Synthesis, Structural Characterization, and Biological Evaluation of a Novel Benzothiazole Schiff Base

Year 2025, Volume: 7 Issue: 3, 282 - 291, 30.09.2025

İrem Akyol , Neslihan Güleç , Mustafa Yıldız

https://doi.org/10.51435/turkjac.1726252

Abstract

: In this study, we investigated the biological activity of a new benzothiazolimine compound, 4-methoxy-2-[(6-methoxybenzo[d]thiazol-2-amine)methyl]phenol, which was synthesized from the reaction of 6-methoxybenzo[d]thiazol-2-amine and 2-hydroxy-5-methoxybenzaldehyde. The chemical structure of the compound was elucidated by various spectroscopic techniques. The antimicrobial activity was evaluated by assessing the minimum inhibitory concentrations against several bacterial and yeast strains, revealing significant effectiveness against yeasts. DNA binding studies demonstrated that the compound interacts with DNA electrostatically. Agarose gel electrophoresis further confirmed that the compound induces oxidative DNA cleavage. The antimutagenicity of the compound was evaluated using the Ames/Salmonella test, showing a high inhibition rate of base-pair mutations. These results suggest that the compound possesses notable biological activity and warrants further investigation.

Keywords

6-Methoxybenzo[d]thiazol-2-amine , Spectroscopy , Antimicrobial activity , DNA cleavage , DNA binding , Antimutagenicity

Yeni Bir Benzotiyazol Schiff Bazının Sentezi, Yapısal Karakterizasyonu ve Biyolojik Değerlendirmesi

Abstract

Bu çalışmada, 6-metoksibenzo[d]tiazol-2-amin ile 2-hidroksi-5-metoksibenzaldehid reaksiyonundan sentezlenen yeni bir benzotiyazolimin bileşiği olan 4-metoksi-2-[(6-metoksibenzo[d]tiyazol-2-amin)metil]fenolün biyolojik aktivitesi incelenmiştir. Bileşiğin kimyasal yapısı çeşitli spektroskopik tekniklerle aydınlatılmıştır. Antimikrobiyal aktivite, farklı bakteri ve maya suşlarına karşı minimum inhibisyon konsantrasyonları belirlenerek değerlendirilmiş ve mayalara karşı anlamlı etkinlik göstermiştir. DNA bağlanma çalışmaları, bileşiğin DNA ile elektrostatik etkileşim yoluyla bağlandığını ortaya koymuştur. Agaroz jel elektroforezi, bileşiğin oksidatif DNA kırılmasına neden olduğunu doğrulamıştır. Ames/Salmonella testi kullanılarak yapılan antimutajenite değerlendirmesinde ise baz çifti mutasyonlarına karşı yüksek oranda inhibisyon gözlenmiştir. Bu bulgular, söz konusu bileşiğin kayda değer biyolojik aktiviteye sahip olduğunu ve daha ileri çalışmaların gerekliliğini göstermektedir.

Keywords

6-Metoksibenzo[d]tiyazol-2-amin , Spektroskopi , Antimikrobiyal aktivite , DNA kırma , DNA bağlanma , Antimutajenite

References

• T.L. Dadmal, S.D. Katre, M.C. Mandewale, R.M. Kumbhare, Contemporary progress in the synthesis and reactions of 2-aminobenzothiazole: a review, New J Chem, 42, 2018, 776–797.
• D.K. Jangid, A. Guleria, S. Dhadda, K. Yadav, P.G. Goswami, C.L. Khandelwal, An efficient synthesis of 2-aminobenzothiazole and its derivatives in ionic liquids, Int. J. Pharm. Sci. Res., 8(7), 2017, 2960–2964.
• M. Singh, S.K. Singh, M. Gangwar, G. Nath, S.K. Singh, Design, synthesis and mode of action of some benzothiazole derivatives bearing an amide moiety as antibacterial agents, RSC Adv, 4(36), 2014, 19013-19023.
• X. Xu, Z. Zhu, S. Chen, Y. Fu, J. Zhang, Y. Guo, X. Yang, Synthesis and biological evaluation of novel benzothiazole derivatives as potential anticancer and antiinflammatory agents, Front Chem, 12, 2024, 1384301.
• Ü. Demir Özkay, C. Kaya, U. Acar Çevik, Ö.D. Can, Synthesis and antidepressant activity profile of some novel benzothiazole derivatives, Molecules, 22(9), 2017, 1490.
• R. Bhutani, D.P. Pathak, G. Kapoor, A. Husain, M.A. Iqbal, Novel hybrids of benzothiazole 1,3,4 oxadiazole 4 thiazolidinone: synthesis, in silico ADME study, molecular docking and in vivo anti-diabetic assessment, Bioorg. Chem., 83, 2019, 6–19.
• C. Kharbanda, M.S. Alam, H. Hamid, K. Javed, S. Bano, A. Dhulap, S. Haider, Synthesis and evaluation of pyrazolines bearing benzothiazole as anti-inflammatory agents, Bioorg Med Chem, 22(21), 2014, 5804-5812.
• Y.I. Asiri, A. Alsayari, A.B. Muhsinah, Y.N. Mabkhot, M.Z. Hassan, Benzothiazoles as potential antiviral agents, J Pharm Pharmacol, 72(11), 2020, 1459–1480.
• V.S. Padalkar, B.N. Borse, V.D. Gupta, K.R. Phatangare, V.S. Patil, P.G. Umape, N. Sekar, Synthesis and antimicrobial activity of novel 2-substituted benzimidazole, benzoxazole and benzothiazole derivatives, Arab J Chem, 9, 2016, S1125–S1130.
• J.N. Philoppes, P.F. Lamie, Design and synthesis of new benzoxazole/benzothiazole-phthalimide hybrids as antitumor-apoptotic agents, Bioorg Chem, 89, 2019, 102978.
• M.K. Islam, A.R. Baek, B. Sung, B.W. Yang, G. Choi, H.J. Park, Y. Chang, Synthesis, characterization, and anticancer activity of benzothiazole aniline derivatives and their platinum(II) complexes as new chemotherapy agents, Pharmaceuticals, 14(8), 2021, 832.
• D. Cressier, C. Prouillac, P. Hernandez, C. Amourette, M. Diserbo, C. Lion, G. Rima, Synthesis, antioxidant properties and radioprotective effects of new benzothiazoles and thiadiazoles, Bioorg. Med. Chem., 17(14), 2009, 5275–5284.
• P.K. Sharma, M. Kumar, V. Mohan, Synthesis and antimicrobial activity of 2H-pyrimido[2,1-b]benzothiazol-2-ones, Res. Chem. Intermed., 36, 2010, 985–993.
• B. Barare, M. Yıldız, G. Alpaslan, N. Dilek, H. Ünver, S. Tadesse, K. Aslan, Synthesis, characterization, theoretical calculations, DNA binding and colorimetric anion sensing applications of 1-[(E)-[(6-methoxy-1,3-benzothiazol-2-yl)imino]methyl]naphthalen-2-ol, Sens Actuators B Chem, 215, 2015, 52–61.
• B. Barare, M. Yıldız, H. Ünver, K. Aslan, Characterization and use of (E)-2-[(6-methoxybenzo[d]thiazol-2-ylimino)methyl]phenol as an anion sensor and a DNA-binding agent, Tetrahedron Lett, 57(5), 2016, 537–542.
• G. Alpaslan, B. Boyacıoğlu, N. Demir, Y. Tümer, G. Yapar, N. Yıldırım, H. Ünver, Synthesis, characterization, biological activity and theoretical studies of a 2-amino-6-methoxybenzothiazole-based fluorescent Schiff base, J Mol Struct, 1180, 2019, 170–178.
• M. Nath, P.K. Saini, Chemistry and applications of organotin(IV) complexes of Schiff bases, Dalton Trans., 40(27), 2011, 7077–7121.
• O.M. Salih, M.A. Al-Sha’er, H.A. Basheer, Novel 2-aminobenzothiazole derivatives: docking, synthesis, and biological evaluation as anticancer agents, ACS Omega, 9(12), 2024, 13928–13950.
• R. Saad, Discovery, development, and current applications of DNA identity testing, Baylor Univ. Med. Cent. Proc., 18(2), 2005, 130–133.
• S. Khashkhashi-Moghadam, S. Ezazi-Toroghi, M. Kamkar-Vatanparast, P. Jouyaeian, P. Mokaberi, H. Yazdyani, J. Chamani, Novel perspective into the interaction behavior study of the cyanidin with human serum albumin-holo transferrin complex: spectroscopic, calorimetric and molecular modeling approaches, J. Mol. Liq., 356, 2022, 119042.
• N. Marjani, M. Dareini, M. Asadzade Lotfabad, M. Pejhan, P. Mokaberi, Z. Amiri Tehranizadeh, J. Chamani, Evaluation of the binding effect and cytotoxicity assay of 2 ethyl 5 (4 methylphenyl)pyramido pyrazole ophthalazine trione on calf thymus DNA: spectroscopic, calorimetric, and molecular dynamics approaches, Luminescence, 37(2), 2022, 310–322.
• D.M. Maron, B.N. Ames, Revised methods for the Salmonella mutagenicity test, Mutat. Res. Environ. Mutagen., 113(3–4), 1983, 173–215.
• M.L. Grayson, S.M. Crowe, J.S. McCarthy, J. Mills, J.W. Mouton, S.R. Norrby, M.A. Pfaller, Kucers’ The Use of Antibiotics Sixth Edition: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs, CRC Press, 2010.
• J. Marmur, A procedure for the isolation of deoxyribonucleic acid from micro-organisms, J Mol Biol, 3(2), 1961, 208–IN1.
• S.G. Kazarian, K.A. Chan, ATR-FTIR spectroscopic imaging: recent advances and applications to biological systems, Analyst, 138(7), 2013, 1940–1951.
• K.A. Chan, S.G. Kazarian, Attenuated total reflection Fourier-transform infrared (ATR-FTIR) imaging of tissues and live cells, Chem. Soc. Rev., 45(7), 2016, 1850–1864.
• R.K. Harris, NMR and the periodic table, Chem. Soc. Rev., 5, 1976, 1–22.
• N. Mitschke, S.P.B. Vemulapalli, T. Dittmar, NMR spectroscopy of dissolved organic matter: a review, Environ. Chem. Lett., 21(2), 2023, 689–723.
• A. El-Aneed, A. Cohen, J. Banoub, Mass spectrometry, review of the basics: electrospray, MALDI, and commonly used mass analyzers, Appl. Spectrosc. Rev., 44(3), 2009, 210–230.
• G.L. Glish, R.W. Vachet, The basics of mass spectrometry in the twenty-first century, Nat. Rev. Drug Discov., 2(2), 2003, 140–150.
• F. Baquero, Gram-positive resistance: challenge for the development of new antibiotics, J. Antimicrob. Chemother., 39(suppl_1), 1997, 1–6.
• M.N. Alekshun, S.B. Levy, Molecular mechanisms of antibacterial multidrug resistance, Cell, 128(6), 2007, 1037–1050.
• J. Afeltra, P.E. Verweij, Antifungal activity of nonantifungal drugs, Eur. J. Clin. Microbiol. Infect. Dis., 22, 2003, 397–407.
• V.R. Mishra, C.W. Ghanavatkar, S.N. Mali, H.K. Chaudhari, N. Sekar, Schiff base clubbed benzothiazole: synthesis, potent antimicrobial and MCF-7 anticancer activity, DNA cleavage and computational study, J. Biomol. Struct. Dyn., 2020.
• S. Maddila, S. Gorle, N. Seshadri, P. Lavanya, S.B. Jonnalagadda, Synthesis, antibacterial and antifungal activity of novel benzothiazole pyrimidine derivatives, Arab. J. Chem., 9(5), 2016, 681–687.
• A. Zubenko, V. Kartsev, A. Petrou, A. Geronikaki, M. Ivanov, J. Glamočlija, A. Klimenko, Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents, Antibiotics, 11(11), 2022, 1654.
• R.A. Azzam, H.A. Elboshi, G.H. Elgemeie, Synthesis, physicochemical properties and molecular docking of new benzothiazole derivatives as antimicrobial agents targeting DHPS enzyme, Antibiotics, 11(12), 2022, 1799.
• A. Alharbi, M. Alsahag, A. Alisaac, N.A.H. Alshammari, S.T. Alsharif, A.I. Alalawy, N.M. El-Metwaly, Molecular modeling and antimicrobial activity of newly synthesized benzothiazole-thiazole conjugates, J. Photochem. Photobiol. A Chem., 456, 2024, 115852.
• L. Strekowski, B. Wilson, Noncovalent interactions with DNA: an overview, Mutat. Res. Fundam. Mol. Mech. Mutagen., 623(1–2), 2007, 3–13.
• S. Ibrahim, P. Gavisiddegowda, H.N. Deepakumari, S.P. Kollur, N. Naik, Newly synthesized benzothiazole derived ligand and its Co(III) and Ru(III) complexes as biological potent molecules: chemical preparation, structure, antimicrobial, in vitro and in vivo cytotoxicity studies, Biointerface Res. Appl. Chem., 12(6), 2022, 7817–7844.
• N.N. Rao, K. Gopichand, R. Nagaraju, A.M. Ganai, P.V. Rao, Design, synthesis, spectral characterization, DNA binding, photo cleavage and antibacterial studies of transition metal complexes of benzothiazole Schiff base, Chem. Data Collect., 27, 2020, 100368.
• S. Daravath, M.P. Kumar, A. Rambabu, N. Vamsikrishna, N. Ganji, Design, synthesis, spectral characterization, DNA interaction and biological activity studies of copper(II), cobalt(II) and nickel(II) complexes of 6-amino benzothiazole derivatives, J. Mol. Struct., 1144, 2017, 147–158.
• A.K. Basavaraju, P. Gavisiddegowda, S.P. Kollur, H.D. Revanasiddappa, Synthesis and Spectral Characterisation of new Benzothiazole-based Schiff Base Ligand and its Co(III) and Ni(II) Complexes as DNA Binding and DNA Cleavage Agents, Nanobio Lett, 12, 2023, 76.
• K. Barakat, M.A. Ragheb, M.H. Soliman, A.M. Abdelmoniem, I.A. Abdelhamid, Novel thiazole-based cyanoacrylamide derivatives: DNA cleavage, DNA/BSA binding properties and their anticancer behaviour against colon and breast cancer cells, BMC Chem, 18(1), 2024, 183.
• S. Daravath, A. Rambabu, N. Vamsikrishna, N. Ganji, S. Raj, Synthesis, structural characterization, antioxidant, antimicrobial, DNA incision evaluation and binding investigation studies on copper(II) and cobalt(II) complexes of benzothiazole cored Schiff bases, J Coord Chem, 72(12), 2019, 1973–1993.
• S. Ibrahim, N. Naik, C. Shivamallu, H.L. Raghavendra, A.A. Shati, M.Y. Alfaifi, S.P. Kollur, Synthesis, structure, and in vitro biological studies of benzothiazole based Schiff base ligand and its binary and ternary Co(III) and Ni(II) complexes, Inorg Chim Acta, 559, 2024, 121792.
• D.S. Shankar, A. Rambabu, P.A. Lakshmi, Shivaraj, Copper(II) Complexes Derived from Schiff Bases Containing 4 Methylbenzylamine as a Core Unit: Cytotoxicity, pBR322-DNA Studies, Biological Assays, and Quantum Chemical Parameters, Chem Biodivers, 20(7), 2023, e202300030.
• K. Mortelmans, E. Zeiger, The Ames Salmonella/microsome mutagenicity assay, Mutat. Res. Fundam. Mol Mech Mutagen, 455(1–2), 2000, 29–60.
• H. Ünver, B. Boyacıoğlu, C.T. Zeyrek, M. Yıldız, N. Demir, N. Yıldırım, A. Elmalı, Synthesis, spectral and quantum chemical studies and use of (E)-3-[(3,5-bis(trifluoromethyl)phenylimino)methyl]benzene-1,2-diol and its Ni(II) and Cu(II) complexes as anion sensor, DNA binding, DNA cleavage, antimicrobial, antimutagenic and anticancer agent, J Mol Struct, 1125, 2016, 162–176.
• N. Yıldırım, N. Demir, DNA Interactions, Mutagenic, Anti-Mutagenic and Antimicrobial Activities of (E)-2-((3,5-Bis(trifluoromethyl)phenylimino)methyl)-4,6-dimethoxyphenol, Sakarya Univ J Sci, 25(2), 2021, 339–348.
• M. Ashram, A. Maslat, S. Mizyed, Synthesis and biological activities of new azacrown ether Schiff bases and spectrophotometric studies of their complexation with [60] fullerene, Toxicol Environ Chem, 91(6), 2009, 1095–1104.
• K.D. Onuska, N. Lahitová, J. Cársky, Antimutagenic and bacteriostatic activities of Schiff-base compounds derived from aminoguanidine, semicarbazone and thiosemicarbazone and a copper(II)-coordination complex, Toxicol Environ Chem, 57(1–4), 1996, 163–170.