Abstract
Background: Heterocyclic sulfone-bearing small molecules are particularly important objects in medicinal chemistry. Structure-diversified pyridinyloxy-substituted imidazo[2,1-b][1,3]thiazines are characterized by satisfactory drug-like parameters and possess significant anti-inflammatory effects in in vivo studies.
Objective: Oxidation of a series of 6-(2-pyridinyloxy) imidazo[2,1-b][1,3]thiazines under the action of m-chloroperbenzoic acid with a view to anti-inflammatory activity enhancement and structure optimization.
Methods: A series of appropriate sulfones was synthesized by the action of m-chloroperbenzoic acid on 6-[(pyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazines. The structure of the synthesized products was confirmed by 1H, 13C NMR, and LC-MS spectra. In vivo anti-inflammatory activity was studied using carrageenin model of inflammatory oedema on white rats. ADMET parameters of compounds were evaluated in silico using AdmetSAR. For the most active compounds, docking studies to COX-1,2, 5-LOX and FLAP were performed.
Results: It was found that transformation to sulfones could be achieved by soft oxidation at room temperature for 48 h using the 3-fold excess of oxidant in the presence of sodium hydrogen phosphate. Antiinflammatory activity screening results revealed that all synthesized sulfones showed significant antiexudative action with inflammation inhibition index in the range of 37.7 - 48.1%. The compound 2i was found to be the most active in the experiment, and its activity was equal to the reference drug effect; it also possesses satisfactory ADMET parameters and high energy of binding to 5-LOX and FLAP.
Conclusion: The synthesized sulfone 2i is of interest for in-depth studies and further design of new potential non-steroidal anti-inflammatory agents.
Keywords: Imidazo[2, 1-b][1, 3]thiazines, m-chloroperbenzoic acid, oxidation, drug-likeness, anti-inflammatory activity, docking.
Graphical Abstract
[1]
Scott, K.A.; Njardarson, J.T. Analysis of US FDA-approved drugs containing sulfur atoms. Top. Curr. Chem. (Cham), 2018, 376(1), 5.
[http://dx.doi.org/10.1007/s41061-018-0184-5] [PMID: 29356979]
[http://dx.doi.org/10.1007/s41061-018-0184-5] [PMID: 29356979]
[2]
Ilardi, E.A.; Vitaku, E.; Njardarson, J.T. Data-mining for sulfur and fluorine: An evaluation of pharmaceuticals to reveal opportunities for drug design and discovery. J. Med. Chem., 2014, 57(7), 2832-2842.
[http://dx.doi.org/10.1021/jm401375q] [PMID: 24102067]
[http://dx.doi.org/10.1021/jm401375q] [PMID: 24102067]
[3]
Sina, M-A. Selected methods for the synthesis of sulfoxides and sulfones with emphasis on oxidative protocols. Phosphorus Sulfur Silicon Relat. Elem., 2020, 195(3), 181-193.
[http://dx.doi.org/10.1080/10426507.2019.1672691]
[http://dx.doi.org/10.1080/10426507.2019.1672691]
[4]
Yan, Y.; Xu, Q.; Zhao, C.; Dong, H.; Xu, W.; Zhang, Y. In vivo pharmacokinetic study and oral glucose tolerance test of sulfoxide analogs of GPR40 agonist TAK-875. Drug Dev. Res., 2020, 81(6), 708-715.
[http://dx.doi.org/10.1002/ddr.21675] [PMID: 32359092]
[http://dx.doi.org/10.1002/ddr.21675] [PMID: 32359092]
[5]
Rui, Z.; Huaiwei, D. Recent advances in the synthesis of sulfides, sulfoxides and sulfones via c-s bond construction from non-halide substrates; Catalyst, 2020.
[http://dx.doi.org/10.3390/catal10111339]
[http://dx.doi.org/10.3390/catal10111339]
[6]
Aono, Y.; Horinaka, M.; Iizumi, Y.; Watanabe, M.; Taniguchi, T.; Yasuda, S.; Sakai, T. Sulindac sulfone inhibits the mTORC1 pathway in colon cancer cells by directly targeting voltage-dependent anion channel 1 and 2. Biochem. Biophys. Res. Commun., 2018, 505(4), 1203-1210.
[http://dx.doi.org/10.1016/j.bbrc.2018.10.050] [PMID: 30327144]
[http://dx.doi.org/10.1016/j.bbrc.2018.10.050] [PMID: 30327144]
[7]
Atlı Şekeroğlu, Z.; Gediz Ertürk, A.; Kontaş Yedier, S.; Şekeroğlu, V. In vitro cytogenetic activity of 3-amino-4-[4-(dimethylamino)phenyl]-4,5-dihydro-1,2,5-thiadiazole 1,1-dioxide. Drug Chem. Toxicol., 2021, 44(6), 595-600.
[http://dx.doi.org/10.1080/01480545.2019.1677703] [PMID: 31621427]
[http://dx.doi.org/10.1080/01480545.2019.1677703] [PMID: 31621427]
[8]
Kryczyk-Poprawa, A.; Zupkó, I.; Bérdi, P.; Żmudzki, P.; Popiół, J.; Muszyńska, B.; Opoka, W. Photostability testing of a third-generation retinoid-tazarotene in the presence of UV absorbers. Pharmaceutics, 2020, 12(9), 899.
[http://dx.doi.org/10.3390/pharmaceutics12090899] [PMID: 32971827]
[http://dx.doi.org/10.3390/pharmaceutics12090899] [PMID: 32971827]
[9]
Wang, P-Y.; Zhou, L.; Zhou, J.; Wu, Z-B.; Xue, W.; Song, B-A.; Yang, S. Synthesis and antibacterial activity of pyridinium-tailored 2,5-substituted-1,3,4-oxadiazole thioether/sulfoxide/sulfone derivatives. Bioorg. Med. Chem. Lett., 2016, 26(4), 1214-1217.
[http://dx.doi.org/10.1016/j.bmcl.2016.01.029] [PMID: 26810264]
[http://dx.doi.org/10.1016/j.bmcl.2016.01.029] [PMID: 26810264]
[10]
Dudek-Wicher, R.K.; Szczęśniak-Sięga, B.M.; Wiglusz, R.J.; Janczak, J.; Bartoszewicz, M.; Junka, A.F. Evaluation of 1,2-benzothiazine 1,1-dioxide derivatives in vitro activity towards clinical-relevant microorganisms and fibroblasts. Molecules, 2020, 25(15), 3503.
[http://dx.doi.org/10.3390/molecules25153503] [PMID: 32752040]
[http://dx.doi.org/10.3390/molecules25153503] [PMID: 32752040]
[11]
Lakshminarayanan, B.; Kannappan, N.; Subburaju, T. Synthesis and biological evalyation of novel chalcones with methanesulfonyl end as potent analgesic and anti-inflammatory agents. IJPSR, 2020, 11(10), 4974-4981.
[http://dx.doi.org/10.13040/IJPSR.0975-8232]
[http://dx.doi.org/10.13040/IJPSR.0975-8232]
[13]
Glomb, T.; Wiatrak, B.; Gębczak, K.; Gębarowski, T.; Bodetko, D.; Czyżnikowska, Z.; Świątek, P. New 1,3,4-oxadiazole derivatives of pyridothiazine-1,1-dioxide with anti-inflammatory activity. Int. J. Mol. Sci., 2020.
[http://dx.doi.org/10.3390/ijms21239122]
[http://dx.doi.org/10.3390/ijms21239122]
[14]
Szczęśniak-Sięga, B.M.; Mogilski, S.; Wiglusz, R.J.; Janczak, J.; Maniewska, J.; Malinka, W.; Filipek, B. Synthesis and pharmacological evaluation of novel arylpiperazine oxicams derivatives as potent analgesics without ulcerogenicity. Bioorg. Med. Chem., 2019, 27(8), 1619-1628.
[http://dx.doi.org/10.1016/j.bmc.2019.03.007] [PMID: 30852078]
[http://dx.doi.org/10.1016/j.bmc.2019.03.007] [PMID: 30852078]
[15]
Mangwegape, D.K.; Zuma, N.H.; Aucamp, J.; N’Da, D.D. Synthesis and in vitro antileishmanial efficacy of novel benzothiadiazine-1,1-dioxide derivatives. Arch. Pharm. (Weinheim), 2021, 354(5), e2000280.
[http://dx.doi.org/10.1002/ardp.202000280] [PMID: 33491807]
[http://dx.doi.org/10.1002/ardp.202000280] [PMID: 33491807]
[16]
Staniszewska, M.; Sobiepanek, A.; Gizicska, M.; Peca-Cabrera, E.; Arroyo-Cyrdoba, I.; Michalina Kazek, M.; Kuryk, L.; Wieczorek, M.; Koronkiewicz, M.; Kobiela, T.; Ochal, Z. Sulfone derivatives enter the cytoplasm of Candida albicans sessile cells. Eur. J. Med. Chem., 2020, 112139.
[http://dx.doi.org/10.1016/j.ejmech.2020.112139]
[http://dx.doi.org/10.1016/j.ejmech.2020.112139]
[17]
Bazine, I.; Bendjedid, S.; Boukhari, A. Potential antibacterial and antifungal activities of novel sulfamidophosphonate derivatives bearing the quinoline or quinolone moiety. Arch Pharm., 2021, e2000291.
[http://dx.doi.org/10.1002/ardp.202000291]
[http://dx.doi.org/10.1002/ardp.202000291]
[18]
Pei, L.; Lijuan, W.; Xiang, W. Recent advances on the pesticidal activity evaluations of sulfone derivatives: A 2010 to 2020 decade in mini-review. J. Heterocycl. Chem., 2021, 58(1), 28-39.
[http://dx.doi.org/10.1002/jhet.4173]
[http://dx.doi.org/10.1002/jhet.4173]
[19]
De Martino, G.; La Regina, G.; Ragno, R.; Coluccia, A.; Bergamini, A.; Ciaprini, C.; Sinistro, A.; Maga, G.; Crespan, E.; Artico, M.; Silvestri, R. Indolyl aryl sulphones as HIV-1 non-nucleoside reverse transcriptase inhibitors: Synthesis, biological evaluation and binding mode studies of new derivatives at indole-2-carboxamide. Antivir. Chem. Chemother., 2006, 17(2), 59-77.
[http://dx.doi.org/10.1177/095632020601700202] [PMID: 17042328]
[http://dx.doi.org/10.1177/095632020601700202] [PMID: 17042328]
[20]
Ivachtchenko, A.V.; Kovalenko, S.M.; Kravchenko, D.V.; Mitkin, O.D.; Ivanov, V.V.; Langer, T. Crystal structure, Hirshfeld analysis and a molecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-[5-(pentan-3-yl)-1,2,4-oxa-diazol-3-yl]meth-yl-2H-1,2,6-thia-diazine-4-carboxyl-ate. Acta Crystallogr. E Crystallogr. Commun., 2020, 76(Pt 1), 12-17.
[http://dx.doi.org/10.1107/S2056989019015986] [PMID: 31921445]
[http://dx.doi.org/10.1107/S2056989019015986] [PMID: 31921445]
[21]
Surur, A.S.; Schulig, L.; Link, A. Interconnection of sulfides and sulfoxides in medicinal chemistry. Arch. Pharm., 2019, e1800248.
[http://dx.doi.org/10.1002/ardp.201800248]
[http://dx.doi.org/10.1002/ardp.201800248]
[22]
Mahdi, J.; Ameneh, A.; Sadegh, K.; Sara, T.; Davood, N. Progress and perspectives of electrochemical insights for C-H and N-H sulfonylation. New J. Chem., 2021, 45(39), 18246-18267.
[http://dx.doi.org/10.1039/D1NJ03574F]
[http://dx.doi.org/10.1039/D1NJ03574F]
[23]
Liang, S.; Hofman, K.; Friedrich, M.; Keller, J.; Manolikakes, G. Recent progress and emerging technologies towards a sustainable synthesis of sulfones. ChemSusChem, 2021, 14(22), 4878-4902.
[http://dx.doi.org/10.1002/cssc.202101635] [PMID: 34476903]
[http://dx.doi.org/10.1002/cssc.202101635] [PMID: 34476903]
[24]
Mangiavacchi, F.; Crociani, L.; Sancineto, L.; Marini, F.; Santi, C. Continuous bioinspired oxidation of sulfides. Molecules, 2020, 25(11), 2711.
[http://dx.doi.org/10.3390/molecules25112711] [PMID: 32545303]
[http://dx.doi.org/10.3390/molecules25112711] [PMID: 32545303]
[25]
Bäckvall, J-E. Modern Oxidation Methods, 2nd ed; Wiley-VCH: Weinheim, Germany, 2010.
[http://dx.doi.org/10.1002/9783527632039]
[http://dx.doi.org/10.1002/9783527632039]
[26]
Saliyeva, L.; Slyvka, N.; Litvinchuk, M.; Holota, S.; Grozav, A.; Yakovychuk, N.; Vovk, M. Synthesis and evaluation of bioactivity of 6-[(2-pyridinyloxy)](benzo)imidazo[2,1-b][1,3]thiazine derivatives. Biointerface Res. Appl. Chem., 2022, 12, 5031-5044.
[http://dx.doi.org/10.33263/BRIAC124.50315044]
[http://dx.doi.org/10.33263/BRIAC124.50315044]
[27]
Reichardt, C.; Welton, T. Solvents and solvent effects in organic chemistry, Fourth edition; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim. Germany, 2010.
[http://dx.doi.org/10.1002/9783527632220]
[http://dx.doi.org/10.1002/9783527632220]
[28]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med., 1962, 111(3), 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[29]
Güleç, Ö.; Türkeş, C.; Arslan, M.; Demir, Y. Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif. Mol. Divers., 2022, 1-21.
[http://dx.doi.org/10.1007/s11030-022-10422-8]
[http://dx.doi.org/10.1007/s11030-022-10422-8]
[30]
Osmaniye, D.; Türkeş, C.; Demir, Y.; Özkay, Y.; Beydemir, Ş.; Kaplancıklı, Z.A. Design, synthesis, and biological activity of novel dithiocarbamate-methylsulfonyl hybrids as carbonic anhydrase inhibitors. Arch. Pharm. (Weinheim), 2022, e2200132.
[http://dx.doi.org/10.1002/ardp.202200132] [PMID: 35502846]
[http://dx.doi.org/10.1002/ardp.202200132] [PMID: 35502846]
[31]
Askin, S.; Tahtaci, H.; Türkeş, C.; Demir, Y.; Ece, A.; Akalın Çiftçi, G.; Beydemir, Ş. Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors. Bioorg. Chem., 2021, 113, 105009.
[http://dx.doi.org/10.1016/j.bioorg.2021.105009] [PMID: 34052739]
[http://dx.doi.org/10.1016/j.bioorg.2021.105009] [PMID: 34052739]
[32]
Sever, B.; Türkeş, C.; Altıntop, M.D.; Demir, Y.; Çiftçi, G.A.; Beydemir, Ş. Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds. Arch. Pharm., 2021, e2100294.
[http://dx.doi.org/10.1002/ardp.202100294]
[http://dx.doi.org/10.1002/ardp.202100294]
[33]
Yapar, G.; Esra Duran, H.; Lolak, N.; Akocak, S.; Türkeş, C.; Durgun, M.; Işık, M.; Beydemir, Ş. Biological effects of bis-hydrazone compounds bearing isovanillin moiety on the aldose reductase. Bioorg. Chem., 2021, 117, 105473.
[http://dx.doi.org/10.1016/j.bioorg.2021.105473] [PMID: 34768205]
[http://dx.doi.org/10.1016/j.bioorg.2021.105473] [PMID: 34768205]
[34]
Akocak, S.; Taslimi, P.; Lolak, N.; Işık, M.; Durgun, M.; Budak, Y.; Türkeş, C.; Gülçin, İ.; Beydemir, Ş. Synthesis, characterization, and inhibition study of novel substituted phenylureido sulfaguanidine derivatives as α-glycosidase and cholinesterase inhibitors. Chem. Biodivers., 2021, 18(4), e2000958.
[http://dx.doi.org/10.1002/cbdv.202000958] [PMID: 33620128]
[http://dx.doi.org/10.1002/cbdv.202000958] [PMID: 33620128]
[35]
Yaşar, Ü.; Gönül, İ.; Türkeş, C.; Demir, Y.; Beydemir, Ş. Transition-metal complexes of bidentate schiff-base ligands: In vitro and in silico evaluation as non-classical carbonic anhydrase and potential acetylcholinesterase inhibitors; Chem. Select, 2021.
[36]
admetSAR: A comprehensive source and free tool for evaluating chemical ADMET properties. Available from: http://lmmd.ecust.edu.cn/admetsar2/
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