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Letters in Drug Design & Discovery


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

Research Article

Synthesis, Antimicrobial Activity, and Molecular Modeling Studies of Some Benzoxazole Derivatives

Author(s): Muhammed Tilahun Muhammed*, Gulcan Kuyucuklu, Fatma Kaynak-Onurdag and Esin Aki-Yalcin

Volume 19, Issue 8, 2022

Published on: 27 May, 2022

Page: [757 - 768] Pages: 12

DOI: 10.2174/1570180819666220408133643

Price: $65


Background: The need to develop novel antimicrobial agents is apparent as infectious diseases are increasing and resistance is rapidly developing against the drugs used in the treatment.

Objective: This study aimed at the synthesis, antimicrobial susceptibility testing, and computational elucidation of the mechanism of action of benzoxazole derivatives. It also aimed to compare the results obtained in this study with the previous studies by our group. This would pave the way for designing novel molecules with better antimicrobial activity. The other goal was pharmacophore analysis and in silico ADMET analysis of them.

Methods: In this study, synthesis, antimicrobial susceptibility testing, molecular docking, pharmacophore analysis, and ADMET prediction were carried out.

Results: The antimicrobial activity studies demonstrated that the synthesized compounds were active against standard strains and clinical isolates at high concentrations. Then, the antimicrobial testing results were compared to similar benzoxazoles tested by our group previously. Benzoxazole derivatives without a methylene bridge between oxazole and phenyl ring were found to be more active than those with the methylene bridge. This was also confirmed by molecular modeling undertaken in this study. The computational results indicated that the antibacterial activity could be achieved by DNA gyrase inhibition. Pharmacophore analysis showed that hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and hydrophobicity features would contribute to the inhibition. In addition, in silico ADMET property investigation of the compounds exhibited that they had the desired pharmacokinetics.

Conclusion: Although antibacterial activity by inhibiting DNA gyrase is selective, the synthesized compounds were active at much higher concentrations than the standards. Therefore, in prospective antimicrobial studies, it is better to focus on benzoxazole derivatives without the methylene bridge. Since the compounds had suitable in silico ADMET properties, screening them against the other pharmacologic activities should be carried out. It is recommended to support the molecular modeling results with in vitro or in vivo studies.

Keywords: ADMET, antimicrobial, benzoxazole, drug design, molecular docking, pharmacophore.

Graphical Abstract
Arandjelovic, P.; Doerflinger, M.; Pellegrini, M. Current and emerging therapies to combat persistent intracellular pathogens. Curr. Opin. Pharmacol., 2019, 48, 33-39.
[] [PMID: 31051429]
González-Bello, C. Recently developed synthetic compounds with anti-infective activity. Curr. Opin. Pharmacol., 2019, 48, 17-23.
[] [PMID: 31005786]
Yilmaz, S.; Yalcin, I.; Okten, S.; Onurdag, F.K.; Aki-Yalcin, E. Synthesis and investigation of binding interactions of 1,4-benzoxazine derivatives on topoisomerase IV in Acinetobacter baumannii. SAR QSAR Environ. Res., 2017, 28(11), 941-956.
[] [PMID: 29206501]
Yilmaz, S.; Yalcin, I.; Kaynak-onurdag, F.; Ozgen, S. Synthesis and in vitro antimicrobial activity of novel 2-(4-substituted-carboxamido)benzyl/phenyl) benzothiazoles. Croat. Chem. Acta, 2013, 86(2), 223-231.
Klein, E.Y.; Van Boeckel, T.P.; Martinez, E.M.; Pant, S.; Gandra, S.; Levin, S.A.; Goossens, H.; Laxminarayan, R. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl. Acad. Sci. USA, 2018, 115(15), E3463-E3470.
[] [PMID: 29581252]
Ebenezer, O.; Singh-Pillay, A.; Koorbanally, N.A.; Singh, P. Antibacterial evaluation and molecular docking studies of pyrazole-thiosemicarbazones and their pyrazole-thiazolidinone conjugates. Mol. Divers., 2021, 25(1), 191-204.
[] [PMID: 32086698]
Pacios, O.; Blasco, L.; Bleriot, I.; Fernandez-Garcia, L. Bardanca; Mónica González Ambroa, A.; López, M.; Bou, G.; Tomas, M. Strate-gies to combat multidrug-resistant and persistent infectious diseases. Antibiotics (Basel), 2020, 9(65), 1-20.
Qin, Y.; Xu, L.; Teng, Y.; Wang, Y.; Ma, P. Discovery of novel antibacterial agents: Recent developments in D-alanyl-D-alanine ligase inhibitors. Chem. Biol. Drug Des., 2021, 98(3), 305-322.
[] [PMID: 34047462]
Macalino, S.J.Y.; Billones, J.B.; Organo, V.G.; Carrillo, M.C.O. In silico strategies in tuberculosis drug discovery. Molecules, 2020, 25(3), 1-32.
[] [PMID: 32033144]
Saurav, K.; Zhang, W.; Saha, S.; Zhang, H.; Li, S.; Zhang, Q.; Wu, Z.; Zhang, G.; Zhu, Y.; Verma, G. In silico molecular docking, preclini-cal evaluation of spiroindimicins A-D, lynamicin A and D isolated from deep marine sea derived Streptomyces sp. SCSIO 03032. Interdiscip. Sci., 2014, 6(3), 187-196.
[] [PMID: 25205496]
Muhammed, M.T.; Aki-Yalcin, E. Pharmacophore modeling in drug discovery: Methodology and current status. J. Turkish Chem. Soc. Sect. A Chem, 2021, 8(3), 759-772.
Surabhi, S.; Singh, B.K. Computer aided drug design: An overview. J. Drug Deliv. Ther., 2018, 8(5), 504-509.
Muhammed, M.T.; Aki-Yalcin, E. Homology modeling in drug discovery: Overview, current applications, and future perspectives. Chem. Biol. Drug Des., 2019, 93(1), 12-20.
[] [PMID: 30187647]
Chen, Y.C. Beware of docking! Trends Pharmacol. Sci., 2015, 36(2), 78-95.
[] [PMID: 25543280]
Khan, T.; Sankhe, K.; Suvarna, V.; Sherje, A.; Patel, K.; Dravyakar, B. DNA gyrase inhibitors: Progress and synthesis of potent com-pounds as antibacterial agents. Biomed. Pharmacother., 2018, 103(January), 923-938.
[] [PMID: 29710509]
Alqahtani, S. In silico ADME-Tox modeling: Progress and prospects. Expert Opin. Drug Metab. Toxicol., 2017, 13(11), 1147-1158.
[] [PMID: 28988506]
Aksenov, N.A.; Aksenov, A.V.; Nadein, O.N.; Aksenov, D.A.; Smirnov, A.N.; Rubin, M. One-Pot Synthesis of Benzoxazoles via the Met-al-Free Ortho-C-H Functionalization of Phenols with Nitroalkanes. RSC Advances, 2015, 5(88), 71620-71626.
Chiarotto, I.; Feroci, M.; Orsini, M.; Sotgiu, G.; Inesi, A. Electrogenerated N-heterocyclic carbenes: N-functionalization of benzoxa-zolones. Tetrahedron, 2009, 65(18), 3704-3710.
Zilifdar, F.; Foto, E.; Ertan-Bolelli, T.; Aki-Yalcin, E.; Yalcin, I.; Diril, N. Biological evaluation and pharmacophore modeling of some benzoxazoles and their possible metabolites. Arch. Pharm. (Weinheim), 2018, 351(2), 1-10.
[] [PMID: 29359805]
Kakkar, S.; Tahlan, S.; Lim, S.M.; Ramasamy, K.; Mani, V.; Shah, S.A.A.; Narasimhan, B. Benzoxazole derivatives: Design, synthesis and biological evaluation. Chem. Cent. J., 2018, 12(1), 92.
[] [PMID: 30101384]
Sondhi, S.M.; Singh, N.; Kumar, A.; Lozach, O.; Meijer, L. Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff’s bases. Bioorg. Med. Chem., 2006, 14(11), 3758-3765.
[] [PMID: 16480879]
Baytas, S.; Turan Dural, N.N.; Özkan, Y.; Simsek, H.B.; Gürsel, T.; Ünlü, S. Synthesis, anti-inflammatory, antiplatelet and in silico evalua-tions of (e)-3-(3-(2,3-dihydro-3-methyl-2-oxo-3h-benzoxazole-6-yl)-1-phenyl-1h-pyrazole- 4-yl)acrylamides. Turk. J. Chem., 2012, 36(3), 367-382.
Wei, C.X.; Guan, L.P.; Jia, J.H.; Chai, K.Y.; Quan, Z.S. Synthesis of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles as potential anticonvulsant agents. Arch. Pharm. Res., 2009, 32(1), 23-31.
[] [PMID: 19183873]
Courtois, M.; Mincheva, Z.; Andreu, F.; Rideau, M.; Viaud-Massuard, M.C. Synthesis and biological evaluation with plant cells of new fosmidomycin analogues containing a benzoxazolone or oxazolopyridinone ring. J. Enzyme Inhib. Med. Chem., 2004, 19(6), 559-565.
[] [PMID: 15662959]
Sakamoto, T.; Cullen, M.D.; Hartman, T.L.; Watson, K.M.; Buckheit, R.W.; Pannecouque, C.; De Clercq, E.; Cushman, M.; Kaçmaz, R.O.; Suhler, E.B. Synthesis and anti-HIV activity of new metabolically stable alkenyldiarylmethane non-nucleoside reverse transcriptase inhibi-tors incorporating N-methoxy imidoyl halide and 1,2,4-oxadiazole systems. J. Med. Chem., 2007, 50(14), 3314-3321.
[] [PMID: 17579385]
Oksuzoglu, E.; Tekiner-Gulbas, B.; Alper, S.; Temiz-Arpaci, O.; Ertan, T.; Yildiz, I.; Diril, N.; Sener-Aki, E.; Yalcin, I. Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitors. J. Enzyme Inhib. Med. Chem., 2008, 23(1), 37-42.
[] [PMID: 18341251]
Han, S.Y.; Lee, C.O.; Ahn, S.H.; Lee, M.O.; Kang, S.Y.; Cha, H.J.; Cho, S.Y.; Ha, J.D.; Ryu, J.W.; Jung, H.; Kim, H.R.; Koh, J.S.; Lee, J. Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo. Invest. New Drugs, 2012, 30(2), 518-523.
[] [PMID: 21080208]
Jonckers, T.H.M.; Rouan, M.C.; Haché, G.; Schepens, W.; Hallenberger, S.; Baumeister, J.; Sasaki, J.C. Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(15), 4998-5002.
[] [PMID: 22765892]
Ertan-Bolelli, T.; Musdal, Y.; Bolelli, K.; Yilmaz, S.; Aksoy, Y.; Yildiz, I.; Aki-Yalcin, E.; Yalcin, I. Synthesis and biological evaluation of 2-substituted-5-(4-nitrophenylsulfonamido)benzoxazoles as human GST P1-1 inhibitors, and description of the binding site features. Chem. Med. Chem., 2014, 9(5), 984-992.
[] [PMID: 24677708]
Aggarwal, N.; Kaur, A.; Anand, K.; Kumar, H.; Wakode, S. Biologically active benzoxazole: A comprehensive review. Int. J. Pharm. Sci. Res., 2017, 2(2), 2455-4685.
Yalçin, I. Ören, I.; Şener, E.; Akin, A.; Uçartürk, N. The synthesis and the structure-activity relationships of some substituted benzoxa-zoles, oxazolo(4,5-b)pyridines, benzothiazoles and benzimidazoles as antimicrobial agents. Eur. J. Med. Chem., 1992, 27(4), 401-406.
Temiz-Arpaci, Ö. Akı-Şener, E.; Yalçın, İ; Altanlar, N. Synthesis and antimicrobial activity of some 2-(p-substituted-phenyl) benzoxa-zol-5-ylarylcarboxyamides. Arch. Pharm. (Weinheim), 2002, 6(6), 283-288.
[;2-m] [<283::AIDARDP283>3.0.CO;2-M]
Temiz-Arpaci, O.; Yildiz, I.; Özkan, S.; Kaynak, F. Aki-Şener, E.; Yalçin, I. Synthesis and biological activity of some new benzoxazoles. Eur. J. Med. Chem., 2008, 43(7), 1423-1431.
[] [PMID: 18023934]
Arisoy, M.; Temiz-Arpaci, O.; Kaynak-Onurdag, F.; Ozgen, S. Novel benzoxazoles: Synthesis and antibacterial, antifungal, and antitubercular activity against antibiotic-resistant and -sensitive microbes. Zeitschrift fur Naturforsch. - Sect. C J. Biosci., 2013, 68C(11-12), 453-460.
Cresp, T.M.; Probert, C.; Sondheimer, F. An approach to the synthesis of ionophores related to A 23187. Tetrahedron Lett., 1978, 19(41), 3955-3958.
Ertan-Bolelli, T. Yildiz, &#304.; Ozgen-ozgacar, S. Synthesis, molecular docking and antimicrobial evaluation of novel benzoxazole derivatives. Med. Chem. Res., 2016, 25(4), 553-567.
Yıldız-Ören, I.; Tekiner-Gulbaş B.; Yalçın, I.; Temiz-Arpaci, O.; Akı-Şener, E.; Altanlar, N. Synthesis and antimicrobial activity of new 2-[p-substituted-benzyl]-5-[substituted-carbonylamino]benzoxazoles. Arch. Pharm. (Weinheim), 2004, 337(7), 402-410.
[] [PMID: 15237391]
Tekiner-Gulbas, B.; Temiz-Arpaci, O.; Yildiz, I.; Altanlar, N. Synthesis and in vitro antimicrobial activity of new 2-[p-substituted-benzyl]-5-[substituted-carbonylamino]benzoxazoles. Eur. J. Med. Chem., 2007, 42(10), 1293-1299.
[] [PMID: 17337097]
Şener, E.; Yalçın, İ.; Temiz, Ö.; Ören, İ.; Akın, A.; Uçartürk, N. Synthesis, antibacterial and QSAR of Some 5-substituted-2-(psubstituted benzyl) benzoxazoles using the free-wilson analysis. ankara üniversitesi eczac. Fakültesi Derg., 1995, 24(1), 9-20.
Performance standards for antimicrobial susceptibility testing, 16th informational supplement, 26th ed.; Clinical and Laboratory Standards Institute: 940 West Valley Road, Wayne, Pennsylvania, USA, 1995.
Reference Method for Broth Dilution Antifungal Susceptibility Testing Yeast, Approved Standard, 3rd ed; Clinical and Laboratory Standards Institute: 940 West Valley Road, Wayne, Pennsylvania, USA,. 1995.
Brvar, M.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors. J. Med. Chem., 2012, 55(14), 6413-6426.
[] [PMID: 22731783]
Cousins, K.R. Computer review of ChemDraw Ultra 12.0. J. Am. Chem. Soc., 2011, 133(21), 8388.
[] [PMID: 21561109]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: An advanced semantic chemical edi-tor, visualization, and analysis platform. J. Cheminform., 2012, 4(1), 17.
[] [PMID: 22889332]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[] [PMID: 19499576]
Barnum, D.; Greene, J.; Smellie, A.; Sprague, P. Identification of common functional configurations among molecules. J. Chem. Inf. Comput. Sci., 1996, 36(3), 563-571.
[] [PMID: 8690757]
Han, Y.; Zhang, J.; Hu, C.Q.; Zhang, X.; Ma, B.; Zhang, P. In silico ADME and toxicity prediction of ceftazidime and its impurities. Front. Pharmacol., 2019, 10, 434-445.
[] [PMID: 31068821]
Noyanalpan, N. Synthesis, structure elucidation and antihistaminic activity of 5-nitro-2-(p-substitutedbenzyl) benzoxazole derivatives. FABAD J. Pharm. Sci., 1986, 11, 111-119.
Noyanalpan, N. Şener, E. Synthesis, structure elucidation and antihistaminic activity of 5-chloro-2-(p-substitutedbenzyl) benzoxazole derivatives. FABAD J. Pharm. Sci., 1986, 11, 22-30.
Noyanalpan, N. Şener, E. Synthesis, structure elucidation and antihistaminic activity of 2-(p-substitutedbenzyl) benzoxazole derivatives. FABAD J. Pharm. Sci., 1985, 10, 275-286.
Oksuzoglu, E.; Temiz-Arpaci, O.; Tekiner-Gulbas, B.; Eroglu, H.; Sen, G.; Alper, S.; Yildiz, I.; Diril, N.; Aki-Sener, E.; Yalcin, I. A study on the genotoxic activities of some new benzoxazoles. Med. Chem. Res., 2008, 16(1), 1-14.
Taşci, M.; Terniz-Arpaci, O.; Kaynak-Onurdag, F.; Okten, S. Synthesis and antimicrobial evaluation of novel 5-substituted-2-(p-tert-butylphenyl) benzoxazoles. Indian J. Chem. - Sect. B Org. Med. Chem., 2018, 57B(3), 385-389.
Hohmann, C.; Schneider, K.; Bruntner, C.; Irran, E.; Nicholson, G.; Bull, A.T.; Jones, A.L.; Brown, R.; Stach, J.E.M.; Goodfellow, M.; Beil, W.; Krämer, M.; Imhoff, J.F.; Süssmuth, R.D.; Fiedler, H.P. Caboxamycin, a new antibiotic of the benzoxazole family produced by the deep-sea strain Streptomyces sp. NTK 937. J. Antibiot. (Tokyo), 2009, 62(2), 99-104.
[] [PMID: 19198633]
Maxwell, A.; Lawson, D.M. The ATP-binding site of type II topoisomerases as a target for antibacterial drugs. Curr. Top. Med. Chem., 2003, 3(3), 283-303.
[] [PMID: 12570764]
Ertan, T.; Yildiz, I.; Tekiner-Gulbas, B.; Bolelli, K.; Temiz-Arpaci, O.; Ozkan, S.; Kaynak, F.; Yalcin, I.; Aki, E. Synthesis, biological eval-uation and 2D-QSAR analysis of benzoxazoles as antimicrobial agents. Eur. J. Med. Chem., 2009, 44(2), 501-510.
[] [PMID: 18524419]
Yalçin, I. Şener, E.; Özden, T.; Özden, S.; Akin, A. Synthesis and microbiological activity of 5-methyl-2-[p-substituted phenyl] benzoxazoles. Eur. J. Med. Chem., 1990, 25(8), 705-708.
Lafitte, D.; Lamour, V.; Tsvetkov, P.O.; Makarov, A.A.; Klich, M.; Deprez, P.; Moras, D.; Briand, C.; Gilli, R. DNA gyrase interaction with coumarin-based inhibitors: The role of the hydroxybenzoate isopentenyl moiety and the 5′-methyl group of the noviose. Biochemistry, 2002, 41(23), 7217-7223.
[] [PMID: 12044152]
Holdgate, G.A.; Tunnicliffe, A.; Ward, W.H.J.; Weston, S.A.; Rosenbrock, G.; Barth, P.T.; Taylor, I.W.F.; Pauptit, R.A.; Timms, D. The entropic penalty of ordered water accounts for weaker binding of the antibiotic novobiocin to a resistant mutant of DNA gyrase: A ther-modynamic and crystallographic study. Biochemistry, 1997, 36(32), 9663-9673.
[] [PMID: 9245398]
Qidwai, T. QSAR modeling, docking and ADMET studies for exploration of potential anti-malarial compounds against Plasmodium falciparum. in silico Pharmacol., 2016, 5(1), 6.
[] [PMID: 28726171]
Fonteh, P.; Elkhadir, A.; Omondi, B.; Guzei, I.; Darkwa, J.; Meyer, D. Impedance technology reveals correlations between cytotoxicity and lipophilicity of mono and bimetallic phosphine complexes. Biometals, 2015, 28(4), 653-667.
[] [PMID: 25829148]
Ponnan, P.; Gupta, S.; Chopra, M.; Tandon, R.; Baghel, A.S.; Gupta, G.; Prasad, A.K.; Rastogi, R.C.; Bose, M.; Raj, H.G. 2D-QSAR, dock-ing studies, and in silico admet prediction of polyphenolic acetates as substrates for protein acetyltransferase function of glutamine syn-thetase of Mycobacterium tuberculosis. ISRN Struct. Biol., 2013, 2013, 1-12.

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