İlaç Adayı olarak Yeni Sentezlenen Pirimidin- Triazole Yapılı Bir Bileşiğin Elektrokimyasal Yapısının İncelenmesi

Öz

Bu çalışmada, umut vadeden yeni bir ilaç adayı olarak triazolopirimidinone türevi olan 5-(klorometil)-2-(2-klorofenil)-[1,2,4]triazolo[1,5-a]pirimidin-7(3H)-on (kısaltılmış olarak CMCP) sentezlenmiştir. Diferansiyel Puls Voltametri (DPV) ve Döngüsel Voltametri (CV) gibi elektrokimyasal teknikler kullanılarak, elektrokimyasal özellikleri, ayrıca tek sarmal DNA (ssDNA) ve çift sarmal DNA (dsDNA) ile etkileşimleri araştırılmıştır. Optimum sonuçlar sağlamak için pH, konsantrasyon, tarama hızı ve immobilizasyon süresi gibi çeşitli deneysel parametreler araştırılmıştır. Çalışmada, ilaçla etkileşimden önce ve sonra guanin bazlarının pik akımı gibi elektrokimyasal sinyallerdeki değişiklikleri analiz edilmiştir. Ayrıca, CMCP üzerinde birkaç gün boyunca kararlılık testleri yapılmıştır. Sonuçlar, CMCP’nin hem ssDNA hem de dsDNA ile etkileşiminden sonra guanin bazlarında dikkat çekici değişiklikler olduğunu ortaya koymuştur ve bu bileşiğin DNA yapısı üzerindeki potansiyel etkisini vurgulamaktadır. Bu deneysel bulgular, CMCP’nin DNA üzerindeki etkisi nedeniyle ilerideki ilaç geliştirme çalışmaları için umut vadeden bir aday olduğu görüşünü desteklemektedir.

Anahtar Kelimeler

• İlaç Adayı
• İlaç-DNA Etkileşimi
• Triazolopirimidinon
• Kalem Grafit Elektrot

Electrochemical Profiling of a Promising Fused Pyrimidine-Triazole Drug Candidate

Öz

In this study, a novel triazolopyrimidinone derivative, 5-(Chloromethyl)-2-(2-chlorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one, abbreviated CMCP,was synthesized as a viable therapeutic candidate. Using electrochemical techniquessuch as Differential Pulse Voltammetry (DPV) and Cyclic Voltammetry (CV), weinvestigated its electrochemical characteristics and interactions with both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). We explored theexperimental parameters, including pH, concentration and scan rate to providebest analytical results. Our methodology involves analyzing changes inelectrochemical signals, specifically the peak current of guanine bases, before andafter interactions with the drug. Furthermore, stability tests were performed onCMCP over several days. The results unveiled noteworthy changes in guanine basesfollowing CMCP interactions with both ssDNA and dsDNA, underscoring thepotential influence of this compound on DNA structure.

Anahtar Kelimeler

• Drug Candidate
• Pencil Graphite Electrode
• Drug-DNA Interaction
• Triazolopyrimidinone

Kaynakça

1. [1] Singh, P. K., Choudhary, S., Kashyap, A., Verma, H., Kapil, S., Kumar, M., Arora, M., Silakari, O. 2019. An exhaustive compilation on chemistry of triazolopyrimidine: A journey through decades. Bioorganic Chemistry, 88, 102919.
2. [2] Tiwari, S., Talreja, S. 2022. A Study on Aromatic Heterocyclic Organic Compounds. Journal of Pharmaceutical Research International, 34(41B), 36-40.
3. [3] Arora, P., Arora, V., Lamba, H. S., Wadhwa, D. 2012. Importance of heterocyclic chemistry: a review. International Journal of Pharmaceutical Sciences and Research, 3(9), 2947.
4. [4] Yu, H., Xu, F. 2023. Advances in the synthesis of nitrogen-containing heterocyclic compounds by in situ benzyne cycloaddition. RSC advances, 13(12), 8238-8253.
5. [5] Strzelecka, M., Świątek, P. 2021. 1, 2, 4-Triazoles as important antibacterial agents. Pharmaceuticals, 14(3), 224.
6. [6] Low, Y. S., Garcia, M. D., Lonhienne, T., Fraser, J.A., Schenk, G., Guddat, L. W. 2021. Triazolopyrimidine herbicides are potent inhibitors of Aspergillus fumigatus acetohydroxyacid synthase and potential antifungal drug leads. Scientific Reports, 11(1), 21055.
7. [7] Karthic, A., Kesarwani, V., Singh, R. K., Yadav, P. K., Chaturvedi, N., Chauhan, P., Yadav, B. S., Kushwaha, S. K. 2022. Computational analysis reveals monomethylated triazolopyrimidine as a novel inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Molecules, 27(3), 801.
8. [8] Ribeiro, C. J., Kankanala, J., Xie, J., Williams, J., Aihara, H., Wang, Z. 2019. Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors. Bioorganic & medicinal chemistry letters, 29(2), 257-261.

9. [9] Abu-Hashem, A. A., Hussein, H. A., Abu-zied, K. M. 2017. Synthesis of novel 1, 2, 4-triazolopyrimidines and their evaluation as antimicrobial agents. Medicinal Chemistry Research, 26, 120-130.
10. [10] Pismataro, M. C., Felicetti, T., Bertagnin, C., Nizi, M.G., Bonomini, A., Barreca, M. L., Cecchetti, V., Jochmans, D., De Jonghe, S., Neyts, J., Loregian, A. 2021. 1, 2, 4-Triazolo [1, 5-a] pyrimidines: Efficient one-step synthesis and functionalization as influenza polymerase PA-PB1 interaction disruptors. European Journal of Medicinal Chemistry, 221, 113494.
11. [11] Zhang, B., Yao, Y., Cornec, A. S., Oukoloff, K., James, M. J., Koivula, P., Trojanowski, J. Q., Smith, A. B., Lee, V. M. Y., Ballatore, C., Brunden, K. R. 2018. A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model. Molecular neurodegeneration, 13, 1-15.
12. [12] Dai, X. J., Xue, L. P., Ji, S. K., Zhou, Y., Gao, Y., Zheng, Y. C., Liu, H. M., Liu, H. M. 2023. Triazole-fused pyrimidines in target-based anticancer drug discovery. European Journal of Medicinal Chemistry, 249, 115101.
13. [13] Patil, S. D., Rhodes, D. G., Burgess, D. J. 2005. DNA-based therapeutics and DNA delivery systems: a comprehensive review. The AAPS journal, 7, E61-E77.
14. [14] Baguley, B. C., Drummond, C. J., Chen, Y. Y., Finlay, G.J. 2021. DNA-binding anticancer drugs: One target, two actions. Molecules, 26(3), 552.
15. [15] Sabir, A., Majeed, M. I., Nawaz, H., Rashid, N., Javed, M. R., Iqbal, M. A., Shahid, Z., Ashfaq, R., Sadaf, N., Fatima, R., Sehar, A. 2023. Surface-enhanced Raman spectroscopy for studying the interaction of N-propyl substituted imidazole compound with salmon sperm DNA. Photodiagnosis and Photodynamic Therapy, 41, 103262.
16. [16] Sharifi-Rad, A., Amiri-Tehranizadeh, Z., Talebi, A., Nosrati, N., Medalian, M., Pejhan, M., Hamzkanloo, N., Saberi, M. R., Mokaberi, P., Chamani, J. 2023. Multi spectroscopic and molecular simulation studies of propyl acridone binding to calf thymus DNA in the presence of electromagnetic force. BioImpacts: BI, 13(1), 5.
17. [17] Agarwal, S., Jangir, D.K., Mehrotra, R. 2013. Spectroscopic studies of the effects of anticancer drug mitoxantrone interaction with calf-thymus DNA. Journal of Photochemistry and Photobiology B: Biology, 120, 177-182.
18. [18] Liu, Z. J., Si, Y. K., Chen, X.G. 2010. Application of circular dichroism to the study of interactions between small molecular compounds and DNA. Yao xue xue bao= Acta Pharmaceutica Sinica, 45(12), 1478-1484.
19. [19] Mollarasouli, F., Dogan-Topal, B., Caglayan, M. G., Taskin-Tok, T., Ozkan, S. A. 2020. Electrochemical, spectroscopic, and molecular docking studies of the interaction between the anti-retroviral drug indinavir and dsDNA. Journal of Pharmaceutical Analysis, 10(5), 473-481.
20. [20] Rauf, S., Gooding, J. J., Akhtar, K., Ghauri, M. A., Rahman, M., Anwar, M. A., Khalid, A.M. 2005. Electrochemical approach of anticancer drugs–DNA interaction. Journal of Pharmaceutical and Biomedical Analysis, 37(2), 205-217.
21. [21] Srinivas, S., Senthil Kumar, A. 2023. Surface-Activated Pencil Graphite Electrode for Dopamine Sensor Applications: A Critical Review. Biosensors, 13(3), 353.
22. [22] Jakóbczyk, P., Dettlaff, A., Skowierzak, G., Ossowski, T., Ryl, J., Bogdanowicz, R. 2022. Enhanced stability of electrochemical performance of few-layer black phosphorus electrodes by noncovalent adsorption of 1, 4-diamine-9, 10-anthraquinone. Electrochimica Acta, 416, 140290.
23. [23] Wang, X., Lim, H.J., Son, A. 2014. Characterization of denaturation and renaturation of DNA for DNA hybridization. Environmental health and toxicology, 29.
24. [24] Buleandra, M., Popa, D. E., David, I. G., Bacalum, E., David, V., Ciucu, A. A. 2019. Electrochemical behavior study of some selected phenylurea herbicides at activated pencil graphite electrode. Electrooxidation of linuron and monolinuron. Microchemical Journal, 147,1109-1116.
25. [25] Wang, L., Vullum, P. E., Asheim, K., Wang, X., Svensson, A. M., Vullum-Bruer, F. 2018. High capacity Mg batteries based on surface-controlled electrochemical reactions. Nano Energy, 48, 227-237.
26. [26] Sirajuddin, M., Ali, S., Badshah, A. 2013. Drug–DNA interactions and their study by UV–Visible, fluorescence spectroscopies and cyclic voltametry. Journal of Photochemistry and Photobiology B: Biology, 124,1-19.
27. [27] Topkaya, S. N., Kaya, H. O., Cetin, A.E. 2021. Electrochemical Detection of Linagliptin and its Interaction with DNA. Turkish Journal of Pharmaceutical Sciences, 18(5), 645.
28. [28] N. miller JCm. 2005. Statistics and Chemometrics for Analytical Chemistry: 5th pearson education, Essex, London, 121 p.