A Promising Copper(II) Complex as Antifungal and Antibiofilm Drug against Yeast Infection
Fabiana Gomes da Silva Dantas 1, Adriana Araújo de Almeida-Apolonio 2, Renata Pires de Araújo 3, Lis Regiane Vizolli Favarin 4, Pamella Fukuda de Castilho 1, Fernanda de Oliveira Galvão 1, Terezinha Inez Estivalet Svidzinski 5, Gleison Antônio Casagrande 4,* and Kelly Mari Pires de Oliveira 1,6,*
1 Faculty of Health Sciences, Federal University of Grande Dourados, Dourados, MS 79804-970, Brazil; [email protected] (F.G.d.S.D.); [email protected] (P.F.d.C.); [email protected] (F.d.O.G.) 2 Faculty of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, MS 79070-900, Brazil; [email protected] (A.A.d.A.A) 3 Faculty of Exact Sciences and Technology, Federal University of Grande Dourados, Dourados, MS 79804- 970, Brazil; [email protected] (R.P.d.A) 4 Institute of Chemistry, Federal University of Mato Grosso do Sul, Campo Grande, MS 79074-460, Brazil; [email protected] (L.R.V.F) 5 Department of Clinical Analysis and Biomedicine, State University of Maringá, Maringá, PR 87020-900, Brazil; [email protected] (T.I.E.S) 6 Faculty of Biological and Environmental Science, Federal University of Grande Dourados, Dourados, MS 79804-970, Brazil * Correspondence: [email protected] (G.A.C.); [email protected] (K.M.P.d.O.); Tel.: +55-067-3345-3595 (G.A.C.); +55-067-3410-2220 (K.M.P.d.O.)
Received: 09 June 2018; Accepted: 26 June 2018; Published: date
Molecules 2018, 23, 1856; doi:10.3390/molecules23081856 www.mdpi.com/journal/molecules Table S1. Anti-Candida activity of the complex 2 [CuCl2Bipy(L2)], free ligands (2-thiouracil and 6-methyl-2-thiouracil) and cooper(II) chloride in planktonic cells by microdilution
in broth technique (µg/mL).
Complex 2 6-methyl-2- 2-thiouracil CuCl2 [CuCl2Bipy(L2)] thiouracil Isolate Source FLCc AmBd
MICa MFCb MICa MFCb MICa MFCb MICa MFCb
C. albicans CA1 Sputum >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.5 0.5
C. albicans CA2 Sputum >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.25 0.25
C. albicans CA3 Vaginal >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.5 0.5
C. albicans CA4 Vaginal >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.5 0.5
C. albicans CA5 Vaginal >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.5 0.5
C. albicans CA6 Vaginal >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.5 0.5
C. albicans CA7 Nasal swab >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.25 0.5
C. albicans CA8 Urine >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.25 0.5
C. albicans CA9 Vaginal >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.25 0.5
C. albicans CA10 Vaginal >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.5 0.5
C. glabrata CG1 Urine >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 16e 0.03
Molecules 2018, 23, 1856; doi:10.3390/molecules23081856 www.mdpi.com/journal/molecules Molecules 2018, 23, 1856 2 of 11
C. glabrata CG2 Urine >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 1 0.03
C. glabrata CG3 Urine >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 16e 0.5
C. glabrata CG4 Urine >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 1 0.03
C. glabrata CG5 Blood >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 32e 0.03
C. glabrata CG6 Urine >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 16e 0.5
C. krusei CK1 Rectal swab >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.5 0.03
C. parapsilosis CP1 Blood >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.25 0.25
C. parapsilosis CP2 Catheter tip >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.25 0.03
C. parapsilosis CP3 Urine >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 0.25 0.03
C. tropicalis CT1 Sputum >1000 >1000 >1000 >1000 >1000 >1000 1000 1000 2 0.5 aMIC: Minimum Inhibitory Concentration (µg/mL); bMFC: Minimum Fungicidal Concentration (µg/mL); cFLC: Fluconazole (µg/mL); AmB: dAmphotericin B (µg/mL); eSusceptible Dose-Dependent (SDD) (µg/mL). Molecules 2018, 23, 1856 3 of 11
Complex 1
Intens. lis-1_pos_1-46_01_9435.d: +MS, 0.4min #56 1+ 1+ x105 1+ 375.0667 157.0759 260.0270 0.5
0.0 5 lis-1_pos_1-46_01_9435.d: +MS2(375.0667), 35.0eV, 0.4min #57 x10 1+ 237.0076 2 Full spectrum 1 0 5 lis-1_pos_1-46_01_9435.d: +MS2(260.0270), 35.0eV, 0.4min #58 x10 1+ 237.0075 Intens. 1+ 1 lis-1_pos_1-46_01_9435.d: +MS, 0.4min #56 x104 375.0667 1+ 4 0 1+ 377.0659 1+ 2 200 300 400 500 376.0694600 700 378.0682800 900 1000 1100 m/z 0 400 lis-1_pos_1-46_01_9435.d: +MS2(375.0667), 35.0eV, 0.4min #57 376.2529 200 Zoom in 375.0667 emphasis on the isotopic distribution of copper.
0 lis-1_pos_1-46_01_9435.d: +MS2(260.0270), 35.0eV, 0.4min #58 60 40 Intens. 1+ lis-1_pos_1-46_01_9435.d: +MS, 0.4min #56 x10420 260.0270 3+ 0 262.0255 2 372 374 1+ 1+ 3761+ 378 380 382 m/z 261.0293 263.0267 264.0064 0 lis-1_pos_1-46_01_9435.d: +MS2(375.0667), 35.0eV, 0.4min #57 1+ 2000 260.0250 265.0427 262.0299 1000 1+ 1+ Zoom in 260.0270 emphasis on the isotopic263.0281 distribution of copper.266.0372 267.0434 0 1+ lis-1_pos_1-46_01_9435.d: +MS2(260.0270), 35.0eV, 0.4min #58 260.0264 1000 262.0244 265.0402 1+ 267.0409 261.0289 0 Figure S1. ESI-HRMS spectrum of the complex 1. 256 258 260 262 264 266 268 270 272 274 m/z Molecules 2018, 23, 1856 4 of 11
Complex 2
Intens. lis-2_pos_1-47_01_9437.d: +MS, 0.6min #62 5 1+ x10 1+ 1+ 1+ 375.0648 157.0760 260.0272 0.5 237.0071
0.0 5 lis-2_pos_1-47_01_9437.d: +MS2(260.0272), 35.0eV, 0.6min #63 x10 1+ 237.0066 1.0 0.5 Full spectrum 0.0 lis-2_pos_1-47_01_9437.d: +MS2(237.0071), 35.0eV, 0.6min #64 1000 237.0062
500 Intens. 154.0616 1+ lis-2_pos_1-47_01_9437.d: +MS, 0.6min #62 x1004 237.0071 200 300 400 500 600 700 800 900 1000 1100 m/z 2 1+ 239.0065 1 1+ 1+ 238.0101 240.0133 0 5 lis-2_pos_1-47_01_9437.d: +MS2(260.0272), 35.0eV, 0.6min #63 x10 1+ 237.0066 1.00 Zoom in 237.0071 emphasis on the isotopic distribution of copper. 0.75 1+ 0.50 239.0061 1+ Intens. lis-2_pos_1-47_01_9437.d:1+ +MS, 0.6min #62 0.25 1+ 238.0082 x105 240.0085 0.8 0.00 375.0648 lis-2_pos_1-47_01_9437.d: +MS2(237.0071), 35.0eV, 0.6min #64 800 237.0062 0.6 1+ 0.4 600 377.0638 0.2 400 239.0076 0.0 200 lis-2_pos_1-47_01_9437.d: +MS2(260.0272), 35.0eV, 0.6min #63 100 0 75 226 228 230 Zoom in 357.0648232 emphasis on234 the isotopic distribution236 of copper. 238 240 242 m/z 50 25 Figure S2. ESI-HRMS spectrum of the complex 2. 0 lis-2_pos_1-47_01_9437.d: +MS2(237.0071), 35.0eV, 0.6min #64 12.5 10.0 7.5 5.0 2.5 0.0 340 350 360 370 380 390 m/z Molecules 2018, 23, 1856 5 of 11
Figure S3. Cuvettes containing the solutions of the complex 1 (light green) and ligand (colorless). Picture taken during the experiment. Complex 2 and respective ligand have been presented similar behavior. Molecules 2018, 23, 1856 6 of 11
Figure S4. UV-Vis absorption spectra of the complex 1 and respective ligand measured at 298 K. This experiment was performed 36 h after preparing the solutions.
Molecules 2018, 23, 1856 7 of 11 Absorption (a.u) Absorption
550 600 650 700 750 800
Wavelength (nm) Absorption (a.u)
Complex (2) Ligand (2)
250 300 350 400 450 500 550 600 650 700 750 Wavelength (nm)
Figure S5. UV-Vis absorption spectra of the complex 2 and respective ligand measured at 298 K. This experiment was performed 36 h after preparing the solutions. Molecules 2018, 23, 1856 8 of 11
Figure S6. Green solid of the Complex 1 obtained after filtration. Figure S7. Green solid of the Complex 2 obtained after filtration. Molecules 2018, 23, 1856 9 of 11
Possible Fragments of the complex 1 Molecules 2018, 23, 1856 10 of 11
Possible fragments of the complex 2