Design, Synthesis, and Biological Evaluation of 1,2,4-Triazole Derivatives as Potential Antimicrobial Agents

In this study, we aimed to develop new biologically active compounds with antibacterial properties. 4-amino-5-methyl-2H-1,2,4-triazol-3(4H)-one (1) was converted to the corresponding Schiff bases (2) with the reaction with a 4-anis aldehyde. Acetic acid ethyl esters containing [1,2,4] triazole ring (3) were synthesized by the condensation of compounds (2) with ethyl bromoacetate in basic media. The reaction of compounds (3) with hydrazine hydrate led to the formation of acid hydrazides (4). The reaction of hydrazide (4) with phenyl isothio - and phenyl isocyanate produced the corresponding carbothioamide (5a) and carboxamide (5b). The basic treatment of carbothioamide (5a) and. carboxamide (5b) produced 1,2,4-triazole (6a, 6b) compounds, respectively. The reactions of ( (6b) with norfloxacin and ciprofloxacin in the presence of formaldehyde afforded the corresponding Mannich bases( 7a, 7b). The structural assignments of the new compounds were based on elemental analysis and spectral (IR, 1H-NMR, and 13C-NMR) data. All newly synthesized compounds were screened for their antimicrobial activity. The in vitro antimicrobial activities of the compounds were evaluated against pathogenic microorganisms, and compounds 7a and 7b were found the most effective antimicrobial activity.

Keywords:

1, 2, 4-triazole, fluoroquinolone, antimicrobial activity multicomponent.,

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[1] World health organization, Global antimicrobial report, 2019. Only available online: https://www.who.int/health-topics/antimicrobial-resistance. 27.
[2] Jagadale S., Chavan A., Shinde A., Sisode V., Bobade, V.D., Mhaske P. C., 2020. Synthesis and antimicrobial evaluation of new thiazolyl-1, 2, 3-triazolyl-alcohol derivatives. Medicinal Chemistry Research, 29, pp. 989-999.
[3] Li D., S Qiao,. Y. G., Yi, F., Jiang, J. Y., Xu, X. X., Piao, X. S., Han, In K., Thacker. P., 2000. Performance of Growing-Finishing Pigs Fed Sesame Meal Supplemented Diets Formulated Using Amino Acid Digestibilities Determined by the Regression Technique. Asian-Australasian Journal of Animal Sciences 13, pp. 46-52.
[4] Ferreira, M.L.G., Pinheiro, L.C.S., Santos-Filho, O. A. Peçanha, M.D. S., Sacramento, C.Q. Machado, V., Ferreira, V.F. Moreno, T., Souza & Núbia Boechat L.. 2014. Design, synthesis, and antiviral activity of new 1H-1,2,3-triazole nucleoside ribavirin analogs. Medicinal Chemistry Research 23, pp. 1501–1511
[5] Hong, M.C., Hsu, D.I., Bounthavong, M., 2013. Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination. Infect Drug Resist, 29, pp. 215–223.
[6] Shaikh, M.H., Subhedar, D.D., Kalam, F. A., Jaiprakash, K., Sangshetti, N., Shingate, B.B., 2016. 1, 2, 3-Triazole incorporated coumarin derivatives as potential antifungal and antioxidant agents. Chinese Chemical Letters, 27, pp. 295-301.
[7] Dofe, V.S., Sarkate, A.P., Kathwate, S. H., Gill, C.H., 2017, Synthesis, antimicrobial activity and anti-biofilm activity of novel tetrazole derivatives. Heterocyclic Communications, 23, pp. 325–330.
[8] Khloya, P., Kumar, S., Kaushik, P., Surain, P., Kaushik, D., Sharma, P. K., 2015. Synthesis and biological evaluation of pyrazolylthiazole carboxylic acids as potent anti-inflammatory-antimicrobial agents. Bioorg Med Chem Lett. 25(6), pp. 1177-1181
[9] Ceylan, S.; Bektas, H.; Bayrak, H.; Demirbas, N.; Alpay-Karaoglu, S.; and Ülker, S. 2013. Syntheses and Biological Activities of New Hybrid Molecules Containing Different Heterocyclic Moieties. Arch. Pharm. Chem. Life Sci., 346, pp. 743–756.
[10] Chen, M.D., Lu, S.J., Yuag, G.P., Yang, S.Y., Du, X.L., 2000. Synthesis and antibacterial activity of some heterocyclic beta-enamino ester derivatives with 1, 2, 3- triazole, Heterocycl. Commun, 6, pp. 421-427.
[11] Holla, B.S., Sarojini, B.K., Sooryanarayana, R., Akberali, P.M., Kumari, N.S., Shetty, V., 2001. Synthesis of some halogen-containing 1,2,4-triazolo-1,3,4-thiadiazines and their antibacterial and anticancer screening studies—Part I, II Farmaco, 56, pp. 565–570.
[12] Ozdemir, S.B., Cebeci, Y.U., Bayrak, H., Mermer, A., Ceylan, S., Demirbas, A., Karaoglu, S.A., Demirbas, N., 2017. Synthesis and antimicrobial activity of new piperazine-based heterocyclic compounds. Heterocycl. Commun.,23(1), pp. 43-54.
[13] Uygun Cebeci, Y., Ceylan, S., Demirbas, N., Alapay Karaoglu, S., 2021. Conventional and Microwave Assisted Synthesis of Novel 1,2,4- Triazole Derivatives Containing Tryptamine Skeleton and Investigation of Antimicrobial Activity, Letters in Organic Chemistry. 18 (2), pp.143-155.
[14] Mentese, M.Y., Bayrak, H., Uygun, Y., Mermer, A., Ulker, S., Karaoglu, S.A., Demirbas, N. 2013. Microwave assisted synthesis of some hybrid molecules derived from norfloxacin and investigation of their biological activities. Eur. J. Med. Chem., 67, pp. 230-242.
[15] Ceylan, S., Bayrak, H., Demirbaş, A.; Ulker, S.; Karaoğlu Alpay, S.; Demirbas, N., 2014. Synthesis of Some New Hybride Molecules Containing Several Azole Moieties and Investigation of Their Biological Activities, Russian Journal of Bioorganic Chemistry, 40, pp. 314–329.
[16] Choudhary, M. I.; Adhikari, A.; Rasheed, S.; Bishnu, P. M.; Hussain, N.; Kaleem, Atta-ur-Rahman, W. A. 2011. Phytochemistry. Lett., 4, pp. 404–406.
[17] Molecular Operating Environment (MOE) C. C. G. I., 1010 Sherbooke St. West, Suite 910, Montreal, QC, Canada, H3A 2R7, 2015.
[18] National Committee for Clinical Laboratory Standard, 1993, 13.
[19] Ebner, C., Culhane, J. C.; Winkelman, T. N.; Haustein, M. D.; Dittyb J. L. and Ippolitia J. T., 2008, Synthesis of novel oxazolidinone antimicrobial agents, Bioorg. Med. Chem., 16, pp. 2651–2656.
[20] Demirbas, N., Ugurluoglu, R., Demirbas, A., 2022, Synthesis of 3-Alkyl (Aryl)-4-alkylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-ones and 3-Alkyl-4-alkylamino-4,5-dihydro-1H-1,2,4-triazol-5-ones as Antitumor Agents, Bioorg. Med. Chem., 10, pp. 3717.
[21] Avramova, P., Danchev, N., Buyukliev, R., Bogoslovova, T., 1998, Synthesis, toxicological, and pharmacological assessment of derivatives of2-aryl-4-(3-arylpropyl) morpholines. Arch. Pharm., 331, pp. 342–346.
[22] Lebouvier, N., Giraud, F., Corbin, T., MinNa, Y., Baut, Le, G., Marchanda, P., Borgne Le, M., 2006. Synthesis, structural determination and photo-antiprolife rativeactivity of new 3-pyrazolyl or-isoxazolyl substituted 4-hydroxy-2 (1H)-quinolinones. Tetrahedron Lett. 47, pp. 6479–6483.
[23] Fang, K. C., Chen, Y. L., Sheu, J. Y., Wang, T. C., Tzeng, C. C., 2000. Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives. J. Med. Chem. 43, pp. 3809.
[24] Aher, N. G., Pore V. S., Mishra, N. N., Kumar, A., Shukla, P. K., Sharma, A., Bhat, M. K., 2009. Synthesis and antifungal activity of 1, 2, 3-triazole containing fluconazole analogues, Bioorg. Med. Chem. Lett. 19 (18), pp. 759–763.
[25] Rezaei, Z., Khabnadideh, S., Pakshir, K., Hossaini, Z., Amiri, F., Assadpour, E., 2009. Design, synthesis, and antifungal activity of triazole and benzotriazole derivatives. Eur. J. Med. Chem. 44(11), pp. 3064–3067.
[26] Holla, B.S., Udupa, K.V., 1991. Synthesis of Novel 5-Mercapto-striazolo[3,4-c]-as-triazino[5,6-b]indoles and Their Mannich Bases. Heterocycles, 32, pp. 1081-1088.
[27] Bhawsar, S.B., Mane, D.V., Shinde, D.B., Shingare, M.S., Deokate, A.S., Gangawane, L.V., 1996. Syntheses of 8-[(6′-Substıtuted1′,3′-Benzothıazol-2′-Yl) Amınomethyl]-Substıtuted Hydrooxycoumarıns And Their Antimicrobial Activity. Indian J. Heterocycl. Chem., 6, pp. 135-138.
[28] Huang, Z.Y., Yang, J.F., Chen, Q., Cao, R.J., Huang, W., Hao, G.F., Yang, G.F., 2015, An efficient one-pot access to N-(pyridin-2- ylmethyl) substituent biphenyl-4-sulfonamides through waterpromoted, palladium-catalyzed, microwave-assisted reactions. RSC Advances, 5(92), pp.75182-75186.
[29] Christophe, T. 2009. et al. High content screening identifies decaprenyl-phosphoribose 2’ epimerase as a target for intracellular antimycobacterial inhibitors. PLoS pathogens, 5, pp. 1000645.
[30] Clin Exp Immunol. PubMed, 1977, 272-7.
[31] Yang, F., Yu, L.Z.T., Diao, P.C., et al. 2019. Novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potent antitubulin agents: design, multicomponent synthesis and antiproliferative activities. Bioorg Chem. 92, pp. 103260.
[32] Naaz, F., Haider, M.R., Shafi, S., Yar, M.S., 2019. Anti-tubulin agents of natural origin: targeting taxol, vinca, and colchicine binding domains. Eur J Med Chem. 171, pp. 310–331.
[33] Mirzaei, H., Emami, S., 2016. Recent advances of cytotoxic chalconoids targeting tubulin polymerization: synthesis and biological activity. Eur J Med Chem. 121, pp. 610–639.
[34] Close A. Benmohammed, D. Hadji, A. Guendouzi, Y. Mouchaal, A. Djafri, A. Khelil, 2021. J. Electro. Mater., 50, pp. 5282-5293, 10.1007/s11664-021-09046-9.
[35] Mermer, A. Faiz, O. Demirbas, A. Demirbas, N. Alagu, muthu, M. S. 2019. Arumugam Piperazine-azole-fluoroquinolone hybrids: conventional and microwave irradiated synthesis, biological activity screening and molecular docking studies Bioorg. Chem., 85. pp. 308-318.
[36] Wajda-Hermanowicz, K. Pieniążczak, D. Zatajska, A. Wrobel, R. Drabent. K. 2015. A study on the condensation reaction of 4-amino-3,5-dimethyl-1,2,4-triazole with benzaldehydes: structure and spectroscopic properties of some new stable hemiaminals Molecules, 20, pp. 17109-17131.
[37] Akin, S. Ayaloglu, H. Gultekin, E. Colak A., Bekircan, O. Yildirim-Akatin, M., 2019. Synthesis of 1,2,4-triazole-5-on derivatives and determination of carbonic anhydrase II isoenzyme inhibition effects Bioorg. Chem., 83. pp. 170-179.
[38] S. Joshi, N. Khosla, P. Tiwari 2004. Bioorg. Med. Chem., 12 p. 571.
[39] F. Lopes, R. Capela, J.O. Gonçaves, P.N. Horton, M.B. Hursthouse, J. Iley, C.M. Casimiro, J. Bom, R. Moreira, 2004. Tetrahedron Lett., 45, p. 7663.
[40] Close B.S. Holla, B. Veerandra, M.K. Shivanada, B. Poojary, 2003.Eur. J. Med. Chem., 38, p. 759.
[41] W. Malinka, P. Świątek, B. Filipek, J. Sapa, A. Jezierska, A. Koll Il Farmaco 2005. 60. p. 961