SYNTHESIS AND PROPERTIES OF S-ALKYL 4-(4-CHLOROPHENYL)-5-(PYRROLE-2-YL)-1,2,4-TRIAZOLE-3-THIOL DERIVATIVES

Öz

Objective: The aim of the work was to develop effective methods for the synthesis of promising heterocyclic systems based on pyrrole and 1,2,4-triazole. In the process of realizing of this aim, 10 new S-alkyl 4-(4-chlorophenyl)-5-(pyrrole-2-yl)-1,2,4-triazole-3-thiol derivatives were synthesized. Material and Method: Chemical structures of synthesized compounds were characterized with elemental analysis, 1H-NMR, LC-MS techniques. The biological potential of the synthesized substances was estimated by the molecular docking method and ADME analysis. Result and Discussion: An optimum method for the synthesis of S-alkyl 4-(4-chlorophenyl)-5-(pyrrole-2-yl)-1,2,4-triazole-3-thiol has been developed. In molecular modeling studies, the compounds were found to be similar to known drugs in some respects. The interaction of each molecule with the crystal structures of cyclooxygenase-2, lanosterol-14α-demethylase in the active site was considered in silico. Pharmacokinetic parameters for a number of the synthesized compounds have been predicted by ADME analysis.

Anahtar Kelimeler

• 1,2,4-triazole
• ADME analysis
• docking
• synthesis

S-ALKİL 4-(4-KLOROFENİL)-5-(PİROL-2-İL)-1,2,4-TRİAZOL-3-TİYOL TÜREVLERİNİN SENTEZİ VE ÖZELLİKLERİ

Öz

Amaç: Çalışmanın amacı, pirol ve 1,2,4-triazole dayalı gelecek vaat eden heterosiklik sistemlerin sentezi için etkili yöntemler geliştirmektir. Belirtilen hedefin gerçekleştirilmesi sürecinde 10 yeni S-alkil 4-(4-klorofenil)-5-(pirol-2-il)-1,2,4-triazol-3-tiyol türevi sentezlenmiştir.. Gereç ve Yöntem: Sentezlenen bileşiklerin kimyasal yapıları element analiz, 1H NMR, LC-MS teknikleri ile karakterize edildi. Sentezlenen maddelerin biyolojik potansiyeli moleküler yerleştirme yöntemi ve ADME analizi ile tahmin edildi. Sonuç ve Tartışma: S-alkil 4-(4-klorofenil)-5-(pirol-2-il)-1,2,4-triazol-3-tiyol türevlerinin sentezi için optimal bir yöntem geliştirilmiştir. Moleküler modelleme çalışmalarında, bileşiklerin bazı açılardan bilinen ilaçlara benzer olduğu bulunmuştur. Her molekülün kristal yapıdaki siklooksijenaz-2 ve lanosterol-14α-demetilaz aktif bölgesi ile etkileşimi in silico olarak değerlendirildi. Sentezlenen bileşiklerin bir kısmı için farmakokinetik parametreler ADME analizi ile tahmin edildi.

Anahtar Kelimeler

• 1,2,4-triazol
• ADME analizi
• moleküler modelleme
• sentez

Kaynakça

1. 1. Grytsai, O., Valiashko, O., Penco-Campillo, M., Dufies, M., Hagege, A., Martial, S., Pagès, G., Ronco, C., Benhida, R. (2020). Synthesis and biological evaluation of 3-amino-1,2,4-triazole derivatives as potential anticancer compounds. Bioorganic Chemistry, 104271. [CrossRef]
2. 2. El-Reedy, A.A.M., Soliman, N.K. (2020). Synthesis, biological activity and molecular modeling study of novel 1,2,4-triazolo[4,3-b][1,2,4,5]tetrazines and 1,2,4-triazolo[4,3-b][1,2,4]triazines. Scientific Reports, 10, 6137. [CrossRef]
3. 3. Abdellatif, K.R.A., Abdelall, E.K.A., Elshemy, H.A.H., Philoppes, J.N., Hassanein, E.H.M., Kahk, N.M. (2021). Optimization of pyrazole-based compounds with 1,2,4-triazole-3-thiol moiety as selective COX-2 inhibitors cardioprotective drug candidates: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory, ulcerogenicity, cardiovascular evaluation, and molecular modeling studies. Bioorganic Chemistry, 114, 105122. [CrossRef]
4. 4. Shcherbyna, R., Panasenko, O., Polonets, O., Nedorezanıuk, N., Duchenko, M. (2021). Synthesis, antimicrobial and antifungal activity of ylidenhydrazides of 2-((4-R-5-R1-4Н-1,2,4-triazol-3-yl)thio)acetaldehydes. Journal of Faculty of Pharmacy of Ankara University, 45(3), 504-514. [CrossRef]
5. 5. El Bakri, Y., Marmouzi, I., El Jemli, M., Anouar, E.H., Karthikeyan, S., Harmaoui, A., Faouzi, M.E.A., Mague, J.T., Essassi, E.M. (2019). Synthesis, biological activity and molecular modeling of a new series of condensed 1,2,4-triazoles. Bioorganic Chemistry, 92, 1031932019. [CrossRef]
6. 6. Samelyuk, Y.G., Kaplaushenko, A.G. (2014). Synthesis of 3-alkylthio(sulfo)-1,2,4-triazoles, containing methoxyphenyl substituents at C5 atoms, their antipyretic activity, propensity to adsorption and acute toxicity. Journal of Chemical and Pharmaceutical Research, 6(5), 1117-1121.
7. 7. Boraei, A.T.A., Sarhan, A.A.M., Yousuf, S., Barakat, A. (2020). Synthesis of a new series of Nitrogen/Sulfur heterocycles by linking four rings: Indole; 1,2,4-triazole; pyridazine; and quinoxaline. Molecules, 25(3), 450. [CrossRef]
8. 8. Mioc, M., Avram, S., Bercean, V., Kurunczi, L., Ghiulai, R.M., Oprean, C., Soica, C. (2018). Design, synthesis and biological activity evaluation of S-substituted 1H-5-mercapto-1,2,4-triazole derivatives as antiproliferative agents in colorectal cancer. Frontiers in Chemistry, 6, 373. [CrossRef]

9. 9. Frolova, Y., Kaplaushenko, A., Nagornaya, N. (2020). Design, synthesis, antimicrobial and antifungal activities of new 1,2,4-triazole derivatives containing 1H-tetrazole moiety. Journal of Faculty of Pharmacy of Ankara University, 44(1), 70-88. [CrossRef]
10. 10. Safonov, A. (2020). Method of synthesis novel N'-substituted 2-((5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazides. Journal of Faculty of Pharmacy of Ankara University, 44(2), 242-252. [CrossRef]
11. 11. Hotsulia, A.S., Fedotov, S.O. (2019). Synthesis, structure and properties of N-R-2-(5-(5-methyl-1H-pyrazole-3-yl)-4-phenyl-4H-1,2,4-triazole-3-ylthio)acetamides. Current Issues in Pharmacy and Medicine: Science and Practice, 12(1), 4-9. [CrossRef]
12. 12. Fedotov, S.O., Hotsulia, A.S. (2021). Synthesis and properties of S-derivatives of 4-amino-5-(5-methylpyrazol-3-yl)-1,2,4-triazole-3-thiol. Current Issues in Pharmacy and Medicine: Science and Practice, 14(3), 268-274. [CrossRef]
13. 13. Simurova, N.V., Maiboroda, O.I. (2021) Antiviral activity of 1,2,4-triazole derivatives (microreview). Chemistry of Heterocyclic Compounds, 57, 420-422. [CrossRef]
14. 14. Roman, G., Bostănaru, A.C., Năstasă, V., Mareş, M. (2019). Design, synthesis, and evaluation of the antimycobacterial activity of 3-mercapto-1,2,4-triazole-pyrrole hybrids. Turkish Journal of Chemistry, 43(2), 531-546. [CrossRef]
15. 15. Bijev, A.T., Prodanova, P. (2007). Derivatives of 4-amino-4H-1,2,4-triazole-3-thiols linked to the pyrrole cycle and some products of their S-alkylation. Chemistry of Heterocyclic Compounds, 43(3), 306-313. [CrossRef]
16. 16. Saidov, N.B., Georgiyants, V.A., Demchenko, A.M. (2014). Directed synthesis of potential antitumor substances among derivatives of 3-mercapto-4-(1H-pyrrol-1-yl)-5-cyclohexyl-1,2,4-triazole(4H). Journal of Organic and Pharmaceutical Chemistry, 12(1(45)). 43-46. [CrossRef]
17. 17. Gotsulya, A.S., Verba, D.P., Panasenko, O.I., Knysh, Y.G. (2017). Synthesis and study of the properties of derivatives 4-phenyl-5-(1H-pyrrole-2-yl)-4H-1,2,4-triazole-3-thiols. Farmatsevtychnyi Zhurnal, 1, 59-66. [CrossRef]
18. 18. Protein Data Bank, pdb. Retrieved from http://www.rcsb.org/pdb/home/home.do. 19. MarvinSketch version 17.21.0, ChemAxon. Retrieved from http://www.chemaxon.com.
19. 20. Trott, O., Olson, A.J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31, 455-461. [CrossRef]
20. 21. Daina, A., Michielin, O., Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Report, 7(1), 42717. [CrossRef]