A series of quaternary salts – 1-phenacyl(4-chlorophenacyl)-6-hydroxy-6,7-dihydro-5H-benzo[4,5]imidazo[2,1-b][1,3]thiazinium bromides 4a-f were obtained. Their structures were rigorously proven by the methods of 1H NMR, 13C NMR spectroscopy, and chromatography-mass spectrometry. All obtained compounds were tested in in vitro experiments for antibacterial, antifungal, and antioxidant activity. Bioscreening results showed that 1-(4-chlorophenacyl)-6-hydroxy-6,7-dihydro-5H-benzo[4,5]imidazo[2,1-b][1,3]thiazinium bromide 4f exhibits the highest antibacterial activity against the strain of gram-positive bacteria Staphylococcus aureus ATCC 25923 at a concentration of 125 μg/mL, and salts 4a, c, f – against strains of gram-negative bacteria Pseudomonas aeruginosa ATCC 27853 at a concentration of 62.5 μg/mL. In turn, salt 4c demonstrated the best rate of radical inhibition at the level of 69.3%.
[1] Tales, A. C.; Goulart, T. A. C.; Kazmirski, J. A. G.; Back, D. F.; Zeni, G. Cyclization of Thiopropargyl Benzimidazoles by Combining Iron (III) Chloride and Diorganyl Diselenides. J. Org. Chem. 2019, 84, 14113–14126.https://doi.org/10.1021/acs.joc.9b02276
[2] Muhammad, Z.A.; Farghaly, T.A.; Althagafi, I.; Al-Hussain, S. A.; Zaki, M. E. A.; Harras, M. F. Synthesis of Antimicrobial Azoloazines and Molecular Docking for Inhibiting COVID-19. J. Het. Chem. 2021, 58, 1286–1301. https://doi.org/10.1002/jhet.4257
[3] Ibeanu, F. N.; Ezeokonkwo, M. A.; Onoabedje, E. A.; Eze, C. C.; Godwin-Nwakwasi, E. U.; Okoro, U. C. Synthesis, Antimicrobial and Computational Studies of New Branched Azaphenothiazinones Derivatives. Chem. Chem. Technol. 2023, 17, 786–795. https://doi.org/10.23939/chcht17.04.786
[4] Radini, A. M.; Abdel-Wahab, B. F.; Khidre R. E. Synthetic Routes to Imidazothiazines. Phosphorus Sulfur Silicon Relat. Elem. 2016, 191, 844–856.https://doi.org/10.1080/10426507.2015.1119148
[5] Yüksek, H.; Medetalibeyoğlu, H.; Karadağ, M.; Manap S. Synthesis, Biological and Acidic Properties of Novel 2-Methoxy-6- [(3-Alkyl/Aryl-4,5-Dihydro-1H-1,2,4-Triazol-5-one-4-yl)- Azomethin]-Phenyl p-Nitrobenzoate Derivatives. Chem. Chem.Technol. 2023, 17, 766–773.https://doi.org/10.23939/chcht17.04.766
[6] Hamama, W. S.; Waly, M. A.; El-Hawary, I. I.; Zoorob, H. H. Utilization of 2-Chloronicotinonitrile in the Syntheses of Novel Fused Bicyclic and Polynuclear Heterocycles of Anticipated Antitumor Activity. J. Heterocycl. Chem. 2016, 53, 953–957. https://doi.org/10.1002/jhet.1631
[7] Nikolova, I.; Slavchev, I.; Ravutsov, M.; Dangalov, M.; Nikolova, Y.; Zagranyarska, I.; Stoyanova, A.; Nikolova, N.; Mukova, L.; Grozdanov, P. et al. Anti-Enteroviral Activity of New MDL-860 Analogues: Synthesis, in vitro/in vivo Studies and QSAR Analysis. Bioorg. Chem. 2019, 85, 487–497. https://doi.org/10.1016/j.bioorg.2019.02.020
[8] Ramos Rodríguez, А. О.; Magaña Vergara, N. Е.; Mojica Sánchez, J. Р.; Sumaya Martínez, М. Т.; Gómez Sandoval, Z.; Cruz, А.; Ramos Organillo, А. Synthesis, Crystal Structure, Antioxidant Activity and dft Study of 2-Aryl-2,3-dihydro-4H-[1,3]thiazino[3,2- a]benzimidazol-4-оne. J. Mol. Struct. 2020, 1199, 127036. https://doi.org/10.1016/j.molstruc.2019.127036
[9] LaFleur, M. D.; Lucumi, E.; Napper, A. D.; Diamond, S. L.; Lewis, K. Novel High-Throughput Screen against Candida albicans Identifies Antifungal Potentiators and Agents Effective against Biofilms. J. Antimicrob. Chemother. 2011, 66, 820–826. https://doi.org/10.1093/jac/dkq530
[10] Thompson, A. M.; O’Connor, P. D.; Marshall, A. J.; Francisco, A. F.; Kelly, J. M.; Riley, J.; Read, K. D.; Perez, C. J.; Cornwall, S.; Thompson, R. C.A. et al. Re-evaluating Pretomanid Analogues for Chagas Disease: Hit-to-Lead Studies Reveal Both in vitro and in vivo Trypanocidal Efficacy. Eur. J. Med. Chem. 2020, 207, 112849. https://doi.org/10.1016/j.ejmech.2020.112849
[11] Meriç, A.; İncesu, Z.; Hatipoğlu, I. Synthesis of Some 3,4- Disubstituted-6,7-dihydro-imidazo[2,1-b][1,3]thiazole and 3,4- Disubstituted-7,8-dihydro-6H-imidazo[2,1-b][1,3]thiazine Derivatives and Evaluation of their Cytotoxicities against F2408 and 5RP7 Cells. Med. Chem. Res. 2008, 17, 30–41.https://doi.org/10.1007/s00044-008-9090-7
[12] Gong, J.-X.; Cui, Y.; He, Z.-L.; Guo, Y.-W. Synthesis, Spectral Characterization, and Antituberculosis Activity of Thiazino[3,2- а]benzimidazole Derivatives. Phosphorus Sulfur Silicon Relat. Elem. 2016, 191, 1036–1041. https://doi.org/10.1080/10426507.2015.1135149
[13] Kim, P.; Kang, S.; Boshoff, H. I.; Jiricek, J.; Collins, M.; Singh, R.; Manjunatha, U. H.; Niyomrattanakit, P.; Patel, S.; Zhang, L.; et al. Structure-Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships. J. Med. Chem. 2009, 52, 1329–1344. https://doi.org/10.1021/jm801374t
[14] Thompson, A. M.; Marshall, A. J.; Maes, L.; Yarlett, N.; Bacchi, C. J. Assessment of a Pretomanid Analogue Library for African Trypanosomiasis: Hit-to-Lead Studies on 6-Substituted 2- Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides. Bioorg. Med. Chem. Lett. 2018, 28, 207–213. https://doi.org/10.1016/j.bmcl.2017.10.067
[15] Schoeder, C. T.; Kaleta, M.; Mahardhika, A. B.; Olejarz- Maciej, A.; Łażewska, D.; Kieć-Kononowicz, K.; Müller, C. E. Structure-Activity Relationships of Imidazothiazinones and Analogs as Antagonists of the Cannabinoid-Activated Orphan G Protein- Coupled Receptor GPR18. Eur. J. Med. Chem. 2018, 155, 381–397. https://doi.org/10.1016/j.ejmech.2018.05.050
[16] Volkov, O. A.; Cosner, C. C.; Brockway, A. J.; Kramer, M., Booker, M.; Zhong, S.; Ketcherside, A.; Wei, S.; Longgood, J.; McCoy, M.; Richardson, T.E. et al. Identification of Trypanosoma brucei AdoMetDC Inhibitors Using a High-Throughput Mass Spectrometry-Based Assay. ACS Infect. Dis. 2017, 3, 512–526. https://doi.org/10.1021/acsinfecdis.7b00022
[17] Saliyeva, L.; Slyvka, N.; Litvinchuk, M.; Holota, S.; Grozav, A.; Yakovychuk, N.; Vovk, M. Synthesis and Evaluation of Bioactivity of (2-Pyridinyloxy)substituted (benzo)imidazo[2,1- b][1,3]thiazines. Biointerface Res. Appl. Chem. 2022, 12, 5031–5044. https://doi.org/10.33263/BRIAC124.50315044
[18] Slyvka, N.; Saliyeva, L.; Holota, S.; Tkachuk, V.; Vaskevych, A.; Vaskevych, R.; Vovk, M. Convenient Synthesis of 4- Pyridinyloxy-modified imidazo [2,1-b][1,3] thiazines as Potential Anti-Inflammatory Agents. Biointerface Res. Appl. Chem. 2023, 13, 6033–6044. https://doi.org/10.33263/BRIAC132.183
[19] Slyvka, N.; Saliyeva, L.; Litvinchuk, M.; Grozav, A.; Yakovychuk, N.; Vovk, M. Regioselective Synthesis of New (Imidazo [2,1-b][1,3]-thiazin-6-yl)-1,2,3-triazolo-5-carboxylates as Potential Antimicrobial Agents. Vopr. Khimii Khimicheskoi Tekhnologii 2023, 5, 114–122. https://doi.org/10.32434/0321-4095-2023-150-5-114-122
[20] Babu, A. V.; Rambabu, A.; Giriprasad, P. V.; Rao, R. Synthesis of (±)-Pisonivanone and Other Analogs as Potent Antituberculosis Agents. J. Chem. 2013, 2013, ID 961201. https://doi.org/10.1155/2013/961201
[21] Rajabi, L.; Courreges, C.; Montoya, J.; Aguilera, R. J.; Primm, T.P. Acetophenones with Selective Antimycobacterial Activity. Lett. Appl. Microbiol. 2005, 40, 212–217. https://doi.org/10.1111/j.1472-765X.2005.01657.x
[22] Noviany, N.; Hasnah, О.; Suriyati, М; Sutopo, H.; Heri, S.; Buhani, B. Synthesis of Some Chalcones Derivatives Series and their Antituberculosis Activity. Pure Appl. Chem. 2024, 96, 351–368. https://doi.org/10.1515/pac-2023-1127
[23] Emami, S.; Esmaili, Z.; Dehghan, G.; Bahmani, M.; Hashemi, S.M.; Mirzaei, H.; Shokrzadeh, M.; Moradi, S.E. Acetophenone Benzoylhydrazones as Antioxidant Agents: Synthesis, in vitro Evaluation and Structure-Activity Relationship Studies. Food Chem. 2018, 268, 292–299. https://doi.org/10.1016/j.foodchem.2018.06.083
[24] Patel, J. R.; Dhorajiya, B. D.; Dholakiya, B. Z.; Badria, F. A.; Ibrahim, A. S. In-vitro Cytotoxicity, Antioxidant, Bleomycin- Dependent DNA Damage and Immunomodulatory Evaluation of 1- (4-Acetylphenyl)-3-aryloxypyrrolidine-2, 5-dione Based Derivatives. Med. Chem. Res. 2014, 23, 3907–3915. https://doi.org/10.1007/s00044-014-0965-5
[25] Jílek, J.; Šindelář, K.; Grimová, J.; Maturová, E.; Holubek, J.; Svátek, E.; Metyšová, J.; Metyš J.; Hrubantová, M.; Protiva, M. Potential Antidepressant and Anti-Inflammatory Agents: 4-(2- Propylthio)acetophenone oximes and 4-(2- propylthio)phenylalkanoic Acids. Collect. Czech. Chem. Commun. 1990, 55, 1266–1277. https://doi.org/10.1135/cccc19901266
[26] Sousa, F. S. S.; Birmann, P. T.; Baldinotti, R.; Fronza, M. G.; Balaguez, R.; Diego Alves, D.; Brüning, C. A., Savegnago, L. α- (Phenylselanyl) Acetophenone Mitigates Reserpine-Induced Pain- Depression Dyad: Behavioral, Biochemical and Molecular Docking Evidences. Brain Res. Bull. 2018, 142, 129–137. https://doi.org/10.1016/j.brainresbull.2018.07.007
[27] Kоwalska-Krochmal, B.; Dudek-Wicher, R. The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance. Pathogens 2021, 10, 165–170. https://doi.org/10.3390/pathogens10020165
[28] Brand-Williams, W.; Cuvelier, M. E.; Berset, C. Use of a Free Radical Method to Evaluate Antioxidant Activity. LWT Food Sci. Technol. 1995, 28, 25–30. https://doi.org/10.1016/S0023-6438(95)80008-5
[29] Thompson, A. M.; Blaser, A.; Anderson, R. F.; Shinde, S. S; Franzblau, S. G.; Ma, Z.; Denny, W. A.; Palmer, B. D. Synthesis, Reduction Potentials, and Antitubercular Activity of Ring A/B Analogues of the Bioreductive Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H- imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2009, 52, 637–645. https://doi.org/10.1021/jm801087e
[30] Orlov, M.; Kapitanov, I.; Korotkikh, N.; Shvaika, O. Synthesis and Recylization of 2,3,9,10-Tetrahydro-8H-[1,4] dioxino [2,3-f][1,3] thiazino[3,2-a]benzimidazolium Salts. Chem. Heterocycl. Comp.2014, 50, 111–116. https://doi.org/10.1007/s10593-014-1453-z