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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Some New 1,2,4-triazole Derivatives Bearing the Pyrimidine Moiety as Potential Antimycobacterial Agents: Synthesis and Docking Analysis

Author(s): Ganji Sreekanth Reddy, Anna Venkateswara Rao, Mukkanti Siva Naga Anjaneya Prasad, Ivaturi Venkata Kasi Viswanath* and Eppakayala Laxminarayana

Volume 20, Issue 10, 2023

Published on: 06 October, 2022

Page: [1664 - 1674] Pages: 11

DOI: 10.2174/1570180819666220829143739

Price: $65

Abstract

Background: Pyrimidine and 1,2,4-triazole heterocycles have been linked to a variety of biological and pharmacological properties such as effective bactericides, fungicides, vermicides, insecticides, anticancer and antiviral agents. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents.

Objective: A novel set of heterocyclic derivatives comprising 1,2,4-triazole, pyrimidine moieties was developed, synthesized, and assessed for their antimicrobial activity.

Methods: In this study, we performed ligand-based pharmacophore modeling as a promising design strategy for the design of substituted triazolyl-pyrimidine derivatives as antitubercular agents. The designed compounds were synthesized and characterized by proton, carbon nuclear magnetic resonance spectroscopy, infrared, and mass spectroscopy. Synthesized compounds were screened for anti-TB activity using the agar micro dilution method against M. tuberculosis H37Rv strain.

Results: Our results revealed that the target 1,2,4-triazoles 7d, 7e, 7c have potent potency against Gram- (+ve) bacteria S. epidermidis (MICs: 1.7, 3.7, 16.4 μg/mL), whereas final pyrimidines 7c, 7e, 7f, have the strongest antibacterial activity against Gram-(-ve) strain P. aeruginosa (MICs: 3.5, 6.4, 8.4 μg/mL). Among all tested compounds, 7a, 7e, and 7h revealed an outstanding antitubercular activity against M. tuberculosis H37Rv strain with MICs of 3.24, 8.93, and 4.70 μg/mL, respectively. The most active ligand 7b reveals highest hydrophobic binding modes with ThrA:127 [2.194 A˚], LysA:103 [3.103, 2.164 A˚], GlyA:102 [1.713 A˚], ArgA:238 [1.713 A˚], ValA:101 [2.113 A˚] (hydrogen bondings), AspA:129, GluA:201 [Pi-anion], AlaA:246, LeuA:180 [Pi-alkyl] and HisA:179 [3.104 A˚] [Pi-Pi], respectively.

Conclusion: In this communication, our aim has been verified by the synthesis of 3-methoxy-10,12- dimethyl-8-phenyl-6,7,8,12-tetrahydrobenzo[2,3]oxepino[4,5-d][1,2,4]triazolo[4,3-a] pyrimidine derivatives 7 in which 1,2,4-triazole and pyrimidine moieties with benzoxepine in a single molecular framework were found. After all the above findings, it can be concluded that these molecules become lead molecules for further synthetic and biological evaluation.

Keywords: 1, 2, 4–Triazole, pyrimidine, benzoxepine, antibacterial activity, tuberculosis, docking

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[1]
World Health Organization. Global Tuberculosis Report, 2016.
[2]
World Health Organization. Tuberculosis Fact sheet; , 2010.
[3]
Okada, M.; Kobayashi, K. Recent progress in mycobacteriology. In: Kekkaku; , 2007; 82, pp. (10)783-799.
[PMID: 18018602]
[4]
World Health Organization (WHO). WHO announces updated definitions of extensively drug-resistant tuberculosis. 2021. Available from: https://www.who.int/news/item/27-012021-who-announces-updated-de
[5]
Nahid, P.; Dorman, S.E.; Alipanah, N.; Barry, P.M.; Brozek, J.L.; Cattamanchi, A.; Chaisson, L.H.; Chaisson, R.E.; Daley, C.L.; Grzemska, M.; Higashi, J.M.; Ho, C.S.; Hopewell, P.C.; Keshavjee, S.A.; Lienhardt, C.; Menzies, R.; Merrifield, C.; Narita, M.; O’Brien, R.; Peloquin, C.A.; Raftery, A.; Saukkonen, J.; Schaaf, H.S.; Sotgiu, G.; Starke, J.R.; Migliori, G.B.; Vernon, A. Official American thoracic society/centers for disease control and prevention/infectious diseases society of America clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clin. Infect. Dis., 2016, 63(7), e147-e195.
[http://dx.doi.org/10.1093/cid/ciw376] [PMID: 27516382]
[6]
Mali, R.; Somani, R.; Toraskar, M.P.; Mali, K.K.; Naik, P.P.; Shirodkar, P.Y. Synthesis of some antifungal and anti-tubercular 1,2,4-triazole analogues. Int. J. Chemtech Res., 2009, 1(2), 168-173.
[7]
World Health Organization. Anti-tuberculosis drug resistance in the world; The WHO Global Project on Anti Tuberculosis Drug Resistance Surveillance. World Health Organization Document, 1997, pp. 1-227.
[8]
World Health Organization (WHO)Global Tuberculosis Report , 2017. Available from: http://www.who.int/tb/publications/global_report/en/ Accessed on 2017]
[9]
Goswami, B.N.; Kataky, J.C.S.; Baruah, J.N. Synthesis and biological activity of bridgehead nitrogen heterocycles. J. Heterocycl. Chem., 1986, 23(5), 1439-1442.
[http://dx.doi.org/10.1002/jhet.5570230538]
[10]
Sekhar, M.M.; Nagarjuna, U.; Padmavathi, V.; Padmaja, A.; Padmaja, A.; 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]
[11]
Dubovis, M.V.; Rudakov, G.F.; Kulagin, A.S.; Tsarkova, K.V.; Popkov, S.V.; Goloveshkin, A.S.; Cherkaev, G.V. A new method of synthesis of substituted 1-(1 H -imidazole-4-yl)-1 H -1,2,3-triazoles and their fungicidal activity. Tetrahedron, 2018, 74(6), 672-683.
[http://dx.doi.org/10.1016/j.tet.2017.12.043]
[12]
Wu, J.; Ni, T.; Chai, X.; Wang, T.; Wang, H.; Chen, J.; Jin, Y.; Zhang, D.; Yu, S.; Jiang, Y. Molecular docking, design, synthesis and antifungal activity study of novel triazole derivatives. Eur. J. Med. Chem., 2018, 143, 1840-1846.
[http://dx.doi.org/10.1016/j.ejmech.2017.10.081] [PMID: 29133044]
[13]
Wu, M.J.; Wu, D.M.; Chen, J.B.; Zhao, J.F.; Gong, L.; Gong, Y.X.; Li, Y.; Yang, X.D.; Zhang, H. Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore. Bioorg. Med. Chem. Lett., 2018, 28(14), 2543-2549.
[http://dx.doi.org/10.1016/j.bmcl.2018.05.038] [PMID: 29884535]
[14]
Cao, X.; Wang, W.; Wang, S.; Bao, L. Asymmetric synthesis of novel triazole derivatives and their in vitro antiviral activity and mechanism of action. Eur. J. Med. Chem., 2017, 139, 718-725.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.057] [PMID: 28858766]
[15]
Yamada, M.; Takahashi, T.; Hasegawa, M.; Matsumura, M.; Ono, K.; Fujimoto, R.; Kitamura, Y.; Murata, Y.; Kakusawa, N.; Tanaka, M.; Obata, T.; Fujiwara, Y.; Yasuike, S. Synthesis, antitumor activity, and cytotoxicity of 4-substituted 1-benzyl-5-diphenylstibano-1H-1,2,3-triazoles. Bioorg. Med. Chem. Lett., 2018, 28(2), 152-154.
[http://dx.doi.org/10.1016/j.bmcl.2017.11.038] [PMID: 29198863]
[16]
Zhang, S.; Xu, Z.; Gao, C.; Ren, Q.C.; Chang, L.; Lv, Z.S.; Feng, L.S. Triazole derivatives and their anti-tubercular activity. Eur. J. Med. Chem., 2017, 138, 501-513.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.051] [PMID: 28692915]
[17]
Pawar, S.V.; Upadhyay, P.K.; Burade, S.; Kumbhar, N.; Patil, R.; Dhavale, D.D. Synthesis and anti-leishmanial activity of TRIS-glycine-β-alanine dipeptidic triazole dendron coated with nonameric mannoside glycocluster. Carbohydr. Res., 2019, 485, 107815.
[http://dx.doi.org/10.1016/j.carres.2019.107815] [PMID: 31622943]
[18]
Saadaoui, I.; Krichen, F.; Ben Salah, B.; Ben Mansour, R.; 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 enzyme inhibitors and antioxidant activities. J. Mol. Struct., 2019, 1180, 344-354.
[http://dx.doi.org/10.1016/j.molstruc.2018.12.008]
[19]
Ouellette, W.; Jones, S.; Zubieta, J. Solid state coordination chemistry of metal-1,2,4-triazolates and the related metal-4-pyridyltetrazolates. CrystEngComm, 2011, 13(14), 4457-4485.
[http://dx.doi.org/10.1039/c0ce00919a]
[20]
Chu, X.M.; Wang, C.; Wang, W.L.; Liang, L.L.; Liu, W.; Gong, K.K.; Sun, K.L. Triazole derivatives and their antiplasmodial and antimalarial activities. Eur. J. Med. Chem., 2019, 166, 206-223.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.047] [PMID: 30711831]
[21]
Kamboj, V.K.; Verma, P.K.; Dhanda, A.; Ranjan, S. 1,2,4-triazole derivatives as potential scaffold for anticonvulsant activity. Cent. Nerv. Syst. Agents Med. Chem., 2015, 15(1), 17-22.
[http://dx.doi.org/10.2174/1871524915666150209100533] [PMID: 25675400]
[22]
Zhou, C.; Gan, L.; Zhang, Y.; Zhang, F.; Wang, G.; Jin, L.; Geng, R. Review on supermolecules as chemical drugs. Sci. China B Chem., 2009, 52(4), 415-458.
[http://dx.doi.org/10.1007/s11426-009-0103-2]
[23]
Xu, M.; Peng, Y.; Zhu, L.; Wang, S.; Ji, J.; Rakesh, K.P. Triazole derivatives as inhibitors of Alzheimer’s disease: Current developments and structure-activity relationships. Eur. J. Med. Chem., 2019, 180, 656-672.
[http://dx.doi.org/10.1016/j.ejmech.2019.07.059] [PMID: 31352246]
[24]
Ceesay, M.M.; Couchman, L.; Smith, M.; Wade, J.; Flanagan, R.J.; Pagliuca, A. Triazole antifungals used for prophylaxis and treatment of invasive fungal disease in adult haematology patients: Trough serum concentrations in relation to outcome. Med. Mycol., 2016, 54(7), 691-698.
[http://dx.doi.org/10.1093/mmy/myw031] [PMID: 27161786]
[25]
Liégeois, J.F.; Deville, M.; Dilly, S.; Lamy, C.; Mangin, F.; Résimont, M.; Tarazi, F.I. New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): Chemical synthesis and pharmacological evaluation. J. Med. Chem., 2012, 55(4), 1572-1582.
[http://dx.doi.org/10.1021/jm2013419] [PMID: 22268448]
[26]
Catapano, F.; Perris, F.; Fabrazzo, M.; Cioffi, V.; Giacco, D.; De Santis, V.; Maj, M. Obsessive-compulsive disorder with poor insight: A three-year prospective study. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2010, 34(2), 323-330.
[http://dx.doi.org/10.1016/j.pnpbp.2009.12.007] [PMID: 20015461]
[27]
Rani, A.; Singh, G.; Singh, A.; Maqbool, U.; Kaur, G.; Singh, J. CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery Review . RSC Advances, 2020, 10(10), 5610-5635.
[http://dx.doi.org/10.1039/C9RA09510A] [PMID: 35497465]
[28]
Gandham, S.K.; Kudale, A.A.; Rao Allaka, T.; Jha, A. Design, synthesis of novel benzoxepine based 1,2,3-triazoles: Molecular docking and in vitro antimicrobial activity evaluation. ChemistrySelect, 2022, 7(21), e202200683.
[http://dx.doi.org/10.1002/slct.202200683]
[29]
Afanasenko, A.; Barta, K. Pharmaceutically relevant (hetero)cyclic compounds and natural products from lignin-derived monomers: Present and perspectives. iScience, 2021, 24(3), 102211.
[http://dx.doi.org/10.1016/j.isci.2021.102211] [PMID: 33733071]
[30]
Aouad, M.R.; Almehmadi, M.A.; Rezki, N.; Al-blewi, F.F.; Messali, M.; Ali, I. Design, click synthesis, anticancer screening and docking studies of novel benzothiazole-1,2,3-triazoles appended with some bioactive benzofused heterocycles. J. Mol. Struct., 2019, 1188, 153-164.
[http://dx.doi.org/10.1016/j.molstruc.2019.04.005]
[31]
Takeuchi, C.S.; Kim, B.G.; Blazey, C.M.; Ma, S.; Johnson, H.W.B.; Anand, N.K.; Arcalas, A.; Baik, T.G.; Buhr, C.A.; Cannoy, J.; Epshteyn, S.; Joshi, A.; Lara, K.; Lee, M.S.; Wang, L.; Leahy, J.W.; Nuss, J.M.; Aay, N.; Aoyama, R.; Foster, P.; Lee, J.; Lehoux, I.; Munagala, N.; Plonowski, A.; Rajan, S.; Woolfrey, J.; Yamaguchi, K.; Lamb, P.; Miller, N. Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR). J. Med. Chem., 2013, 56(6), 2218-2234.
[http://dx.doi.org/10.1021/jm3007933] [PMID: 23394126]
[32]
Stuart, A.L.; Ayisi, N.K.; Tourigny, G.; Gupta, V.S. Antiviral activity, antimetabolic activity, and cytotoxicity of 3′-substituted deoxypyrimidine nucleosides. J. Pharm. Sci., 1985, 74(3), 246-249.
[http://dx.doi.org/10.1002/jps.2600740305] [PMID: 2409264]
[33]
Cieplik, J.; Stolarczyk, M.; Pluta, J.; Gubrynowicz, O.; Bryndal, I.; Lis, T.; Mikulewicz, M. Synthesis and antibacterial properties of pyrimidine derivatives. Acta Pol. Pharm., 2011, 68(1), 57-65.
[PMID: 21485702]
[34]
Morgan, J.; Haritakul, R.; Keller, P. Antimalarial activity of 2,4-diamino pyrimidines. Lett. Drug Des. Discov., 2008, 5(4), 277-280.
[http://dx.doi.org/10.2174/157018008784619843]
[35]
Pore, Y.; Kuchekar, B. Synthesis of novel N1,6-disubstituted 5-cyano2-thiouracil derivatives as anti nociceptive agents. Dig. J. Nanomater. Biostruct., 2008, 3, 293-298.
[36]
Trivedi, A.R.; Dodiya, D.K.; Ravat, N.R.; Shah, V.H. Synthesis and biological evaluation of some new pyrimidines via a novel chalcone series. ARKIVOC, 2008, XI, 131-141.
[http://dx.doi.org/10.3998/ark.5550190.0009.b13]
[37]
Sondhi, S.M.; Dinodia, M.; Rani, R.; Shukla, R.; Raghubir, R. Synthesis, anti inflammatory and analgesic activity evaluation of some pyrimidine derivatives. Indian J. Chem., 2009, 49B, 273-281.
[38]
Naik, T.A.; Chikhalia, K.H. Studies on synthesis of pyrimidine derivatives and their pharmacological evaluation. J. Chem., 2007, 4, 60-66.
[http://dx.doi.org/10.1155/2007/507590]
[39]
Agarwal, A.; Ramesh, A. Ashutosh; Goyal, N.; Chauhan, P.M.S.; Gupta, S. Dihydropyrido[2,3-d]pyrimidines as a new class of antileishmanial agents. Bioorg. Med. Chem., 2005, 13(24), 6678-6684.
[http://dx.doi.org/10.1016/j.bmc.2005.07.043] [PMID: 16126395]
[40]
Rao, P.V.; Prasad, Y.R.; Kotra, V.; Bhaskararao, B. Design, synthesis and anticancer activity of some new pyrimidine derivatives. Int. J. Pharm. Technol, 2010, 2, 1263-1269.
[41]
Abdel Fattah, H.A.; Osman, N.A. AL-Mahmoudy, A.M.; EL-Sayed, N.S. Synthesis of novel pyrimidine and fused pyrimidine derivatives and their in vitro antimicrobial and cytotoxic evaluation. World J. Pharm. Res., 2015, 4, 446-469.
[42]
McConkey, B.J.; Sobolev, V.; Edelman, M. The performance of current methods in ligand-protein docking. Curr. Sci., 2002, 83, 845-855.
[43]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[44]
Şahin,, F.; Karaman,, İ.; Güllüce,, M.; Öğütçü, H.; Şengül,, M.; Adıgüzel,, A.; Öztürk, S.; Kotan,, R. Evaluation of antimicrobial activities of Satureja hortensis L J. Ethnopharmacol, 2003, 87(1), 61-65.
[http://dx.doi.org/10.1016/S0378-8741(03)00110-7] [PMID: 12787955]
[45]
Güllüce, M. Adıgüzel, A.; Öğütçü, H.; Şengül, M.; Karaman, İ.; Şahin, F. Antimicrobial effects of Quercus ilex L. extract. Phytother. Res., 2004, 18(3), 208-211.
[http://dx.doi.org/10.1002/ptr.1419] [PMID: 15103667]
[46]
Karczmarzyk, Z.; Swatko-Ossor, M.; Wysocki, W.; Drozd, M.; Ginalska, G.; Pachuta-Stec, A.; Pitucha, M. New application of 1,2,4-triazole derivatives as antitubercular agents. structure, in vitro screening and docking studies. Molecules, 2020, 25(24), 6033.
[http://dx.doi.org/10.3390/molecules25246033] [PMID: 33352814]
[47]
Björkelid, C.; Bergfors, T.; Raichurkar, A.K.V.; Mukherjee, K.; Malolanarasimhan, K.; Bandodkar, B.; Jones, T.A. Structural and biochemical characterization of compounds inhibiting Mycobacterium tuberculosis pantothenate kinase. J. Biol. Chem., 2013, 288(25), 18260-18270.
[http://dx.doi.org/10.1074/jbc.M113.476473] [PMID: 23661699]
[48]
ACD/ChemSketch, version 2020.2.1 In: Advanced Chemistry Development,Inc;, Toronto, ON, Canada. 2021. Available from: www.acdlabs.com
[49]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(1), 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[50]
Laskowski, R.A. Jabłońska, J.; Pravda, L.; Vařeková, R.S.; Thornton, J.M. PDBsum: Structural summaries of PDB entries. Protein Sci., 2018, 27(1), 129-134.
[http://dx.doi.org/10.1002/pro.3289] [PMID: 28875543]

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