Synthesis of Novel 3-(4-tert-Butylphenyl)-5-Cylopropyl-4H-1,2,4-Triazole Derivatives with Antioxidative and Antimicrobial Activities

Nuri       Yildirim

doi:10.2174/1570180817999200424073524

Abstract

Background: In this work, new heterocyclic compounds containing 3-(4-tertbutylphenyl)- 5-cyclopropyl-4H-1,2,4-triazole ring were synthesized, starting from iminoester hydrochlorides and 4-tert-butylbenzhyrazide.

Methods: Ethyl N-[(4-tert-butylphenyl)carbonyl]cyclopropanecarbohydrazonoate was used to synthesize 4-amino-3-(4-tert-butylphenyl)-5-cyclopropyl-4H-1,2,4-triazole, 3-(4-tert-butylphenyl)-5- cyclopropyl-4-(arylmethyleneamino)-4H-1,2,4-triazole, 3-(4-tert-butylphenyl)-5-cyclopropyl-4- (arylmethylamino)-4H-1,2,4-triazole and their phthalonitrile derivatives sequentially.

Results: Seventeen new 3-(4-tert-butylphenyl)-5-cyclopropyl-4H-1,2,4-triazole derivatives were synthesized and their antioxidant and antimicrobial activities were determined.

Conclusion: Imine and amine derivatives were better antioxidants than phthalonitrile derivatives. Doubly fluorination compounds appeared to result in higher activity. The compounds tested with five microorganisms showed better activity against B. subtilis with the antimicrobial activity of two far exceeding that of ampicillin. Imine and amine derivatives were better antimicrobials than phthalonitrile derivatives.

Keywords: 4H-1, 2, 4-triazoles, 4-arylmethyleneamino-4H-1, 2, 4-triazoles, Reactive oxygen species, phthalonitrile derivates, antioxidant, antimicrobial.

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[1] 
Cadenas, E.; Davies, K.J.A. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med.,  2000, 29(3-4), 222-230.
[http://dx.doi.org/10.1016/S0891-5849(00)00317-8] [PMID: 11035250] 
[2] 
Lü, J.M.; Lin, P.H.; Yao, Q.; Chen, C. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J. Cell. Mol. Med.,  2010, 14(4), 840-860.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00897.x] [PMID: 19754673] 
[3] 
Frieri, M.; Kumar, K.; Boutin, A. Antibiotic resistance. J. Infect. Public Health,  2017, 10(4), 369-378.
[http://dx.doi.org/10.1016/j.jiph.2016.08.007] [PMID: 27616769] 
[4] 
Kandile, N.G.; Zaky, H.T.; Saleh, Y.G.; Ahmed, N.A. Synthesis of a new class of antimicrobial agents incorporating the indolin-2-one moiety. J. Enzyme Inhib. Med. Chem.,  2013, 28(4), 853-862.
[http://dx.doi.org/10.3109/14756366.2012.689298] [PMID: 22651801] 
[5] 
Gomtsyan, A. Heterocycles in drugs and drug discovery. Chem. Heterocycl. Compd.,  2012, 48, 7-10.
[http://dx.doi.org/10.1007/s10593-012-0960-z] 
[6] 
Kharb, R.; Sharma, P.C.; Yar, M.S. Pharmacological significance of triazole scaffold. J. Enzyme Inhib. Med. Chem.,  2011, 26(1), 1-21.
[http://dx.doi.org/10.3109/14756360903524304] [PMID: 20583859] 
[7] 
Lauko, J.; Kouwer, P.H.J.; Rowan, A.E. 1H-1,2,3-Triazole: From Structure to Function and Catalysis. J. Heterocycl. Chem.,  2017, 54, 1677-1699.
[http://dx.doi.org/10.1002/jhet.2770] 
[8] 
Bekircan, O.; Küxük, M.; Kahveci, B.; Kolayli, S. Convenient synthesis of fused heterocyclic 1,3,5-triazines from some N-acyl imidates and heterocyclic amines as anticancer and antioxidant agents. Arch. Pharm. (Weinheim),  2005, 338(8), 365-372.
[http://dx.doi.org/10.1002/ardp.200400964] [PMID: 16041836] 
[9] 
Madhu Sekhar, M.; Nagarjuna, U.; Padmavathi, V.; Padmaja, A.; Reddy, N.V.; Vijaya, T. Synthesis and antimicrobial activity of pyrimidinyl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles. Eur. J. Med. Chem.,  2018, 145, 1-10.
[http://dx.doi.org/10.1016/j.ejmech.2017.12.067] [PMID: 29310025] 
[10] 
Dengale, S.G.; Karale, B.K.; Akolkar, H.N.; Darekar, N.R.; Deshmukh, K.K. Microwave assisted synthesis and antimicrobial activity of novel 1,3,4-thiadiazoles and 1,2,4-triazoles derived from 2-(3-fluorophenyl)-4-methylthiazole-5-carbohydrazide. Russ. J. Gen. Chem.,  2019, 89, 1535-1540.
[http://dx.doi.org/10.1134/S1070363219070259] 
[11] 
Küçükgüzel, I.; Tatar, E.; Küçükgüzel, S.G.; Rollas, S.; De Clercq, E. Synthesis of some novel thiourea derivatives obtained from 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and evaluation as antiviral/anti-HIV and anti-tuberculosis agents. Eur. J. Med. Chem.,  2008, 43(2), 381-392.
[http://dx.doi.org/10.1016/j.ejmech.2007.04.010] [PMID: 17583388] 
[12] 
Li, J.; Ren, G.Y.; Zhang, Y.; Yang, M.Y.; Ma, H.X. Two Cu(II) complexes of 1,2,4-triazole fungicides with enhanced antifungal activities. Polyhedron,  2019, 157, 163-169.
[http://dx.doi.org/10.1016/j.poly.2018.09.052] 
[13] 
Sen Gupta, A.K.; Misra, H.K. Synthesis and pesticidal activities of some new substituted 1,2,4-triazoles and their derivatives. Agric. Biol. Chem.,  1980, 4, 1009-1013.
[http://dx.doi.org/10.1080/00021369.1980.10864094] 
[14] 
Chai, B.; Qian, X.; Cao, S.; Liu, H.; Song, G. Synthesis and insecticidal activity of 1,2,4-triazole derivatives. ARKIVOC,  2003, ii, 141-145.
[15] 
Wang, B.L.; Shi, Y.X.; Ma, Y.; Liu, X.H.; Li, Y.H.; Song, H.B.; Li, B.J.; Li, Z.M. Synthesis and biological activity of some novel trifluoromethyl-substituted 1,2,4-triazole and bis(1,2,4-triazole) Mannich bases containing piperazine rings. J. Agric. Food Chem.,  2010, 58(9), 5515-5522.
[http://dx.doi.org/10.1021/jf100300a] [PMID: 20384340] 
[16] 
Radwan, R.R.; Zaher, N.H.; El-Gazzar, M.G. Novel 1,2,4-triazole derivatives as antitumor agents against hepatocellular carcinoma. Chem. Biol. Interact.,  2017, 274, 68-79.
[http://dx.doi.org/10.1016/j.cbi.2017.07.008] [PMID: 28693887] 
[17] 
Ghammamy, S.; Sedaghat, S. Synthesis, Characterization, and antitumor activity of azomethine derivative of triazole and its complexes with Copper(I) and Zinc(II) salts. Russ. J. Gen. Chem.,  2013, 83, 722-725.
[http://dx.doi.org/10.1134/S1070363213040191] 
[18] 
Krzemińska, A.; Frączek, T.; Paneth, P. Oxygen binding isotope effects of triazole-based HIV-1 reverse transcriptase inhibitors indicate the actual binding site. Arch. Biochem. Biophys.,  2017, 635, 87-95.
[http://dx.doi.org/10.1016/j.abb.2017.10.017] [PMID: 29111294] 
[19] 
Abdel-Aziz, M.; Beshr, E.A.; Abdel-Rahman, I.M.; Ozadali, K.; Tan, O.U.; Aly, O.M. 1-(4-Methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamides: synthesis, molecular modeling, evaluation of their anti-inflammatory activity and ulcerogenicity. Eur. J. Med. Chem.,  2014, 77, 155-165.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.001] [PMID: 24631895] 
[20] 
Chen, J.; Sun, X.Y.; Chai, K.Y.; Lee, J.S.; Song, M.S.; Quan, Z.S. Synthesis and anticonvulsant evaluation of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines. Bioorg. Med. Chem.,  2007, 15(21), 6775-6781.
[http://dx.doi.org/10.1016/j.bmc.2007.08.004] [PMID: 17761423] 
[21] 
Liu, J.; Liu, Q.; Yang, X.; Xu, S.; Zhang, H.; Bai, R.; Yao, H.; Jiang, J.; Shen, M.; Wu, X.; Xu, J. Design, synthesis, and biological evaluation of 1,2,4-triazole bearing 5-substituted biphenyl-2-sulfonamide derivatives as potential antihypertensive candidates. Bioorg. Med. Chem.,  2013, 21(24), 7742-7751.
[http://dx.doi.org/10.1016/j.bmc.2013.10.017] [PMID: 24200932] 
[22] 
Turan-Zitouni, G.; Sivaci, M.; Kiliç, F.S.; Erol, K. Synthesis of some triazolyl-antipyrine derivatives and investigation of analgesic activity. Eur. J. Med. Chem.,  2001, 36(7-8), 685-689.
[http://dx.doi.org/10.1016/S0223-5234(01)01252-1] [PMID: 11600237] 
[23] 
Sztanke, K.; Tuzimski, T.; Rzymowska, J.; Pasternak, K.; Kandefer-Szerszeń, M. Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives. Eur. J. Med. Chem.,  2008, 43(2), 404-419.
[http://dx.doi.org/10.1016/j.ejmech.2007.03.033] [PMID: 17531354] 
[24] 
Aperis, G.; Mylonakis, E. Newer triazole antifungal agents: pharmacology, spectrum, clinical efficacy and limitations. Expert Opin. Investig. Drugs,  2006, 15(6), 579-602.
[http://dx.doi.org/10.1517/13543784.15.6.579] [PMID: 16732713] 
[25] 
Clemons, M.; Coleman, R.E.; Verma, S. Aromatase inhibitors in the adjuvant setting: bringing the gold to a standard? Cancer Treat. Rev.,  2004, 30(4), 325-332.
[http://dx.doi.org/10.1016/j.ctrv.2004.03.004] [PMID: 15145507] 
[26] 
Nitenberg, G.; Raynard, B. Nutritional support of the cancer patient: issues and dilemmas. Crit. Rev. Oncol. Hematol.,  2000, 34(3), 137-168.
[27] 
Silku, P.; Özkinali, S.; Özturk, Z.; Asan, A.; Kose, D.A. Synthesis of novel Schiff Bases containing acryloyl moiety and the investigation of spectroscopic and electrochemical properties. J. Mol. Struct.,  2016, 1116, 72-83.
[http://dx.doi.org/10.1016/j.molstruc.2016.03.028] 
[28] 
Dzeikala, A.; Sykula, A. Schiff Bases as Important Class of Pharmacological Agents. J. Pharm. Pharmacol.,  2018, 6, 989-1009.
[29] 
Tanaka, K.; Shimoura, R.; Caira, M.R. Synthesis, crystal structures and photochromic properties of novel chiral Schiff base macrocycles. Tetrahedron Lett.,  2010, 51(2), 449-452.
[http://dx.doi.org/10.1016/j.tetlet.2009.11.062] 
[30] 
Mocanu, A.S.; Ilis, M.; Dumitrascu, F.; Ilie, M.; Circu, V. Synthesis, mesomorphism and luminescence properties of palladium(II) and platinum(II) complexes with dimeric Schiff base liquid crystals. Inorg. Chim. Acta,  2010, 363(4), 729-736.
[http://dx.doi.org/10.1016/j.ica.2009.11.028] 
[31] 
Saadaoui, I.; Krichen, F.; Salah, B.B.; Mansour, R.B.; Miled, N.; Bougatef, A.; Kossentini, M. Design, synthesis and biological evaluation of Schiff bases of 4-amino-1,2,4-triazole derivatives as potent angiotensin converting enzymeinhibitors and antioxidant activities. J. Mol. Struct.,  2019, 1180, 344-354.
[http://dx.doi.org/10.1016/j.molstruc.2018.12.008] 
[32] 
Brandt, C.D.; Kitchen, K.D.; Beckmann, U.; White, N.G.; Jameson, G.B.; Brooker, S. Synthesis and structures of 3,5-disubstituted 1,2,4-triazole head units and incorporation of 3,5-dibenzoyl-1,2,4-triazolate into new [2 + 2] Schiff-base macrocyclic complexes. Supramol. Chem.,  2007, 19, 17-27.
[http://dx.doi.org/10.1080/10610270600902340] 
[33] 
Sumangala, V.; Poojary, B.; Chidananda, N.; Arulmoli, T.; Shenoy, S. Synthesis and biological evaluation of some Schiff bases of 4- amino-5-(4-methylsulfonyl)benzyl-2,4-dihydro-3H-[1,2,4]-triazole3-thione. Med. Chem. Res.,  2013, 22, 2921-2928.
[http://dx.doi.org/10.1007/s00044-012-0294-5] 
[34] 
Holla, B.S.; Poojary, K.N.; Rao, B.S.; Shivananda, M.K. New bis-aminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents. Eur. J. Med. Chem.,  2002, 37(6), 511-517.
[http://dx.doi.org/10.1016/S0223-5234(02)01358-2] [PMID: 12204477] 
[35] 
Shivarama Holla, B.; Veerendra, B.; Shivananda, M.K.; Poojary, B. Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles. Eur. J. Med. Chem.,  2003, 38(7-8), 759-767.
[http://dx.doi.org/10.1016/S0223-5234(03)00128-4] [PMID: 12932907] 
[36] 
Bayrak, H.; Demirbas, A.; Karaoglu, S.A.; Demirbas, N. Synthesis of some new 1,2,4-triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial activities. Eur. J. Med. Chem.,  2009, 44(3), 1057-1066.
[http://dx.doi.org/10.1016/j.ejmech.2008.06.019] [PMID: 18676062] 
[37] 
Wu, S.; Zhang, W.; Qi, L.; Ren, Y.; Ma, H. Investigation on 4-amino-5-substituent-1,2,4-triazole-3-thione Schiff bases an antifungal drug by characterization (spectroscopic, XRD), biological activities, molecular docking studies and electrostatic potential (ESP). J. Mol. Struct.,  2019, 1197, 171-182.
[http://dx.doi.org/10.1016/j.molstruc.2019.07.013] 
[38] 
Khan, K.M.; Siddiqui, S.; Saleem, M.; Taha, M.; Saad, S.M.; Perveen, S.; Choudhary, M.I. Synthesis of triazole Schiff bases: novel inhibitors of nucleotide pyrophosphatase/phosphodiesterase-1. Bioorg. Med. Chem.,  2014, 22(22), 6509-6514.
[http://dx.doi.org/10.1016/j.bmc.2014.08.032] [PMID: 25440732] 
[39] 
Zhang, F.; Wen, Q.; Wang, S.F.; Shahla Karim, B.; Yang, Y.S.; Liu, J.J.; Zhang, W.M.; Zhu, H.L. Design, synthesis and antibacterial activities of 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiol derivatives containing Schiff base formation as FabH inhibitory. Bioorg. Med. Chem. Lett.,  2014, 24(1), 90-95.
[http://dx.doi.org/10.1016/j.bmcl.2013.11.079] [PMID: 24332628] 
[40] 
Bekircan, O.; Menteşe, E.; Ulker, S.; Kucuk, C. Synthesis of some new 1,2,4-triazole derivatives starting from 3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol with anti-lipase and anti-urease activities. Arch. Pharm. (Weinheim),  2014, 347(6), 387-397.
[http://dx.doi.org/10.1002/ardp.201300344] [PMID: 24532369] 
[41] 
Bekircan, O.; Bektas, H. Synthesis of new bis-1,2,4-triazole derivatives. Molecules,  2006, 11(6), 469-477.
[http://dx.doi.org/10.3390/11060469] [PMID: 17962780] 
[42] 
Bekircan, O.; Ozen, T.; Gumrukcuoglu, N.; Bektas, H. Synthesis and antioxidant properties of Some new 3-(4-Chlorophenyl)-5-(pyridin-4-yl)-4H-1,2,4-triazole derivatives. Z. Naturforsch.,  2008, 63b, 548-554.
[http://dx.doi.org/10.1515/znb-2008-0512] 
[43] 
Kahn, O.; Martinez, C.J. Spin-transition polymers: From molecular materials toward memory devices. Science,  1998, 279, 44-48.
[http://dx.doi.org/10.1126/science.279.5347.44] 
[44] 
Garcia, Y.; Koningsbruggen, P.J.; Codjovi, E.; Lapouyede, R.; Kahn, O.; Rabardel, L. Non-classical FeII spin-crossover behaviour leading to an unprecedented extremely large apparent thermal hysteresis of 270 K: Application for displays. J. Mater. Chem.,  1997, 7, 857-858.
[http://dx.doi.org/10.1039/a701242j] 
[45] 
Bekircan, O.; Gumrukcuoglu, N. Synthesis of some 3,5-diphenyl-4H-1,2,4-triazole derivatives as antitumor agents. Indian J. Chem.,  2005, 44B, 2107-2113.
[46] 
Bekircan, O.; Kahveci, B.; Kucuk, M. Synthesis and anticancer evaluation of some new unsymmetrical 3,5-diaryl-4H-1,2,4-triazole derivatives. Turk. J. Chem.,  2006, 30, 29-40.
[47] 
Gumrukcuoglu, N.; Ugras, S.; Ugras, H.I.; Cakır, U. Synthesis, extraction, and anti-bacterial studies of some new bis-1,2,4-triazole derivatives part i. J. Appl. Polym. Sci.,  2012, 123(4), 2011-2019.
[http://dx.doi.org/10.1002/app.34700] 
[48] 
Serdar, M.; Gumrukcuoglu, N.; Alpay Karaoglu, S.; Demirbas, N. Synthesis of some novel 3,5-diaryl-1,2,4-triazole derivatives and investigation of their antimicrobial activities. Turk. J. Chem.,  2007, 31, 315-326.
[49] 
Sokmen, B.B.; Gumrukcuoglu, N.; Ugras, S.; Sahin, H.; Sagkal, Y.; Ugras, H.I. Synthesis, antibacterial, antiurease, and antioxidant activities of some new 1,2,4-triazole schiff base and amine derivatives. Appl. Biochem. Biotechnol.,  2015, 175(2), 705-714.
[http://dx.doi.org/10.1007/s12010-014-1307-2] [PMID: 25342259] 
[50] 
Cronin, S.; Chandrasekar, P.H. Safety of triazole antifungal drugs in patients with cancer. J. Antimicrob. Chemother.,  2010, 65(3), 410-416.
[http://dx.doi.org/10.1093/jac/dkp464] [PMID: 20035021] 
[51] 
Ayati, A.; Emami, S.; Foroumadi, A. The importance of triazole scaffold in the development of anticonvulsant agents. Eur. J. Med. Chem.,  2016, 109, 380-392.
[http://dx.doi.org/10.1016/j.ejmech.2016.01.009] [PMID: 26826582] 
[52] 
Heim, D.R.; Larrinua, I.M.; Murdoch, M.G.; Roberts, J.L. Triazofenamide is a cellulose biosynthesis inhibitör. Pestic. Biochem. Physiol.,  1998, 59, 163-168.
[http://dx.doi.org/10.1006/pest.1998.2317] 
[53] 
Schwack, W.; Hartmann, M. Fungicides and photochemistry: photodegradation of the azole fungicide penconazole. Z. Lebensm. Unters. Forsch.,  1994, 198(1), 11-14.
[http://dx.doi.org/10.1007/BF01195274] [PMID: 8171912] 
[54] 
Brookes, R.F.; Copping, L.G. Some chemical and physical properties of epronaz, a new herbicide. Pestic. Sci.,  1975, 6, 665-673.
[http://dx.doi.org/10.1002/ps.2780060614] 
[55] 
Leznoff, C.C.; Lever, A.B.P. Phthalocyanines: Properties and applications; VCH Publisher: New York, 1996, Vol. 4, . 
[56] 
Bekircan, O.; Bıyıklıoglu, Z.; Acar, I.; Bektas, H.; Kantekin, H. Novel metallophthalocyanines bearing 3-(p-chlorophenyl)-5-p--tolyl-4H-1,2,4-triazole bulky substituents by microwave irradiation. J. Organomet. Chem.,  2008, 693, 3425-3429.
[http://dx.doi.org/10.1016/j.jorganchem.2008.08.007] 
[57] 
Berger, O.; Wein, S.; Duckert, J.F.; Maynadier, M.; El Fangour, S.; Escale, R.; Durand, T.; Vial, H.; Vo-Hoang, Y. Reverse-benzamidine antimalarial agents: design, synthesis, and biological evaluation. Bioorg. Med. Chem. Lett.,  2010, 20(19), 5815-5817.
[http://dx.doi.org/10.1016/j.bmcl.2010.07.124] [PMID: 20800484] 
[58] 
Akar, Z.; Küçük, M.; Doğan, H. A new colorimetric DPPH• scavenging activity method with no need for a spectrophotometer applied on synthetic and natural antioxidants and medicinal herbs. J. Enzyme Inhib. Med. Chem.,  2017, 32(1), 640-647.
[http://dx.doi.org/10.1080/14756366.2017.1284068] [PMID: 28262029] 
[59] 
Ronald, M.A. Microbiologia; Compania Editorial Continental S.A. de C.V.: DF, Mexico, 1990, p. 505.
[60] 
Katritzky, A.R.; Laurenzo, K.S. Alkylaminonitrobenzenes by vicarious nucleophilic amination with 4-(alkylamino)-1,2,4-triazoles. J. Org. Chem.,  1998, 53, 3978-3982.
[http://dx.doi.org/10.1021/jo00252a018] 
[61] 
Gumrukcuoglu, N.; Serdar, M.; Çelik, E.; Sevim, A.; Demirbas, N. Synthesis and antimicrobial activities of some new 1,2,4-triazole derivatives. Turk. J. Chem.,  2007, 31, 335-348.

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Synthesis of Novel 3-(4-tert-Butylphenyl)-5-Cylopropyl-4H-1,2,4-Triazole Derivatives with Antioxidative and Antimicrobial Activities

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