Research Article
Rifampisin Dirençli Mycobacterium tuberculosis Kompleks Suşları Üzerine Benzimidazolyum Tuzlarının Antimikobakteriyel Etkinliğinin Araştırılması
Abstract
Çalışmada, Sağlık Bakanlığı Adana Bölge Tüberküloz Laboratuvarı’na gönderilen klinik örneklerden izole edilen rifampisin dirençli tüberküloz suşları ile referans suş M. tuberculosis H37Rv üzerine benzimidazol çekirdeği içeren 3 farklı bileşiğin ((S1): 1-(N-metilftalimid)-3-benzilbenzimidazolyum bromür, (S2): 1-(N-metilftalimid)-3-(4-metilbenzil) benzimidazolyum bromür, (S3): 1-(N-metilftalimid)-3-(naftalen-1-ilmetil) benzimidazolyum bromür) antimikobakteriyel aktivitesinin tespiti amaçlandı. Benzimidazol türevi bileşiklerinin rifampisin dirençli 35 klinik M. tuberculosis ve H37Rv suşlarında antimikobakteriyel aktiviteleri in vitro şartlarda BACTEC MGIT 960 sistemi kullanılarak test edildi. Ayrıca, antimikobakteriyel etkili bileşiklerin olası etkileşimleri moleküler doking ile incelendi. Çalışma sonucunda sadece S2 bileşiğinin yalnız M. tuberculosis H37Rv suşuna karşı antimikobakteriyel aktivite gösterdiği, rifampisin dirençli M. tuberculosis suşlarına karşı aktivitesinin olmadığı belirlendi. S1 ve S3 bileşiklerinin ise hem klinik hem de referans suşa karşı antimikobakteriyel aktivitesi tespit edilemedi. Moleküler doking sonuçları S2’nin InhA ile bağlandığını ve onu inhibe ederek antimikobakteriyel etkisini gösterebileceği ortaya çıkardı. Sonuç olarak S2 bileşiğinin tüberküloz tedavisinde yeni ajan olarak sunulabilir ancak daha kapsamlı çalışmaların yapılmasına da ihtiyaç duyulmaktadır.
Keywords
Supporting Institution
Çukurova Üniversitesi
Project Number
TYL-2021-14313
Thanks
Çukurova Üniversitesi’ne çalışmayı destekledikleri için teşekkür ederiz.
References
- Akkoç, S., Gök, Y., İlhan, İ.Ö., & Kayser, V. (2016a). N-Methylphthalimide substituted benzimidazolium salts and PEPPSI Pd-NHC complexes: synthesis, characterization and catalytic activity in carbon-carbon bond forming reactions. Beilstein Journal of Organic Chemistry 12, 81-88.
- Akkoç, S., Gök, Y., İlhan, İ.Ö., & Kayser, V. (2016b). In situ generation of efficient palladium N-heterocyclic carbene catalysts using benzimidazolium salts for the Suzuki-Miyaura cross-coupling reaction. Current Organic Synthesis 13(5), 761-766.
- Aridoss, G., Amirthaganesan, S., Kumar, N.A., Kim, J.T., Lim, K.T., Kabilan, S.,... & Jeong, Y.T. (2008). A facile synthesis, antibacterial, and antitubercular studies of some piperidin-4- one and tetrahydropyridine derivatives. Bioorganic & Medicinal Chemistry Letters 18, 6542-8.
- Camacho, J., Barazarte, A., Gamboa, N., Rodrigues, J., Rojas, R., Vaisberg, A.,... & Charris, J. (2011). Synthesis and biological evaluation of benzimidazole-5-carbohydrazide derivatives as antimalarial, cytotoxic and antitubercular agents. Bioorganic & Medicinal Chemistry 19, 2023-9.
- Cousins, K.R. (2011). Computer review of ChemDraw ultra 12.0. Journal of the American Chemical Society 133, 8388.
- Gill, C.M., Dolan, L., Piggott, L.M., & McLaughlin, A.M. (2022). New developments in tuberculosis diagnosis and treatment. Breathe (Sheff) 18(1), 210149.
- Gong, Y., Karakaya, S.S., Guo, X., Zhenga, P., Gold, B., Ma, Y.,... & Liu, G. (2014). Benzimidazole-based compounds kill M. tuberculosis . European Journal of Medicinal Chemistry 75, 336-353.
- Gygli, S.M., Borrell, S., Trauner, A., & Gagneux, S. (2017). Antimicrobial resistance in M. tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiology Reviews 41(3), 354-373.
- Juárez, R.J., Chávez, W.C., Ramírez, N.J., Ramírez, G.I.C., González, I.U., Mejía, G.M.,... & García-Pérez, B.E. (2020). Synthesis and Antimycobacterial Activity of 2,5-Disubstituted and 1,2,5-Trisubstituted Benzimidazoles. Frontiers in Chemistry 8, 433.
- Kamsri, P., Hanwarinroj, C., Phusi, N., Pornprom, T., Chayajarus, K., Punkvang, A.,... & Pungpo, P. (2020). Discovery of new and potent inha inhibitors as antituberculosis Agents: Structure-based virtual screening validated by biological assays and X-ray Crystallography. Journal of Chemical Information and Modeling 60(1), 226-234.
- Keri, R.S., Rajappa, C.K., Patil, S.A., & Nagaraja, B.M. (2016). Benzimidazole-core as an antimycobacterial agent. Pharmacological Reports 68(6), 1254-1265.
- Khan, A.S., Phelan, J.E., Khan, M.T., Ali, S., Qasim, M., Napier, G.,... & Khan, T.A. (2021). Characterization of rifampicin‑resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa, Pakistan. Scientific Reports 11, 14194.
- Khawbung, J.L., Nath, D., & Chakraborty, S. (2021). Drug resistant Tuberculosis: a review. Comparative Immunology Microbiology and Infectious Diseases 74, 101574.
- Kuo, M.R., Morbidoni, H.R., Alland, D., Sneddon, S.F., Gourlie, B.B., Staveski, M.M.,... & Fidock, D.A. (2003). Targeting tuberculosis and malaria through inhibition of enoyl reductase: Compound actıvıty and structural data. The Journal of Biological Chemistry 278, 20851-9.
- Malasala, S., Ahmad, N., Akunuri, R., Shukla, M., Kaul, G., Dasgupta, A.,... & Nanduri, S. (2021). Synthesis and evaluation of new quinazoline-benzimidazole hybrids as potent anti-microbial agents against multidrug resistant Staphylococcus aureus and M. tuberculosis. European Journal of Medicinal Chemistry 212, 112996.
- Malenfant, J.H., & Brewer, T.F. (2021). Rifampicin mono-resistant tuberculosis-a review of an uncommon but growing challenge for global tuberculosis control. Open Forum Infectious Diseases 8(2), ofab018.
- Manjunatha, U.H., Rao, S.P.S., Reddy, R.R., Noble, C.G., Camacho, L.R., Tan, B.H.,... & Diagana, T.T. (2015). Direct inhibitors of InhA active against M. tuberculosis. Science Translational Medicine7(269), 269ra3.
- Martínez-Hoyos, M., Perez-Herran, E., Gulten, G., Encinas, L., Álvarez-Gómez, D., Alvarez, E.,... & Mendoza-Losana, A. (2016). Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine 8, 291.
- Muhammed, M.T., Kuyucuklu, G., Kaynak-Onurdag, F., Aki-Yalcin, E. (2022). Synthesis, antimicrobial activity, and molecular modeling studies of some benzoxazole derivatives. Letters in Drug Design & Discovery 19, 757-768.
- Prasad, R., Gupta, N., & Banka, A. (2018). Multidrug-resistant tuberculosis/rifampicin-resistant tuberculosis: Principles of management. Lung India 35(1), 78-81.
- Rozwarski, D.A., Vilchèze, C., Sugantino, M., Bittman, R., Sacchettini, J.C. (1999). Crystal structure of the M. tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. The Journal of Biological Chemistry 274, 15582-15589.
- Sangani, C.B., Jardosh, H.H., Patel, M.P., Patel, R.G. (2013). Microwave-assisted synthesis of pyrido[1,2-a]benzimidazole derivatives of b-aryloxyquinoline and their antimicrobialand antituberculosis activities. Medicinal Chemistry Research 22, 3035-47.
- Schwœbel, V., Trebucq, A., Kashongwe, Z., Bakayoko, A.S., Kuaban, C., Noeske, J.,... & Rieder, H.L. (2020). Outcomes of a nine-month regimen for rifampicin-resistant tuberculosis up to 24 months after treatment completion in nine African countries. EClinical Medicine 20, 100268.
- Siddiki, A.A., Bairwa, V.K., Telveka, V.N. (2014). Synthesis and biological evaluation of novel N' (4-aryloxybenzylidene)- 1H-benzimidazole-2 carbohydrazide derivatives as anti-tubercular agents. Combinatorial Chemistry & High Throughput Screening, 17(7), 630-8.
- Sullivan, T.J., Truglio, J.J., Boyne, M.E., Novichenok, P., Zhang, X., Stratton, C.F.,... & Tonge, P.J. (2006). High affinity InhA inhibitors with activity against drug-resistant strains of M. tuberculosis. ACS Chemical Biology 1, 43-53.
- Trott, O., & Olson, A. (2010). Autodock vina: improving the speed and accuracy of docking. Journal of Computational Chemistry 3, 455-461.
- World Health Organization. (2018). Global Tuberculosis Report 2018. Geneva: World Health Organization (WHO). Available from: https://www.who.int/publications/i/item/9789241565646. Erişim tarihi: 02 Ocak 2023.
- Yoon, Y.K., Ali, M.A., Choon, T.S., Ismail, R., Wei, A.C., Kum, R.S.,... & Beevi,F. (2013). Antituberculosis: Synthesis and antimycobacterial activity of novel benzimidazole derivatives. BioMed Research International 2013, 926309.
Investigation of the Antimicobacterial Activity of Benzimidazolium Salts on Rifampicin Resistant Mycobacterium tuberculosis Complex Strains
Abstract
In this study, it was aimed to determine the antimycobacterial activity of 3 different compounds ((S1): 1-(N-methylphthalimide)-3-benzylbenzimidazolium bromide, (S2): 1-(N-methylphthalimide)-3-(4-methylbenzyl) benzimidazolium bromide, (S3): 1-(N-methylphthalimide)-3-(naphthalen-1-ylmethyl) benzimidazolium bromide) containing benzimidazole nuclei on M. tuberculosis reference strain H37Rv and rifampicin resistant tuberculosis strains isolated from clinical samples sent to the Ministry of Health Adana Regional Tuberculosis Laboratory. Using the BACTEC MGIT 960 system, the antimycobacterial activity of benzimidazole derivative compounds were examined in vitro against M. tuberculosis H37Rv and 35 clinical strains of M. tuberculosis that were resistant to rifampicin. Furthermore, molecular docking was used to look into the possible interactions of the antimycobacterial compounds. According to the results of the study, compound S2 showed antimycobacterial activity against the M. tuberculosis H37Rv strain but it didn’t have any effect on rifampicin-resistant M. tuberculosis strains. Compounds S1 and S3 didn’t exhibit any antimycobacterial activity against both clinical and reference strains. The results of the molecular docking analysis revealed that S2 could bind to InhA and thus could exert its antimycobacterial activity by inhibiting it. As a result, the S2 compound can be suggested as a new agent for the treatment of tuberculosis, however, more comprehensive studies are needed.
Project Number
TYL-2021-14313
References
- Akkoç, S., Gök, Y., İlhan, İ.Ö., & Kayser, V. (2016a). N-Methylphthalimide substituted benzimidazolium salts and PEPPSI Pd-NHC complexes: synthesis, characterization and catalytic activity in carbon-carbon bond forming reactions. Beilstein Journal of Organic Chemistry 12, 81-88.
- Akkoç, S., Gök, Y., İlhan, İ.Ö., & Kayser, V. (2016b). In situ generation of efficient palladium N-heterocyclic carbene catalysts using benzimidazolium salts for the Suzuki-Miyaura cross-coupling reaction. Current Organic Synthesis 13(5), 761-766.
- Aridoss, G., Amirthaganesan, S., Kumar, N.A., Kim, J.T., Lim, K.T., Kabilan, S.,... & Jeong, Y.T. (2008). A facile synthesis, antibacterial, and antitubercular studies of some piperidin-4- one and tetrahydropyridine derivatives. Bioorganic & Medicinal Chemistry Letters 18, 6542-8.
- Camacho, J., Barazarte, A., Gamboa, N., Rodrigues, J., Rojas, R., Vaisberg, A.,... & Charris, J. (2011). Synthesis and biological evaluation of benzimidazole-5-carbohydrazide derivatives as antimalarial, cytotoxic and antitubercular agents. Bioorganic & Medicinal Chemistry 19, 2023-9.
- Cousins, K.R. (2011). Computer review of ChemDraw ultra 12.0. Journal of the American Chemical Society 133, 8388.
- Gill, C.M., Dolan, L., Piggott, L.M., & McLaughlin, A.M. (2022). New developments in tuberculosis diagnosis and treatment. Breathe (Sheff) 18(1), 210149.
- Gong, Y., Karakaya, S.S., Guo, X., Zhenga, P., Gold, B., Ma, Y.,... & Liu, G. (2014). Benzimidazole-based compounds kill M. tuberculosis . European Journal of Medicinal Chemistry 75, 336-353.
- Gygli, S.M., Borrell, S., Trauner, A., & Gagneux, S. (2017). Antimicrobial resistance in M. tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiology Reviews 41(3), 354-373.
- Juárez, R.J., Chávez, W.C., Ramírez, N.J., Ramírez, G.I.C., González, I.U., Mejía, G.M.,... & García-Pérez, B.E. (2020). Synthesis and Antimycobacterial Activity of 2,5-Disubstituted and 1,2,5-Trisubstituted Benzimidazoles. Frontiers in Chemistry 8, 433.
- Kamsri, P., Hanwarinroj, C., Phusi, N., Pornprom, T., Chayajarus, K., Punkvang, A.,... & Pungpo, P. (2020). Discovery of new and potent inha inhibitors as antituberculosis Agents: Structure-based virtual screening validated by biological assays and X-ray Crystallography. Journal of Chemical Information and Modeling 60(1), 226-234.
- Keri, R.S., Rajappa, C.K., Patil, S.A., & Nagaraja, B.M. (2016). Benzimidazole-core as an antimycobacterial agent. Pharmacological Reports 68(6), 1254-1265.
- Khan, A.S., Phelan, J.E., Khan, M.T., Ali, S., Qasim, M., Napier, G.,... & Khan, T.A. (2021). Characterization of rifampicin‑resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa, Pakistan. Scientific Reports 11, 14194.
- Khawbung, J.L., Nath, D., & Chakraborty, S. (2021). Drug resistant Tuberculosis: a review. Comparative Immunology Microbiology and Infectious Diseases 74, 101574.
- Kuo, M.R., Morbidoni, H.R., Alland, D., Sneddon, S.F., Gourlie, B.B., Staveski, M.M.,... & Fidock, D.A. (2003). Targeting tuberculosis and malaria through inhibition of enoyl reductase: Compound actıvıty and structural data. The Journal of Biological Chemistry 278, 20851-9.
- Malasala, S., Ahmad, N., Akunuri, R., Shukla, M., Kaul, G., Dasgupta, A.,... & Nanduri, S. (2021). Synthesis and evaluation of new quinazoline-benzimidazole hybrids as potent anti-microbial agents against multidrug resistant Staphylococcus aureus and M. tuberculosis. European Journal of Medicinal Chemistry 212, 112996.
- Malenfant, J.H., & Brewer, T.F. (2021). Rifampicin mono-resistant tuberculosis-a review of an uncommon but growing challenge for global tuberculosis control. Open Forum Infectious Diseases 8(2), ofab018.
- Manjunatha, U.H., Rao, S.P.S., Reddy, R.R., Noble, C.G., Camacho, L.R., Tan, B.H.,... & Diagana, T.T. (2015). Direct inhibitors of InhA active against M. tuberculosis. Science Translational Medicine7(269), 269ra3.
- Martínez-Hoyos, M., Perez-Herran, E., Gulten, G., Encinas, L., Álvarez-Gómez, D., Alvarez, E.,... & Mendoza-Losana, A. (2016). Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine 8, 291.
- Muhammed, M.T., Kuyucuklu, G., Kaynak-Onurdag, F., Aki-Yalcin, E. (2022). Synthesis, antimicrobial activity, and molecular modeling studies of some benzoxazole derivatives. Letters in Drug Design & Discovery 19, 757-768.
- Prasad, R., Gupta, N., & Banka, A. (2018). Multidrug-resistant tuberculosis/rifampicin-resistant tuberculosis: Principles of management. Lung India 35(1), 78-81.
- Rozwarski, D.A., Vilchèze, C., Sugantino, M., Bittman, R., Sacchettini, J.C. (1999). Crystal structure of the M. tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. The Journal of Biological Chemistry 274, 15582-15589.
- Sangani, C.B., Jardosh, H.H., Patel, M.P., Patel, R.G. (2013). Microwave-assisted synthesis of pyrido[1,2-a]benzimidazole derivatives of b-aryloxyquinoline and their antimicrobialand antituberculosis activities. Medicinal Chemistry Research 22, 3035-47.
- Schwœbel, V., Trebucq, A., Kashongwe, Z., Bakayoko, A.S., Kuaban, C., Noeske, J.,... & Rieder, H.L. (2020). Outcomes of a nine-month regimen for rifampicin-resistant tuberculosis up to 24 months after treatment completion in nine African countries. EClinical Medicine 20, 100268.
- Siddiki, A.A., Bairwa, V.K., Telveka, V.N. (2014). Synthesis and biological evaluation of novel N' (4-aryloxybenzylidene)- 1H-benzimidazole-2 carbohydrazide derivatives as anti-tubercular agents. Combinatorial Chemistry & High Throughput Screening, 17(7), 630-8.
- Sullivan, T.J., Truglio, J.J., Boyne, M.E., Novichenok, P., Zhang, X., Stratton, C.F.,... & Tonge, P.J. (2006). High affinity InhA inhibitors with activity against drug-resistant strains of M. tuberculosis. ACS Chemical Biology 1, 43-53.
- Trott, O., & Olson, A. (2010). Autodock vina: improving the speed and accuracy of docking. Journal of Computational Chemistry 3, 455-461.
- World Health Organization. (2018). Global Tuberculosis Report 2018. Geneva: World Health Organization (WHO). Available from: https://www.who.int/publications/i/item/9789241565646. Erişim tarihi: 02 Ocak 2023.
- Yoon, Y.K., Ali, M.A., Choon, T.S., Ismail, R., Wei, A.C., Kum, R.S.,... & Beevi,F. (2013). Antituberculosis: Synthesis and antimycobacterial activity of novel benzimidazole derivatives. BioMed Research International 2013, 926309.
There are 28 citations in total.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Structural Biology |
| Journal Section | RESEARCH ARTICLE |
| Authors | |
| Project Number | TYL-2021-14313 |
| Early Pub Date | October 13, 2023 |
| Publication Date | February 28, 2024 |
| Submission Date | April 8, 2023 |
| Acceptance Date | August 25, 2023 |
| Published in Issue | Year 2024Volume: 27 Issue: 1 |
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