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Current Drug Discovery Technologies

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ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

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Research Article

Synthesis, Molecular Docking, and Biological Evaluation of Novel Indole-triazole Conjugates

Author(s): Paras Berwal, Suman Rohilla*, Nancy Mathur and Ketki Rani

Volume 21, Issue 6, 2024

Published on: 12 March, 2024

Article ID: e120324227917 Pages: 15

DOI: 10.2174/0115701638295739240222074426

Price: $65

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Abstract

Background: Indole-triazole conjugates have emerged as promising candidates for new drug development. Their distinctive structural characteristics, coupled with a wide array of biological activities, render them a captivating and promising field of research for the creation of novel pharmaceutical agents.

Objective: This study aimed to synthesize indole-triazole conjugates to investigate the influence of various substituents on the functional characteristics of indole-triazole hybrids. It also aimed to study the binding modes of new hybrids with the DNA Gyrase using molecular docking studies.

Methods: A new set of indole-triazole hybrids was synthesized and characterized using various physicochemical and spectral analyses. All hybrids underwent in-silico pharmacokinetic prediction studies. The antimicrobial efficacy of the hybrids was assessed using tube dilution and agar diffusion methods. Additionally, the in-vitro antioxidant activity of synthesized compounds was determined using the 1,1-diphenyl-2-picryl-hydrazyl free radical scavenging assay. Furthermore, in silico molecular docking studies were performed to enhance our comprehension of how the synthesized compounds interact at the molecular level with DNA gyrase.

Results: Pharmacokinetic predictions of synthesized hybrids indicated favourable pharmacokinetic profiles, and none of the compounds violated the Lipinski rule of five. Notably, compound 6, featuring a cyclohexanol substituent, demonstrated superior antimicrobial and antioxidant activity (EC50 value = 14.23 μmol). Molecular docking studies further supported the in vitro antioxidant and antimicrobial findings, revealing that all compounds adeptly fit into the binding pocket of DNA Gyrase and engaged in interactions with crucial amino acid residues.

Conclusion: In summary, our research underscores the efficacy of molecular hybridization in shaping the physicochemical, pharmacokinetic, and biological characteristics of novel indole-triazole derivatives.

Keywords: Indole, triazole, molecular hybrids, antibacterial, antioxidant.

[1]
Tran TN, Henary M. Synthesis and applications of nitrogen-containing heterocycles as antiviral agents. Molecules 2022; 27(9): 2700.
[http://dx.doi.org/10.3390/molecules27092700] [PMID: 35566055]
[2]
Lang DK, Kaur R, Arora R, Saini B, Arora S. Nitrogen-containing heterocycles as anticancer agents: An overview. Anti-Cancer Agents Med Chem 2020; 20(18): 2150-68.
[3]
Rathod B, Kumar K. Synthetic and medicinal perspective of 1,2,4-triazole as anticancer agents. Chem Biodivers 2022; 19(11): e202200679.
[http://dx.doi.org/10.1002/cbdv.202200679] [PMID: 36226542]
[4]
Sakakibara N, Balboni G, Congiu C, et al. Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives. Antivir Chem Chemother 2015; 24(2): 62-71.
[http://dx.doi.org/10.1177/2040206615612208] [PMID: 26514833]
[5]
Ashok P, Lu CL, Chander S, Zheng YT, Murugesan S. Design, synthesis, and biological evaluation of 1-(thiophen-2-yl)-9 H -pyrido[3,4- b ]indole derivatives as anti-HIV-1 agents. Chem Biol Drug Des 2015; 85(6): 722-8.
[http://dx.doi.org/10.1111/cbdd.12456] [PMID: 25328020]
[6]
Liu J, Ren Z, Fan L, et al. Design, synthesis, biological evaluation, structure-activity relationship, and toxicity of clinafloxacin-azole conjugates as novel antitubercular agents. Bioorg Med Chem 2019; 27(1): 175-87.
[http://dx.doi.org/10.1016/j.bmc.2018.11.035] [PMID: 30522898]
[7]
Emami L, Faghih Z, Ataollahi E, Sadeghian S, Rezaei Z, Khabnadideh S. Azole derivatives: Recent advances as potent antibacterial and antifungal agents. Curr Med Chem 2023; 30(2): 220-49.
[http://dx.doi.org/10.2174/0929867329666220407094430] [PMID: 35392780]
[8]
Hu C, Xu Z, Huang Z, Wang R, Zhang Y, Mao Z. Synthesis and antifungal evaluation of new azole derivatives against candida albicans. ACS Med Chem Lett 2023; 14(10): 1448-54.
[http://dx.doi.org/10.1021/acsmedchemlett.3c00361] [PMID: 37849555]
[9]
Li L, Ding H, Wang B, et al. Synthesis and evaluation of novel azoles as potent antifungal agents. Bioorg Med Chem Lett 2014; 24(1): 192-4.
[http://dx.doi.org/10.1016/j.bmcl.2013.11.037] [PMID: 24332489]
[10]
Atukuri D, Gunjal R, Holagundi N, Korlahalli B, Gangannavar S, Akkasali K. Contribution of N-heterocycles towards anti-tubercular drug discovery (2014–2019); predicted and reengineered molecular frameworks. Drug Dev Res 2021; 82(6): 767-83.
[http://dx.doi.org/10.1002/ddr.21809] [PMID: 33660325]
[11]
Sharma S, Sharma PK, Kumar N, Dudhe R. A review on various heterocyclic moieties and their antitubercular activity. Biomed Pharmacother 2011; 65(4): 244-51.
[http://dx.doi.org/10.1016/j.biopha.2011.04.005] [PMID: 21715130]
[12]
Farwa U, Raza MA. Heterocyclic compounds as a magic bullet for diabetes mellitus: A review. RSC Advances 2022; 12(35): 22951-73.
[http://dx.doi.org/10.1039/D2RA02697J] [PMID: 36105949]
[13]
Kaur G, Rani I. Synthesis and antidiabetic evaluation of some novel nitrogen containing small heterocyclic derivatives. Int J Pharm Sci Drug Res 2020; 12(5): 473-9.
[http://dx.doi.org/10.25004/IJPSDR.2020.120507]
[14]
Kabir E, Uzzaman M. A review on biological and medicinal impact of heterocyclic compounds. Results Chem 2022; 4: 100606.
[http://dx.doi.org/10.1016/j.rechem.2022.100606]
[15]
Heravi MM, Zadsirjan V. Prescribed drugs containing nitrogen heterocycles: An overview. RSC Advances 2020; 10(72): 44247-311.
[http://dx.doi.org/10.1039/D0RA09198G] [PMID: 35557843]
[16]
Walsh CT. Nature loves nitrogen heterocycles. Tetrahedron Lett 2015; 56(23): 3075-81.
[http://dx.doi.org/10.1016/j.tetlet.2014.11.046]
[17]
Singh TP, Singh OM. Recent progress in biological activities of indole and indole alkaloids. Mini Rev Med Chem 2018; 18(1): 9-25.
[PMID: 28782480]
[18]
Speck K, Magauer T. The chemistry of isoindole natural products. Beilstein J Org Chem 2013; 9(1): 2048-78.
[http://dx.doi.org/10.3762/bjoc.9.243] [PMID: 24204418]
[19]
Ebenezer O, Jordaan MA, Carena G, Bono T, Shapi M, Tuszynski JA. An overview of the biological evaluation of selected nitrogen-containing heterocycle medicinal chemistry compounds. Int J Mol Sci 2022; 23(15): 8117.
[http://dx.doi.org/10.3390/ijms23158117] [PMID: 35897691]
[20]
Hosseinzadeh Z, Ramazani A, Razzaghi-Asl N. Anti-cancer nitrogen-containing heterocyclic compounds. Curr Org Chem 2018; 22(23): 2256-79.
[http://dx.doi.org/10.2174/1385272822666181008142138]
[21]
Matada BS, Pattanashettar R, Yernale NG. A comprehensive review on the biological interest of quinoline and its derivatives. Bioorg Med Chem 2021; 32: 115973.
[http://dx.doi.org/10.1016/j.bmc.2020.115973] [PMID: 33444846]
[22]
Shang XF, Yang CJ, Morris-Natschke SL, et al. Biologically active isoquinoline alkaloids covering 2014–2018. Med Res Rev 2020; 40(6): 2212-89.
[http://dx.doi.org/10.1002/med.21703] [PMID: 32729169]
[23]
Salahuddin , Shaharyar M, Mazumder A. Benzimidazoles: A biologically active compounds. Arab J Chem 2017; 10: S157-73.
[http://dx.doi.org/10.1016/j.arabjc.2012.07.017]
[24]
Zhang B, Li X, Li B, Gao C, Jiang Y. Acridine and its derivatives: A patent review (2009 – 2013). Expert Opin Ther Pat 2014; 24(6): 647-64.
[http://dx.doi.org/10.1517/13543776.2014.902052] [PMID: 24848259]
[25]
Aggarwal R, Sumran G. An insight on medicinal attributes of 1,2,4-triazoles. Eur J Med Chem 2020; 205: 112652.
[http://dx.doi.org/10.1016/j.ejmech.2020.112652] [PMID: 32771798]
[26]
Kumar S, Ritika . A brief review of the biological potential of indole derivatives. Futur J Pharm Sci 2020; 6(1): 121.
[http://dx.doi.org/10.1186/s43094-020-00141-y]
[27]
Teraiya N, Agrawal K, Patel TM, et al. A review of the therapeutic importance of indole scaffold in drug discovery. Curr Drug Discov Technol 2023; 20(6): e050523216584.
[http://dx.doi.org/10.2174/1570163820666230505120553] [PMID: 37151073]
[28]
da S M Forezi L, Lima CGS, Amaral AAP, et al. Bioactive 1,2,3-triazoles: An account on their synthesis, structural diversity and biological applications. Chem Rec 2021; 21(10): 2782-807.
[http://dx.doi.org/10.1002/tcr.202000185] [PMID: 33570242]
[29]
Teixeira MM, Carvalho DT, Sousa E, Pinto E. New antifungal agents with azole moieties. Pharmaceuticals 2022; 15(11): 1427.
[http://dx.doi.org/10.3390/ph15111427] [PMID: 36422557]
[30]
Gontijo VS, Viegas FPD, Ortiz CJC, et al. Molecular hybridization as a tool in the design of multi-target directed drug candidates for neurodegenerative diseases. Curr Neuropharmacol 2020; 18(5): 348-407.
[http://dx.doi.org/10.2174/1385272823666191021124443] [PMID: 31631821]
[31]
Singh AK, Kumar A, Singh H, et al. Concept of hybrid drugs and recent advancements in anticancer hybrids. Pharmaceuticals 2022; 15(9): 1071.
[http://dx.doi.org/10.3390/ph15091071] [PMID: 36145292]
[32]
Mokariya JA, Kalola AG, Prasad P, Patel MP. Simultaneous ultrasound- and microwave-assisted one-pot ‘click’ synthesis of 3-formyl-indole clubbed 1,2,3-triazole derivatives and their biological evaluation. Mol Divers 2022; 26(2): 963-79.
[http://dx.doi.org/10.1007/s11030-021-10212-8] [PMID: 33834361]
[33]
Suryapeta S, Papigani N, Banothu V, Dubey PK, Mukkanti K, Pal S. Synthesis, biological evaluation, and docking study of a series of 1,4-disubstituted 1,2,3-triazole derivatives with an indole-triazole-peptide conjugate. J Heterocycl Chem 2020; 57(8): 3126-41.
[http://dx.doi.org/10.1002/jhet.4020]
[34]
Deswal S, Naveen , Tittal RK, Ghule Vikas D, Lal K, Kumar A. 5-Fluoro-1H-indole-2,3-dione-triazoles-synthesis, biological activity, molecular docking, and DFT study. J Mol Struct 2020; 1209: 127982.
[http://dx.doi.org/10.1016/j.molstruc.2020.127982]
[35]
Al-Wabli RI, Alsulami MA, Bukhari SI, Moubayed NMS, Al-Mutairi MS, Attia MI. Design, synthesis, and antimicrobial activity of certain new indole-1, 2, 4 triazole conjugates. Molecules 2021; 26(8): 2292.
[http://dx.doi.org/10.3390/molecules26082292] [PMID: 33920952]
[36]
Marzi M, Farjam M, Kazeminejad Z, Shiroudi A, Kouhpayeh A, Zarenezhad E. A recent overview of 1, 2, 3-triazole-containing hybrids as novel antifungal agents: focusing on synthesis, mechanism of action, and structure-activity relationship (SAR). J Chem 2022; 2022: 1-50.
[http://dx.doi.org/10.1155/2022/7884316]
[37]
Sahu A, Agrawal RK, Pandey R. Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency. Bioorg Chem 2019; 88: 102939.
[http://dx.doi.org/10.1016/j.bioorg.2019.102939] [PMID: 31028993]
[38]
Yele V, Pindiprolu SK, Sana S, Ramamurty DS, Madasi JR, Vadlamani S. Synthesis and preclinical evaluation of indole triazole conjugates as microtubule targeting agents that are effective against MCF-7 breast cancer cell lines. Anticancer Agents Med Chem 2021; 21(8): 1047-55.
[http://dx.doi.org/10.2174/1871520620666200925102940]
[39]
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7(1): 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[40]
Dardeer HM, Taha AG, Toghan A, Abdelmonsef AH. Synthesis, in silico molecular docking studies and antimicrobial evaluation of some new anthracene derivatives tagged with arylidene, pyridine, oxazole, and chromene moieties as promising inhibitors of bacterial DNA gyrase. Biointerface Res Appl Chem 2022; 13(3): 299.
[http://dx.doi.org/10.33263/BRIAC133.299]
[41]
Spencer AC, Panda SS. DNA gyrase as a target for quinolones. Biomedicines 2023; 11(2): 371.
[http://dx.doi.org/10.3390/biomedicines11020371] [PMID: 36830908]
[42]
Rosignoli S, Paiardini A. DockingPie: A consensus docking plugin for PyMOL. Bioinformatics 2022; 38(17): 4233-4.
[http://dx.doi.org/10.1093/bioinformatics/btac452] [PMID: 35792827]
[43]
Kumar A, Lal K, Kumar L, Kumar A, Naveen , Tittal RK. Phenylhydrazone linked 1,2,3-triazole hybrids: synthesis, antimicrobial evaluation and docking studies as dual inhibitors of DNA gyrase and lanosterol 14-α demethylase. Res Chem Intermed 2022; 48(12): 5089-111.
[http://dx.doi.org/10.1007/s11164-022-04849-9]
[44]
Sander T, Freyss J, von Korff M, Rufener C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J Chem Inf Model 2015; 55(2): 460-73.
[http://dx.doi.org/10.1021/ci500588j] [PMID: 25558886]
[45]
Kumar A, Singh AK, Singh H, et al. Nitrogen containing heterocycles as anticancer agents: A medicinal chemistry perspective. Pharmaceuticals 2023; 16(2): 299.
[http://dx.doi.org/10.3390/ph16020299] [PMID: 37259442]
[46]
Cousins KR. Computer review of chemdraw ultra 12.0. J Am Chem Soc 2011; 133(21): 8388.
[http://dx.doi.org/10.1021/ja204075s]
[47]
Liebeschuetz JW, Cole JC, Korb O. Pose prediction and virtual screening performance of GOLD scoring functions in a standardized test. J Comput Aided Mol Des 2012; 26(6): 737-48.
[http://dx.doi.org/10.1007/s10822-012-9551-4] [PMID: 22371207]
[48]
Biovia DS. BIOVIA Discovery Studio 2017 R2: A comprehensive predictive science application for the Life Sciences 2017. Available from: http://accelrys. com/products/collaborative-science/biovia-discovery-studio
[49]
Suzen S, Cihaner SS, Coban T. Synthesis and comparison of antioxidant properties of indole-based melatonin analogue indole amino Acid derivatives. Chem Biol Drug Des 2012; 79(1): 76-83.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01216.x] [PMID: 21883955]

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