Synthesis, antimicrobial activity, and molecular docking study of fluorine-substituted indole-based imidazolines
- 67 Downloads
A series of 2- or 3-(4,5-dihydro-1H-imidazol-2-yl)-1H-indole derivatives were synthesized, characterized, and evaluated for their in vitro antibacterial and antifungal activities. Additionally, the synthesized compounds were docked into the II DNA gyrase B active site, and their predicted binding modes were inspected. Inhibitory activity were tested against two species of Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), two species of Gram-positive bacteria (Staphylococcus aureus, Listeria monocytogenes) and two fungi (Candida albicans, Aspergillus niger) using the broth microdilution method. The fluorine-substituted 2-(2-imidazolyl)indole 2b was found to be the most potent antibacterial compound against E. coli and S. aureus strains (MIC value 80 μg/mL). Compounds showed better activity against Gram-positive bacteria compared to Gram-negative bacteria. The docking results predicted that the imidazoline-indole hybrid moiety bind to the active site protein ATP-binding pocket from E. coli and S. aureus with good interaction energy scores. The significant loss of antibacterial activity for some imidazoline-indole analogs could be attributed to several nonoptimal enzyme interactions, including poor hydrogen bonds provided by Asp73 (E. coli gyrase numbering) or Asp81 (S. aureus gyrase numbering) and an associated water molecule.
KeywordsImidazole Indole Tautomers Antibacterial activity Docking studies Gyrase B
The present work is partially supported by CONACYT grant 179187 and Programa de Fortalecimiento Académico del Posgrado de Alta Calidad.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Bansal S, Kumar S, Aggarwal V, Joseph A (2014) Design, synthesis, docking study & antibacterial evaluation of 1,3-diarylpyrazolyl substituted indolin-2-ones. Indo Global J Pharm Sci 4:1–7Google Scholar
- Desroy N, Denis A, Oliveira C, Atamanyuk D, Briet S, Faivre F, LeFralliec G, Bonvin Y, Oxoby M, Escaich S, Floquet S, Drocourt E, Vongsouthi V, Durant L, Moreau F, Verhey TB, Lee T-W, Junop MS, Gerusz V (2013) Novel HldE-K inhibitors leading to attenuated gram negative bacterial virulence. J Med Chem 56:1418–1430CrossRefPubMedGoogle Scholar
- Fonquerna S, Miralpeix M, Pagès L, Puig C, Cardús A, Antón F, Cárdenas A, Vilella D, Aparici M, Calaf E, Prieto J, Gras J, Huerta JM, Warrellow G, Beleta J, Ryder H (2004) Synthesis and structure-activity relationships of novel Histamine H1 antagonists: Indolylpiperidinyl benzoic acid derivatives. J Med Chem 47:6326–6337CrossRefPubMedGoogle Scholar
- Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09. Gaussian, Inc., Wallingford CTGoogle Scholar
- Joshi KC, Joshi R (2000) Fluorinated indole derivatives: synthetic and biomedicinal aspects. J Indian Chem Soc 77:627–634Google Scholar
- KumarMittal A, Singh D, Tripathi S (2011) Synthesis and antifungal activity of some new fluorinated 1-[2-hydroxyethyl]-3-ethoxycarbonyl-5-oxadiazolyl/triazolyl/pyrrolyl-aminocarbonylmethoxy-2-methylbenz[g]indoles. J Chem Bio Phy Sci 1:141–152Google Scholar
- Morales-Ríos MS, García-Vázquez B, Florán-Garduño B, Serrano-Alva MT (2015) Preparation of serotonin reuptake inhibitor for treating central nervous system disorders. Mex Pat Appl MX 2014011573 A 20150310.Google Scholar
- NCCLS (2003) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard, M7-A6. National Committee for Clinical Laboratory Standards, Wayne, PAGoogle Scholar
- Panchal RG, Ulrich RL, Lane D, Butler MM, Houseweart C, Opperman T, Williams JD, Peet NP, Moir DT, Nguyen T, Gussio R, Bowlin T, Bavari S (2009) Novel broad-spectrum Bis-(imidazolinylindole) derivatives with potent antibacterial activities against antibiotic-resistant strains. Antimicrob Agents Chemother 53:4283–4291CrossRefPubMedPubMedCentralGoogle Scholar
- Sawa N (1968) Nippon Kagaku Zasshi 89:780. (1969) Chem Abstr 70:19983Google Scholar
- Spadoni G, Diamantini G, Bedini A, Tarzia G, Vacondio F, Silva C, Rivara M, Mor M, Plazzi PV, Zusso M, Franceschini D, Giusti P (2006) Synthesis, antioxidant activity and structure–activity relationships for a new series of 2-(N-acylaminoethyl)indoles with melatonin-like cytoprotective activity. J Pineal Res 40:259–269CrossRefPubMedGoogle Scholar
- Spartan 14 (2013) Spartan’14 for Windows, macintosh, and linux. Wavefunction Inc., Irvine. http://downloads.wavefun.com/Spartan14Manual.pdf.
- WHO (World Health Organization) Antimicrobial resistance, Global Report on Surveillance (2014). http://www.who.int/drugresistance/documents/surveillance-report/en/ Accessed 2 December 2016
- Wysong V, Whithe HC (1968) Substituted imidazolinyl índoles. US Patent 3,586,695.Google Scholar
- Zhang J, Yang Q, Cross JB, Romero JA, Poutsiaka KM, Epie F, Bevan D, Wang B, Zhang Y, Chavan A, Zhang X, Moy T, Daniel A, Nguyen K, Chamberlain B, Carter N, Shotwell J, Silverman J, Metcalf CA, Ryan D, Lippa B, Dolle RE (2015) Discovery of azaindole ureas as a novel class of bacterial Gyrase B inhibitors. J Med Chem 58:8503–8512CrossRefPubMedGoogle Scholar
- Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H (2016) Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II−III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem Rev 116:422–518CrossRefPubMedGoogle Scholar
- Zidar N, Macut H, Tomašič T, Brvar M, Montalvão S, Tammela P, Solmajer T, Peterlin Mašič L, Ilaš J, Kikelj D (2015) N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides as ATP competitive DNA gyrase B inhibitors: design, synthesis, and evaluation. J Med Chem 58:6179–6194CrossRefPubMedGoogle Scholar
- Zoidis G, Giannakopoulou, Stevaert A, Frakolaki E, Myrianthopoulos V, Fytas G, Mavromara P, Mikros E, Bartenschlager R, Vassilaki N, Naesens L (2016) Novel indole–flutimide heterocycles with activity against influenza PA endonuclease and hepatitis C virus. Med Chem Comm 7:447–456CrossRefGoogle Scholar