Abstract
Background: Mycobacterium Tuberculosis (Mtb) is the causative pathogen of Tuberculosis (TB) and outbreaks are more common among immunosuppressed persons infected with HIV. The current treatment regimens are lengthy and toxic, yet the therapy has remained unchanged for many decades, so there is a need to find new structures with selective mechanism of action. Moreover, the increased incidence of severe disseminated infections produced by undiagnosed Multidrug-resistant (MDR), worsen clinical treatment and contribute the spread of the disease.
Objective: The aim of our study was to evaluate the potential of imidazole and triazole moieties for antimycobacterial activity, by synthesizing some 1-(1-(aryl)-2-(2,6-dichlorophenyl)hydrazono)ethyl- 1H-imidazole and 1H-1,2,4-triazole derivatives 2a-l.
Methods: The title compounds were obtained via classical organic synthesis. The antimicrobial activity was evaluated using the method of microdilution and the cytotoxicity assay was performed by MTT method.
Results: The results indicated that the presence of both the imidazole ring and that of the 2,6- dichlorosubstituted phenyl moiety, is more relevant for inhibitory activity against Mtb than the triazole nucleus and the unsubstituted phenyl ring. Among the series, (E)-1-(2-(5-chlorothiophen-2-yl)-2-(2- (2,6-dichlorophenyl)hydrazono)ethyl)-1H-imidazole derivative 2f and (Z)-1-(2-([1,1’-biphenyl]-4-yl)- 2-(2-(2,6-dichlorophenyl)hydrazono)ethyl]-1H-imidazole derivatives 2e exhibited a promising antimycobacterial property and the latter also displayed a safe cytotoxic profile.
Conclusion: The synthesized compounds were studied for their antitubercular activity. Among the series, the compounds 2e and 2f appeared to be the most promising agents and, according to the docking assessment, the compounds could be CYP51 inhibitors. These evidences could be useful for the future development of new antimycobacterial derivatives targeting CYP51 with more specificity for the mycobacterial cell enzyme.
Keywords: CYP51, Cytotoxicity, Imidazole, Molecular modeling, Mycobacterium tuberculosis (Mtb), Triazole.
Graphical Abstract
[2]
Yadav, D.K.; Ahmad, I.; Shukla, A.; Khan, F.; Negi, A.S.; Gupta, A. QSAR and docking studies of chalcone derivatives for antitubercular activity against M. tuberculosis H37Rv. J. Chemometr., 2014, 28, 499-507. [http://dx.doi.org/10.1002/cem.2606].
[3]
Bhat, Z.S.; Rather, M.A.; Syed, K.Y.; Ahmad, Z. α-pyrones and their hydroxylated analogs as promising scaffolds against Mycobacterium tuberculosis. Future Med. Chem., 2017, 9(17), 2053-2067. [http://dx.doi.org/10.4155/fmc-2017-0116]. [PMID: 29076769].
[4]
Makarov, V.; Manina, G.; Mikusova, K.; Möllmann, U.; Ryabova, O.; Saint-Joanis, B.; Dhar, N.; Pasca, M.R.; Buroni, S.; Lucarelli, A.P.; Milano, A.; De Rossi, E.; Belanova, M.; Bobovska, A.; Dianiskova, P.; Kordulakova, J.; Sala, C.; Fullam, E.; Schneider, P.; McKinney, J.D.; Brodin, P.; Christophe, T.; Waddell, S.; Butcher, P.; Albrethsen, J.; Rosenkrands, I.; Brosch, R.; Nandi, V.; Bharath, S.; Gaonkar, S.; Shandil, R.K.; Balasubramanian, V.; Balganesh, T.; Tyagi, S.; Grosset, J.; Riccardi, G.; Cole, S.T. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 2009, 324(5928), 801-804. [http://dx.doi.org/10.1126/science.1171583]. [PMID: 19299584].
[5]
Sharma, K.; Tanwar, O.; Sharma, S.; Ali, S.; Alam, M.M.; Zaman, M.S.; Akhter, M. Structural comparison of Mtb-DHFR and h-DHFR for design, synthesis and evaluation of selective non-pteridine analogues as antitubercular agents. Bioorg. Chem., 2018, 80, 319-333. [http://dx.doi.org/10.1016/j.bioorg.2018.04.022]. [PMID: 29986181].
[6]
Fioravanti, R.; Biava, M.; Porretta, G.C.; Artico, M.; Lampis, G.; Deidda, D.; Pompei, R. N-substituted 1-aryl-2(1H-imidazol-1-yl)1-ethanamines with broad spectrum in vitro antimycobacterial and antifungal activities. Med. Chem. Res., 1997, 7, 87-97.
[7]
Biava, M.; Fioravanti, R.; Porretta, G.C.; Sleiter, G.; Ettorre, A.; Deidda, D.; Lampis, G.; Pompei, R. New toluidine derivatives with antimycobacterial and antifungal activities. Med. Chem. Res., 1997, 7, 228-250.
[8]
Mamolo, M.G.; Zampieri, D.; Falagiani, V.; Vio, L.; Fermeglia, M.; Ferrone, M.; Pricl, S.; Banfi, E.; Scialino, G. Antifungal and antimycobacterial activity of new N1-[1-aryl-2-(1Himidazol-1-yl and 1H-1,2,4-triazol-1-yl)-ethylidene]-pyridine-2-carboxami-drazone derivatives: a combined experimental and computational approach. ARKIVOC, 2004, 5, 231-250.
[9]
Banfi, E.; Scialino, G.; Zampieri, D.; Mamolo, M.G.; Vio, L.; Ferrone, M.; Fermeglia, M.; Paneni, M.S.; Pricl, S. Antifungal and antimycobacterial activity of new imidazole and triazole derivatives. A combined experimental and computational approach. J. Antimicrob. Chemother., 2006, 58(1), 76-84. [http://dx.doi.org/ 10.1093/jac/dkl182]. [PMID: 16709593].
[10]
Zampieri, D.; Mamolo, M.G.; Vio, L.; Banfi, E.; Scialino, G.; Fermeglia, M.; Ferrone, M.; Pricl, S. Synthesis, antifungal and antimycobacterial activities of new bis-imidazole derivatives, and prediction of their binding to P450(14DM) by molecular docking and MM/PBSA method. Bioorg. Med. Chem., 2007, 15(23), 7444-7458. [http://dx.doi.org/10.1016/j.bmc.2007.07.023]. [PMID: 17888669].
[11]
Zampieri, D.; Mamolo, M.G.; Laurini, E.; Scialino, G.; Banfi, E.; Vio, L. Antifungal and antimycobacterial activity of 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives. Bioorg. Med. Chem., 2008, 16(8), 4516-4522. [http://dx.doi.org/ 10.1016/j.bmc.2008.02.055]. [PMID: 18321714].
[12]
Zampieri, D.; Mamolo, M.G.; Laurini, E.; Scialino, G.; Banfi, E.; Vio, L. 2-aryl-3-(1H-azol-1-yl)-1H-indole derivatives: a new class of antimycobacterial compounds - conventional heating in comparison with MW-assisted synthesis. Arch. Pharm. (Weinheim), 2009, 342(12), 716-722. [http://dx.doi.org/10.1002/ardp. 200900031]. [PMID: 19921681].
[13]
Bellamine, A.; Mangla, A.T.; Nes, W.D.; Waterman, M.R. Characterization and catalytic properties of the sterol 14alpha-demethylase from Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA, 1999, 96(16), 8937-8942. [http://dx.doi.org/10.1073/pnas. 96.16.8937]. [PMID: 10430874].
[14]
Dyer, R.L.; Ellames, G.J.; Hamill, B.J.; Manley, P.W.; Pope, A.M. Synthesis of (E)-1-(5-chlorothien-2-yl)-2-(1H-imidazol-1-yl)ethanone 2,6-dichlorophenylhydrazone hydrochloride, a novel, orally active antifungal agent. J. Med. Chem., 1983, 26(3), 442-445. [http://dx.doi.org/10.1021/jm00357a023]. [PMID: 6298430].
[15]
Ali, M.A.; Shaharyar, M.; Siddiqui, A.A. Synthesis, structural activity relationship and anti-tubercular activity of novel pyrazoline derivatives. Eur. J. Med. Chem., 2007, 42(2), 268-275. [http://dx.doi.org/10.1016/j.ejmech.2006.08.004]. [PMID: 17007966].
[16]
Ali, M.A.; Yar, M.S. Antitubercular activity of novel substituted 4,5-dihydro-1H-1-pyrazolylmethanethiones. J. Enzyme Inhib. Med. Chem., 2007, 22(2), 183-189. [http://dx.doi.org/10.1080/ 14756360601072437]. [PMID: 17518345].
[17]
Mullen, J.B.; Swift, P.A.; Marinyak, D.M.; Allen, S.D.; Mitchell, J.T.; Kinsolvin, C.R.; Georgiev, V.St. Studies on antifungal agents. Part 22. 3-Aryl-5[(aryloxy)alkyl]-3-[(1H-imidazol-1-yl)methyl]-2-methylisoxazolidines and related derivatives. Helv. Chim. Acta, 1988, 71, 18-32. [http://dx.doi.org/10.1002/hlca.19880710406].
[18]
Chapman, D.R.; Bauer, L. Synthesis and carbon-13 NMR spectra of cis- and trans-2-(haloaryl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanols. J. Het. Chem., 1990, 27, 2053-2061. [http://dx.doi.org/10.1002/jhet.5570270738].
[19]
Lakshmanan, B.; Mazumder, P.M.; Sasmal, D.; Ganguly, S. Synthesis, antispasmodic and antidiarrheal activities of some 1-substituted imidazole derivatives. Acta Pharm., 2011, 61(2), 227-236. [http://dx.doi.org/10.2478/v10007-011-0014-6]. [PMID: 21684849].
[20]
Astleford, B.A.; Goe, G.L.; Keay, J.G.; Scriven, E.F.V. Synthesis of 1-alkyl-1,2,4-triazoles: a new one-pot regiospecific procedure. J. Org. Chem., 1989, 54, 731-732. [http://dx.doi.org/10.1021/ jo00264a048].
[21]
Roman, G.; Vlahakis, J.Z.; Vukomanovic, D.; Nakatsu, K.; Szarek, W.A. Heme oxygenase inhibition by 1-aryl-2-(1h-imidazol-1-yl/1h-1,2,4-triazol-1-yl)ethanones and their derivatives. ChemMedChem, 2010, 5(9), 1541-1555. [http://dx.doi.org/10.1002/ cmdc.201000120]. [PMID: 20652928].
[22]
Xu, Liang-zhong; Zhang, Shu-sheng; Gao, Hong-rong; Jiao, Kui. Studies on synthesis and biological activities of novel triazole compounds containing pyrimidine or N,N-dialkyldithiocarbamate ring. Chem. Res. In China Univ, 2003, 19, 437-441.
[24]
Palomino, J.C.; Martin, A.; Camacho, M.; Guerra, H.; Swings, J.; Portaels, F. Resazurin microtiter assay plate: simple and inexpensive method for detection of drug resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2002, 46(8), 2720-2722. [http://dx.doi.org/10.1128/AAC.46.8.2720-2722.2002]. [PMID: 12121966].
[25]
Taneja, N.K.; Tyagi, J.S. Resazurin reduction assays for screening of anti-tubercular compounds against dormant and actively growing Mycobacterium tuberculosis, Mycobacterium bovis BCG and Mycobacterium smegmatis. J. Antimicrob. Chemother., 2007, 60(2), 288-293. [http://dx.doi.org/10.1093/jac/dkm207]. [PMID: 17586560].
[26]
Zampieri, D.; Mamolo, M.G.; Laurini, E.; Fermeglia, M.; Posocco, P.; Pricl, S.; Banfi, E.; Scialino, G.; Vio, L. Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations. Bioorg. Med. Chem., 2009, 17(13), 4693-4707. [http://dx.doi.org/10.1016/ j.bmc.2009.04.055]. [PMID: 19467603].
[27]
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].
[28]
Mehler, E.L.; Solmajer, T. Electrostatic effects in proteins: comparison of dielectric and charge models. Protein Eng., 1991, 4(8), 903-910. [http://dx.doi.org/10.1093/protein/4.8.903]. [PMID: 1667878].
[29]
aOnufriev, A.; Bashford, D.; Case, D.A. Modification of the Generalized Born Model Suitable for Macromolecules. J. Phys. Chem., 2000, 104, 3712-3720.
bFeig, M.; Onufriev, A.; Lee, M.S. Im, W.; Case, D.A.; Brooks, C.L., III Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures. J. Comput. Chem., 2004, 25(2), 265-284. [http://dx.doi.org/10.1002/jcc.10378]. [PMID: 14648625].
bFeig, M.; Onufriev, A.; Lee, M.S. Im, W.; Case, D.A.; Brooks, C.L., III Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures. J. Comput. Chem., 2004, 25(2), 265-284. [http://dx.doi.org/10.1002/jcc.10378]. [PMID: 14648625].
[30]
Case, D.A.; Darden, T.A.; Cheatham, T.E., III; Babin, V.; Berryman, J.; Betz, R.M.; Cai, Q.; Cerutti, D.S.; Duke, R.E.; Gohlke, H.; Goetz, A.W.; Gusarov, S.; Homeyer, N.; Janowski, P.; Kaus, J.; Kolossváry, I.; Kovalenko, A.; Lee, T.S.; LeGrand, S.; Luchko, T.; Luo, R.; Madej, B.; Merz, K.M.; Paesani, F.; Roe, D.R.; Roitberg, A.; Sagui, C.; Salomon-Ferrer, R.; Seabra, G.; Simmerling, C.L.; Smith, W.; Swails, J.; Walker, R.C.; Wang, J.; Wolf, R.M.; Wu, X.; Kollman, P.A. AMBER 14; University of California: San Francisco, 2012.
[31]
Jorgensen, W.L.; Chandrasekhar, J.; Madura, J.D.; Impey, R.W.; Klein, M.L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys., 1983, 79, 926-935. [http://dx.doi.org/10.1063/1.445869].
[32]
Ryckaert, J.P.; Ciccotti, G.; Berendsen, H.J.C. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. Comput. Phys., 1977, 23, 327-341. [http://dx.doi.org/10.1016/0021-9991(77)90098-5].
[33]
Toukmaji, A.; Sagui, C.; Board, J.; Darden, T. Efficient particle-mesh Ewald based approach to fixed and induced dipolar interactions. J. Chem. Phys., 2000, 113, 10913-10927. [http://dx.doi.org/ 10.1063/1.1324708].
[34]
Briguglio, I.; Loddo, R.; Laurini, E.; Fermeglia, M.; Piras, S.; Corona, P.; Giunchedi, P.; Gavini, E.; Sanna, G.; Giliberti, G.; Ibba, C.; Farci, P.; La Colla, P.; Pricl, S.; Carta, A. Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Eur. J. Med. Chem., 2015, 105, 63-79. [http://dx.doi.org/10.1016/ j.ejmech.2015.10.002]. [PMID: 26479028].
[35]
Carta, A.; Briguglio, I.; Piras, S.; Corona, P.; Ibba, R.; Laurini, E.; Fermeglia, M.; Pricl, S.; Desideri, N.; Atzori, E.M.; La Colla, P.; Collu, G.; Delogu, I.; Loddo, R. A combined in silico/in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems. Eur. J. Med. Chem., 2016, 117, 321-334. [http://dx.doi.org/ 10.1016/j.ejmech.2016.03.080]. [PMID: 27161176].
[36]
Zampieri, D.; Vio, L.; Fermeglia, M.; Pricl, S.; Wünsch, B.; Schepmann, D.; Romano, M.; Mamolo, M.G.; Laurini, E. Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands. Eur. J. Med. Chem., 2016, 121, 712-726. [http://dx.doi.org/10.1016/j.ejmech.2016.06.001]. [PMID: 27366902].
[38]
Hartkoorn, R.C.; Chandler, B.; Owen, A.; Ward, S.A.; Bertel Squire, S.; Back, D.J.; Khoo, S.H. Differential drug susceptibility of intracellular and extracellular tuberculosis, and the impact of P-glycoprotein. Tuberculosis (Edinb.), 2007, 87(3), 248-255. [http://dx.doi.org/10.1016/j.tube.2006.12.001]. [PMID: 17258938].
[39]
Podust, L.M.; Poulos, T.L.; Waterman, M.R. Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc. Natl. Acad. Sci. USA, 2001, 98(6), 3068-3073. [http://dx.doi.org/ 10.1073/pnas.061562898]. [PMID: 11248033].
[40]
Yadav, D.K.; Khan, F.; Negi, A.S. Pharmacophore modeling, molecular docking, QSAR, and in silico ADMET studies of gallic acid derivatives for immunomodulatory activity. J. Mol. Model., 2012, 18(6), 2513-2525. [http://dx.doi.org/10.1007/s00894-011-1265-3]. [PMID: 22038459].
[41]
Yadav, D.K.; Kalani, K.; Khan, F.; Srivastava, S.K. QSAR and docking based semi-synthesis and in vitro evaluation of 18 β-glycyrrhetinic acid derivatives against human lung cancer cell line A-549. Med. Chem., 2013, 9(8), 1073-1084. [http://dx.doi.org/ 10.2174/1573406411309080009]. [PMID: 23675978].
[42]
Yadav, D.K.; Khan, F. QSAR, docking and ADMET studies of camptothecin derivatives as inhibitors of DNA topoisomerase‐I. J. Chemom., 2013, 27, 21-33.
[43]
Yadav, D.K.; Dhawan, S.; Chauhan, A.; Qidwai, T.; Sharma, P.; Bhakuni, R.S.; Dhawan, O.P.; Khan, F. QSAR and docking based semi-synthesis and in vivo evaluation of artemisinin derivatives for antimalarial activity. Curr. Drug Targets, 2014, 15(8), 753-761. [http://dx.doi.org/10.2174/1389450115666140630102711]. [PMID: 24975562].
[44]
Yadav, D.K.; Kalani, K.; Singh, A.K.; Khan, F.; Srivastava, S.K.; Pant, A.B. Design, synthesis and in vitro evaluation of 18β-glycyrrhetinic acid derivatives for anticancer activity against human breast cancer cell line MCF-7. Curr. Med. Chem., 2014, 21(9), 1160-1170. [http://dx.doi.org/10.2174/09298673113206660330]. [PMID: 24180274].
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