Investigation of Antituberculosis Activity of Some Compounds Containing Benzimidazole Core Against M. tuberculosis H37Rv Strain

Öz

Tuberculosis is one of the main causes of death due to infectious diseases. As tuberculosis treatment is long and complex, drug resistance is becoming widespread. It has been reported that some benzimidazole derivative compounds that will be promising in the treatment of tuberculosis exhibit antituberculous activity. In this study, it was aimed to determine the antituberculosis activity of 3 different compounds containing benzimidazole core synthesized (A1: 1-(2-methylbenzonitrile)-3-(naphthalen-1-yl-methyl)-1H-benzo[d]imidazole-3-ium chloride, A2: 1-(2-hydroxyethyl)-3-(2) -(piperidinium-1-yl)ethyl chloride)-1H-benzo[d]imidazol-3-ium bromide, A3: 1-(3-methylbenzyl)-3-(2-(piperidin-1-yl)ethyl)- 1H-benzo[d]imidazole-3-ium chloride) against the reference strain M. tuberculosis H37Rv. The antituberculosis activities of benzimidazole-containing compounds (A1, A2, and A3) against M. tuberculosis H37Rv strain were investigated in vitro using the BACTEC MGIT 960 system. In the study, it was determined that A1, A2, and A3 compounds did not show any antituberculosis activity against M. tuberculosis H37Rv strain. As a result, it is thought that antituberculosis activity studies should be continued by synthesizing different benzimidazole compounds.

Anahtar Kelimeler

• Antituberculosis
• BACTEC MGIT 960
• M. tuberculosis

Benzimidazol Çekirdeği İçeren Bazı Bileşiklerin M. tuberculosis H37Rv Suşuna Karşı Antitüberküloz Aktivitesinin İncelenmesi

Öz

Tüberküloz, bulaşıcı hastalıklara bağlı ölümlerin başlıca nedenlerinden biridir. Tüberküloz tedavisinin uzun ve karmaşık olması, ilaç direncini yaygınlaşmaktadır. Tüberküloz tedavisinde umut olacak bazı benzimidazol türevi bileşiklerin antitüberküloz aktivite sergilediği bildirilmiştir. Çalışmada, referans M. tuberculosis H37Rv suşuna karşı sentezlenen benzimidazol çekirdeği içeren 3 farklı bileşiğin (A1: 1-(2-metilbenzonitril)-3-(naftalen-1-il-metil)-1H-benzo[d]imidazol-3-yum klorür, A2: 1-(2-hidroksietil)-3-(2-(piperidinyum-1-il)etil klorür)-1H-benzo[d]imidazol-3-yum bromür, A3: 1-(3-metilbenzil)-3-(2-(piperidin-1-il)etil)-1H-benzo[d]imidazol-3-yum klorür) antitüberküloz aktivitesinin tespiti amaçlandı. Benzimidazol çekirdeği içeren bileşiklerin (A1, A2 ve A3), M. tuberculosis H37Rv suşuna karşı antitüberküloz aktiviteleri in vitro şartlarda BACTEC MGIT 960 sistemi kullanılarak araştırıldı. Çalışmada A1, A2 ve A3 bileşiklerinin M. tuberculosis H37Rv suşuna karşı herhangi bir antitüberküloz aktivite göstermediği tespit edildi. Sonuç olarak, farklı benzimidazol bileşikler sentezlenerek antitüberküloz aktivite çalışmalarının devam edilmesi gerektiği düşünülmektedir.

Anahtar Kelimeler

• Antitüberküloz
• BACTEC MGIT 960
• M. tuberculosis

Kaynakça

1. [1] Sia, J.K., and Rengarajan, J. 2019. Immunology of Mycobacterium tuberculosis infections. Microbiol Spectr, 7(4), 10.
2. [2] Ortiz, A.T., Coronel, J., Vidal, J.R., Bonilla, C., Moor, D.A.J., et al. 2021. Genomic signatures of pre-resistance in Mycobacterium tuberculosis. Nat Commun, 12, 7312.
3. [3] Vilchèze, C., and Jacobs, W.A. 2019. The ısoniazid paradigm of killing, resistance, and persistence in Mycobacterium tuberculosis. J Mol Biol, 431(18), 3450-3461.
4. [4] Tăbăran, A.F., Matea, C.T., Mocan, T., Tăbăran, A., Mihaiu, M., et al. 2020. Silver nanoparticles for the therapy of tuberculosis. Int J Nanomedicine, 15, 2231-2258.
5. [5] Zaw, M.T, Emran, N.A., Zaw, L. 2018. Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis. Journal of Infection and Public Health, 11, 605-610.
6. [6] World health Organization, Multidrug-resistant tuberculosis (MDR-TB). 2017. https://www.who.int/tb/challenges/mdr/MDR-RR_TB_factsheet_2017.pdf 2018. (Erişim tarihi: 01.12.2022).
7. [7] Xu, Y., Liu, F., Chen, S., Wu, J., Hu, Y., Zhu, B., and Sun, Z. 2018. In vivo evolution of drug-resistant Mycobacterium tuberculosis in patients during long-term treatment. BMC Genomics, 19, 640.
8. [8] Fernández-Soto, P., Casulli, J., Solano-Castro, D., Rodríguez-Fernánde, P., Jowitt, T.A., et al. 2021. Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis. Sci Rep, 11, 7667.

9. [9] Tsenova, L., Singhal, A. 2020. Effects of host-directed therapies on the pathology of tuberculosis. JPatho, 250, 636-646.
10. [10] Ates-Alagoz, Z. 2016. Antimicrobial activities of 1-H-Benzimidazole-based molecules. Curr Top Med Chem, 16(26), 2953-2962.
11. [11] Kazimierczuk, Z., Andrzejewska, M., Kaustova, J., Klimesova, V. 2005. Synthesis and antimycobacterial activity of 2-substituted halogenobenzimidazoles. Eur. J. Med. Chem,40, 203-208.
12. [12] Stanley, S.A., Grant, S.S., Kawate, T., Iwase, N., Shimizu, M., and et al. 2012. Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening. Chem Biol, 7, 1377-1384.
13. [13] Akkoç, S., Kayser,V., İlhan, İ.Ö., Hibbs, D.E., Gök, Y., Peter, A., et al. 2017. New compounds based on a benzimidazole nucleus: synthesis, characterization and cytotoxic activity against breast and colon cancer cell lines. Journal of Organometallic Chemistry, 839, 98-107.
14. [14] Akkoç, S. 2019. Derivatives of 1-(2-(Piperidin-1-yl)ethyl)-1H-benzo[d]imidazole: Synthesis, characterization, determining of electronic properties and cytotoxicity studies' ChemistrySelect, 4(17), 4938-4943.
15. [15] Moreira, J.B., Mann. J., Neidle, S., McHugh, T.D., Taylor, P.E. 2013. Antibacterial activity of head-to-head bis-benzimidazoles. Int J Antimicrob Agents, 42(4), 361-6.
16. [16] Gong, J.X., He, Y., Cui, Z.L., and Guo, Y.W. 2016. Synthesis, spectral characterization, and antituberculosis activity ofthiazino[3,2-A]benzimidazole derivatives. Phosphorus, Sulfur, and Silicon and the Related Elements, 191(7), 1036-1041.
17. [17] Zhang, H.Y., Wang, B., Sheng, L., Li, D., Zhang, D.F., Lin, Z.Y., an et al. 2014. Design and synthesis of novel benzimidazole derivatives as anti-tuberculosis agents. Yao Xue Xue Bao, 49(5), 644-51.
18. [18] Keri, R.S., Rajappa, C.K., Patil, S.A., and Nagaraja, B.M. 2016. Benzimidazole-core as an antimycobacterial agent. Pharmacol Rep, 68, 1254-1265.
19. [19] Yoon, Y.K., Ali, M.A., Choon, T.S., Ismail, R., Wei, A.C., Kuma, R.S., and et al. 2013. Antituberculosis: synthesis and antimycobacterial activity of novel benzimidazole derivatives. Biomed Res Int, 926309.
20. [20] Klimesová, V., Kocí, J., Pour, M., Stachel, J., Waisser K., Kaustová ,J. 2002. Synthesis and preliminary evaluation of benzimidazole derivatives as antimicrobial agents. Eur. J. Med. Chem. 37, 409-418.
21. [21] Juárez, R.J., Chávez, W.C., Ramírez, N.J., Ramírez, G.I.C., González I. U.,Mejía, G.M., et al. 2020. Synthesis and antimycobacterial activity of 2,5-disubstituted and 1,2,5-trisubstituted benzimidazoles. Front Chem, 8, 433.