2-(Butiltiyo)-3-Kloronaftalen-1,4-Dion Bileşiğinden Yeni Naftakinon Bileşiklerin Sentezi, Karakterizasyonu ve Antimikrobiyal Aktivitelerinin İncelenmesi

Öz

Bu çalışmada, 2,3-dikloro-1,4-naftakinon (1) bileşiğinin alkali ortamda 1-butantiyol ile reaksiyoundan 2-(butiltiyo)-3-kloronaftalen-1,4-dion (3) bileşiği sentezlendi. Sentezlenen 2-(butiltiyo)-3-kloronaftalen-1,4-dion (3) bileşiği başlangıç bileşiği olarak kullanıldı. 2-(butiltiyo)-3-kloronaftalen-1,4-dion (3) bileşiğin azot, kükürt ve oksijen atomu içeren heterosiklik bileşikler ile nükleofilik sübstitüsyonu sonucu bir seri 10, 11, 12, 13, 14, 15, naftakinon türevi bileşikler sentezlendi. Sentezlenen bileşiklerin yapıları FTIR, 13C NMR, 1H NMR ve Mass Spektroskopisi ile karakterize edildi. Sentezlenen bileşiklerin Gram pozitif ve Gram negative bakteriler ile antimikrobiyal çalışması yapılarak antimikrobiyal özellikleri incelendi. 2-(butiltiyo)-3-kloronaftalen-1,4-dion (3) bileşiğinin antimikrobiyal aktivitesi en yüksek, 2-(butylthio)-3-((2,5-dihydrothiazol-5-yl) thio) naphthalene-1,4-dione (10) bileşiğinin antimikrobiyal aktivitesi en düşük olarak gözlenmiştir. 3, 11, 12, 13, 14 ve 15 bileşikleri, Gram-pozitif B. subtilis ve S. aureus ile Gram-negatif E. coli, K. pneumoniae 'ye karşı daha iyi aktivite göstermiştir. Ayrıca, 11, 12 ve 14 bileşikleri Gram-pozitif B. subtilis ve S. aureus ile Gram-negatif E. coli, K. pneumoniae ve P. aeruginosa'ya karşı aktivite gösterdi. Bu çalışma ile literatürde olan çalışmaların geliştirilmesi ve bilinmeyen yeni bileşiklerin sentezlenmesi amaçlanmıştır.

Anahtar Kelimeler

• Sübstitüe kinonlar
• nükleofilik sübstitüsyon
• antimikrobiyal aktivite

Synthesis, Characterization, and Investigation of Antimicrobial Activities of New Naphthoquinone Compounds from 2-(butylthio)-3-chloronaphthalene-1,4-dione

Öz

In this study, the compound 2-(butylthio)-3-chloronaphthalene-1,4-dione (3) was synthesized from the reaction of the compound 2,3-dichloro-1,4-naphthoquinone (1) with 1-butanethiol in alkaline medium. The synthesized compound 2-(butylthio)-3-chloronaphthalene-1,4-dione (3) was used as the starting compound. As a result of the nucleophilic substitution of 2-(butylthio)-3-chloronaphthalene-1,4-dione (3) with heterocyclic compounds containing nitrogen, sulfur, and oxygen atoms, a series of 10, 11, 12, 13, 14, 15, naphthoquinone derivative compounds were synthesized. The structures of the synthesized compounds were characterized by FTIR, 13C-NMR, 1H-NMR, and Mass Spectroscopy techniques. The antimicrobial properties of the synthesized compounds were examined by performing antimicrobial studies with Gram-positive and Gram-negative bacteria. The compound 2-(butylthio)-3-chloronaphthalene-1,4-dione (3) shows the highest antimicrobial activity, whereas the compound 2-(butylthio)-3-((4,5-dihydrothiazol-2-yl)thio) naphhalene-1,4-dione (10) exhibits the lowest antimicrobial activity. Compounds 3, 11, 12, 13, 14, and 15 exhibited enhanced activity against Gram-positive bacteria, such as B. subtilis and S. aureus, as well as Gram-negative E. coli and K. pneumoniae. In addition, compounds 11, 12, and 14 exhibited activity against Gram-positive B. subtilis and S. aureus, as well as Gram-negative E. coli, K. pneumoniae, and P. aeruginosa. The study aims to enhance existing literature research and create new unknown compounds through synthesis.

Anahtar Kelimeler

• Substituted quinones
• nucleophilic substitution
• antimicrobial activity

Kaynakça

1. Noller, C. R. (1957). Chemistry of Organic Compounds, 2nd Edition, W. B. Saunders Company, USA.
2. Fieser, L. F., Fieser, M. (1961). Advanced Organic Chemistry, Reinhold Publishing Corporation Chapman & Hall, Ltd., USA.
3. Noller, C. R. (1966). Chemistry of Organic Compounds, 3nd edition, W.B. Saunders Company, USA.
4. Aststreitwieser, A., & Heatcock, C. H. (1976). Introduction to Organic Chemisrty, Collier Mac Millan International Editions, USA, ISBN:0024180106.
5. English, J. & Cassidy, H. G. (1956). Princeples of Organic Chemistry, Second edition, McGrow-Hill Book Company, USA.
6. Kirk, R. E. & Othmer, D. F. (1968). Encyclopedia of Chemical Technology, 2nd Edition, John Wiley and Sons, Inc., USA.
7. Satheshkumar, A. & Elango, K. P. (2012). Spectroscopic and theoretical studies on the nucleophilic substitution of 2,3-dichloronaphthoquinone with para-substituted anilines in solid state via initial charge transfer complexation. Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy, 98, 378–383.
8. Leyva, E., Schmidtke Sobeck, S. J., Loredo-Carrillo, S. E. & Magaldi-Lara, D. A. (2014). Spectral and structural characterization of 2-(fluorophenylamino)- and 2-(nitrophenylamino)-1,4-naphthoquinone derivatives. Journal of Molecular Structure, 1068(1), 1-7.

9. Tandon, V. K., Maurya, H. K. & Tripathi, A. (2009). 2,3-Disubstituted- 1,4-naphthoquinones, 12H-benzo[b]phenothiazine- 6,11-diones and related compounds: synthesis and Biological evaluation as potential antiproliferative and antifungal agents. European Journal of Medicinal Chemistry, 44(3), 1086–1092.
10. Tandon, V. K. & Maurya, H. K. (2010). Water-promoted unprecedented chemoselective nucleophilic substi tution reactions of 1,4-quinones with oxygen nucleophiles in aqueous micelles. Tetrahedron Letters, 51(29), 3843–3847.
11. Tuyun, A. F., Bayrak, N., Yıldırım, H., Onul, N., Kara E. M. & Celik, B. O. (2015). Synthesis and ın vitro biological evaluation of aminonaphthoquinones and benzo[b]phenazine-6,11-dione derivatives as potential antibacterial and antifungal compounds. Journal of Chemistry, 645902, https://doi.org/10.1155/2015/645902
12. Mital, A. S. M., Bindal, S., Mahlavat, S. & Negi, V. (2010). Substituted 1,4-naphthoquinones as a new class of antimycobacterial agents, Der Pharma Chemica, 2(3), 63-73.
13. Morin, C., Besset, T., Moutet, J. C., Fayolle, M., Bruckner, M., Limosin, D., Becker, K. & Davioud-Charvet, E. (2008). The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase. Organic & Biomolecular Chemistry, 6, 2731-2742. https://doi.org/10.1039/B802649C
14. Biot, C., Bauer, H., Schirmer, R. H. & Davioud-Charvet, E. (2004). 5-substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials. Journal of Medicinal Chemistry, 47(24), 5972-5983. https://doi.org/10.1021/jm0497545
15. İbiş, C., Tuyun, A. F., Bahar, H., Ayla S. S, Stasevych, M. V., Musyanovych, R. Y., Komarovska Porokhnyavets, O. & Novikov, V. (2013). Synthesis of novel 1,4- naphthoquinone derivatives: antibacterial and antifungal agents. Medicinal Chemistry Research, 22(6), 2879-2888. https://doi.org/10.1007/s00044-012-0300-y
16. İbiş, C., Tuyun, A. F., Ozsoy-Gunes, Z., Bahar, H., Stasevych, M. V. & Musyanovych, R. Y., (2011). Synthesis and biological evaluation of novel nitrogen- and sulfur -containing hetero- 1,4-naphthoquinones as potent antifungal and antibacterial agents. European Journal of Medicinal Chemistry, 46, 5861-5867. https://doi.org/10.14293/S2199-1006.1.SOR-CHEM.AALL9P.v1
17. Linzner, N., Fritsch, V. N., Busche, T., Tung, Q. N., Van Loi, V., Bernhardt, J., Kalinowski, J. & Antelmann, H. (2020). The plant-derived naphthoquinone lapachol causes an oxidative stress response in Staphylococcus aureus. Free Radical Biology and Medicine, 158, 126–136. https://doi.org/10.1016/j.freeradbiomed.2020.07.025
18. Novais, J. S., Carvalho, M. F., Ramundo, M. S., Beltrame, C. O., Geraldo, R. B., Jordão, A. K., Ferreira, V. F., Castro, H. C. & Figueiredo, A. M. S. (2020). Antibiofilm effects of N,O-acetals derived from 2-amino-1,4-naphthoquinone are associated with downregulation of important global virulence regulators in methicillin-resistant Staphylococcus aureus. Scientific Reports, 10, 19631. https://doi.org/10.1038/s41598-020-76372-z
19. Campora, M., Canale, C., Gatta, E., Tasso, B., Laurini, E., Relini, A., Pricl, S., Catto, M. & Tonelli, M. (2021). Multitarget biological profiling of new naphthoquinone and anthraquinone-based derivatives for the treatment of alzheimer’s disease. ACS Chemical Neuroscience, 12(3), 447-461. https://doi.org/10.1021/acschemneuro.0c00624
20. Oliveira, V., Dantas, E., Queiroz, A., Oliveira, J., Silva, M., Ferreira, P., Siva, F., Ferreira, V., Lima, Á. (2020). Novel solid dispersions of naphthoquinone using different polymers for ımprovement of antichagasic activity. Pharmaceutics, 12(12), 1136. https://doi.org/10.3390/pharmaceutics12121136
21. Kırk-Othmer, (1969). Encyclopedia of Chemical Technology, Second Edition, 20, 215.
22. İbiş, C., Özsoy Güneş Z., Tuyun A. F., Ayla S. S., Bahar, H. & Stasevych M. V. (2016). Synthesis, antibacterial and antifungal evaluation of thio- or piperazinyl-substituted 1,4-naphthoquinone derivatives. Journal of Sulfur Chemistry, 37(5), 477-487. https://doi.org/10.1080/17415993.2016.1187734
23. İbiş, C., Ayla, S. S., Bahar, H., Stasevych, M., Komarovska - Porokhnyavets, O. & Novikov, V. (2015). Synthesis, characterization and biological properties of novel piperidinolyl-, piperidinyl-, and piperazinyl substituted naphthoquinone compounds and their reactions with some thiols. Phosphorus Sulfur and Silicon and the Related Elements, 190(9), 1422-1433. https://doi.org/10.1080/10426507.2014.986268
24. Chaudhary, A. & Khurana, J. M. (2016). 2-Hydroxy-1,4- naphthoquinone: a versatile synthon in organic synthesis. Current Organic Chemistry, 20(12), 1314. https://doi.org/10.2174/1385272820666151125231522
25. Clark, N. G. (1984). The fungicidal activity of substituted 1,4-naphthoquinones.1. Alkylthio and arylthio derivatives. Pesticide Science, 15(1), 25-30. https://doi.org/10.1002/ps.2780150105
26. Monterrey, I. G., Santelli, G., Campiglia, P., Califano, D., Falasconi, F., Pisano, C., Vesci, L., Lama, T., Grieco, P. & Novellino, E. (2005). Synthesis and cytotoxic evaluation of novel spirohydantoin derivatives of the dihydrothieno[2,3-b] naphtho- 4,9-dione system. Journal of Medicinal Chemistry, 48(4), 1152-1157. https://doi.org/10.1021/jm0408565
27. Shchekotikhin, A. E., Buyanov, V. N. & Preobrazhenskaya, M. N. (2004). Synthesis of 1-(omegaaminoalkyl) naphthoindolediones with antiproliferative properties. Bioorganic & Medicinal Chemistry, 12(14), 3923-3930. https://doi.org/10.1016/j.bmc.2004.04.042
28. Fieser, L. F. & Brown, H. R. (1949). Synthesis of naphthoquinones for studies of the ınhibition of enzyme systems. Journal of American Chemical Society, 71(11), 3609-3614. https://doi.org/10.1021/ja01179a009
29. Ibis, C., Ayla, S. S. & Yavuz, S. (2019) Reactions of quinones with some aryl phenols and synthesis of new quinone derivatives, Synthetic Communications, 49(2), 202-211. https://doi.org/10.1080/00397911.2018.1546403
30. Bayrak, N., Yıldırım, H., Tuyun, A. F., Kara, E. M., Celik, B. O. & Gupta, G. K. (2016). Synthesis, biological, and computational study of naphthoquinone derivatives containing heteroatoms. Journal of the Chemical Society of Pakistan, 38(6), 1211-1221.
31. Ayla, S. S., Bahar, H., Yavuz, S., Hazer, B. & Ibis, C. (2016). The synthesis and characterization of novel quinone-amine polymers from the reactions of 2,3-dichloro-1,4-naphthoquinone and polyoxypropylenediamines, Phosphorus, Sulfur, and Silicon and the Related Elements, 191(3), 438-443. https://doi.org/10.1080/10426507.2015.1100187
32. Schwalbe, R., Steele-Moore, L., & Goodwin, A. C. (Eds.). (2007). Antimicrobial Susceptibility Testing Protocols (1st ed.). CRC Press.
33. Sayıl, Ç., Deniz, N. G., & Çınarlı, A. (2016). Synthesis of n-, s-, o-substituted quinone dyes and their dyeability on polyester fibers. Progress in Organıc Coatings, 98,39-42. https://doi.org/10.1016/j.porgcoat.2016.04.017
34. Bratan, S. & Strohbusch, F. (1980). The structure of naphthazarin in solution: molecule with spectroscopic properties depending on the tunneling rates of protons in ıntramolecular hydrogen bonds. Journal of Molecular Structure, 61, 409-414. https://doi.org/10.1016/0022-2860(80)85170-2