derivatives as dual-/multi-targeting hybrids inhibitors with anticancer and antimicrobial activity. Sci. Rep. 2022, 12, 16988. [Google Scholar] [CrossRef]
  55. Parchebafi, A.; Tamanaee, F.; Ehteram, H.; Ahmad, E.; Nikzad, H.; Haddad Kashani, H. The dual interaction of antimicrobial peptides on bacteria and cancer cells; mechanism of action and therapeutic strategies of nanostructures. Microb. Cell Fact. 2022, 21, 118. [Google Scholar] [CrossRef]
  56. El-Dash, Y.; Elzayat, E.; Abdou, A.M.; Hassan, R.A. Novel thienopyrimidine-aminothiazole hybrids: Design, synthesis, antimicrobial screening, anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis and VEGFR-2 inhibition. Bioorg. Chem. 2021, 114, 105137. [Google Scholar] [CrossRef]
  57. Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural basis for androgen specificity and oestrogen synthesis in human aromatase. Nature 2009, 457, 219–223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Eberhardt, J.; Santos-Martins, D.; Tillack, A.F.; Forli, S. AutoDock Vina 1.2.0: New docking methods, expanded force field, and Python bindings. J. Chem. Inf. Model. 2021, 61, 3891–3898. [Google Scholar] [CrossRef] [PubMed]
  59. Venkatesh, P.; Kasi, A. Anthracyclines; StatPearls Publishing: Tampa, FL, USA, 2022. Available online: https://www.ncbi.nlm.nih.gov/books/NBK538187 (accessed on 22 December 2022).
Applsci 13 02886 sch001 550
Scheme 1. Synthesis of alkoxy 5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chlorides 4a–l. Reagents and conditions: (a) pyridine, 20–80 °C; (b) pyridine, HCl, O2 [53].
Scheme 1. Synthesis of alkoxy 5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chlorides 4a–l. Reagents and conditions: (a) pyridine, 20–80 °C; (b) pyridine, HCl, O2 [53].
Applsci 13 02886 sch001
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Figure 1. Planar ligand interaction diagram for 4-androstene-3-17-dione (a) and the most potent inhibitors, 9-allyloxy derivative 4d (b) and 11-benzyloxy derivative 4l (c), generated by the Schrödinger Maestro program.
Figure 1. Planar ligand interaction diagram for 4-androstene-3-17-dione (a) and the most potent inhibitors, 9-allyloxy derivative 4d (b) and 11-benzyloxy derivative 4l (c), generated by the Schrödinger Maestro program.
Applsci 13 02886 g001
Applsci 13 02886 g002 550
Figure 2. Spatial comparison of binding interactions for ASD (a) and the most potent inhibitors, 9-allyloxy derivative 4d (b) and 11-benzyloxy derivative 4l (c), generated by the PLIP tool.
Figure 2. Spatial comparison of binding interactions for ASD (a) and the most potent inhibitors, 9-allyloxy derivative 4d (b) and 11-benzyloxy derivative 4l (c), generated by the PLIP tool.
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Table
Table 1. Structures of discussed agents 4a–l and in vitro antiproliferative activity against human cancer cell lines and cell viability of normal human cells (IC50 [µM] ± SD, n = 6) of investigated agents compared to drugs.
Table 1. Structures of discussed agents 4a–l and in vitro antiproliferative activity against human cancer cell lines and cell viability of normal human cells (IC50 [µM] ± SD, n = 6) of investigated agents compared to drugs.
Applsci 13 02886 i001
Comp.RIC50 [μM]
SNB-19A549T47DNHDF
4a9-OCH2CH2CH38.9 ± 0.75.3 ± 1.126.9 ± 3.2>100
4b10-OCH2CH2CH311.4 ± 0.818.4 ± 1.214.7 ± 1.165.5 ± 9.7
4c11-OCH2CH2CH318.9 ± 1.423.1 ± 1.819.2 ± 1.2>100
4d9-OCH2CH=CH215.6 ± 0.96.7 ± 0.47.8 ± 09>100
4e10-OCH2CH=CH215.0 ± 1.819.3 ± 1.115.7 ± 0.9>100
4f11-OCH2CH=CH218.9 ± 1.420.6 ± 1.826.7 ± 1.2>100
4g9-OCH2C≡CH17.2 ± 1.318.0 ± 0.912.9 ± 1.2>100
4h10-OCH2C≡CH11.5 ± 0.517.7 ± 0.810.7 ± 1.1>100
4i11-OCH2C≡CH36.1 ± 5.621.8 ± 2.444.3 ± 4.247.5 ± 3.5
4j9-OCH2C6H511.3 ± 0.814.7 ± 0.721.1 ± 1.337.7 ± 3.4
4k10-OCH2C6H512.0 ± 0.914.5 ± 0.613.5 ± 1.1>100
4l11-OCH2C6H56.6 ± 0.414.3 ± 079.3 ± 0.6>100
CPT−16.7 ± 1.33.0 ± 0.29.0 ± 0.729.9 ± 3.3
DOX−1.7 ± 0.21.3 ± 0.10.8 ± 0.15.5 ± 0.5
SNB-19—human glioblastoma cells; A549—lung adenocarcinoma cells; T47D—breast cancer cells; NHDF—normal human dermal fibroblasts; CPT—cisplatin; DOX—doxorubicin.
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Kisiel-Nawrot, E.; Latocha, M.; Bak, A.; Kozik, V.; Jampilek, J.; Zieba, A. Anticancer Efficacy of Antibacterial Quinobenzothiazines. Appl. Sci. 2023, 13, 2886. https://doi.org/10.3390/app13052886

AMA Style

Kisiel-Nawrot E, Latocha M, Bak A, Kozik V, Jampilek J, Zieba A. Anticancer Efficacy of Antibacterial Quinobenzothiazines. Applied Sciences. 2023; 13(5):2886. https://doi.org/10.3390/app13052886

Chicago/Turabian Style

Kisiel-Nawrot, Ewa, Malgorzata Latocha, Andrzej Bak, Violetta Kozik, Josef Jampilek, and Andrzej Zieba. 2023. "Anticancer Efficacy of Antibacterial Quinobenzothiazines" Applied Sciences 13, no. 5: 2886. https://doi.org/10.3390/app13052886

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