Metal (II) Complexes of Fluconazole: Thermal, XRD and Cytotoxicity Studies

Document Type : Research article

Authors

1 Department of Applied Chemistry and Chemical Technology, Faculty of Science, University of Karachi, Karachi-75270, Pakistan.

2 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA.

3 Department of Chemistry, Faculty of Science, University of Karachi, Karachi-75270, Pakistan.

4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Karachi, Karachi-75270, Pakistan.

5 Industrial Analytical Center (ICCBS), University of Karachi, Karachi-75270, Pakistan.

6 Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

7 Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

We report thermal, X-ray diffraction (XRD) and cytotoxicity studies of complexes of fluconazole (FCZ) with Cu (II), Fe(II), Cd(II), Co(II), Ni(II), and Mn(II). From XRD measurements, FCZ and its metal complexes were identified as polycrystalline. Marked differences in the X-ray patterns of drug and its metal complexes revealed that the complexes are indeed different compounds and not just the mixture of the starting materials. Unlike pristine FCZ, which did not exhibit cytotoxicity, three complexes derived from Fe(II), Cu(II) and Co (II) proved to be effective in the cytotoxicity assay. The Cu(II)-FCZ exhibited significant activity against SNB-19, HCT-15, COLO-205, and KB-3-1 cell lines, while Fe(II)-FCZ and Co(II)-FCZ were found cytotoxic only to KB-3-1 cell line. For the pure FCZ, thermogravimetry revealed massive weight loss in the temperature range of 215 to 297 °C, due to the volatilization of FCZ. All the complexes followed multi-stage degradation profiles, eventually resulting in the formation of metal oxides. For pure FCZ, differential scanning calorimetry revealed melting point at 137°C, followed by two further endothermic transitions at 294 °C and 498.44 °C representing the volatilization and subsequent degradation of FCZ, respectively. The absence of endothermic FCZ melting peak at around 137 °C indicates that the complexes represent different compounds. All complexes exhibit endothermic transitions at around 240-300 °C, representing melting and removal of ligand moiety, followed by another endothermic transition at around 498-499 °C, representing the ligand decomposition.

Graphical Abstract

Metal (II) Complexes of Fluconazole: Thermal, XRD and Cytotoxicity Studies

Keywords


(1)        Berber I, Cokmus C, and Atalan E. Characterization of Staphylococcus species by SDS–PAGE of whole-cell and extracellular proteins.Microbiology. (2003) 72: 42-47.
(2)        Harbarth S, Albrich W, Goldmann DA, and Huebner J. Control of multiply resistant cocci: do international comparisons help? The Lancet infectious diseases. (2001) 1: 251-61.
(3)        Mitscher LA, Pillai SP, Gentry EJ, and Shankel DM. Multiple drug resistance.Medicinal research reviews. (1999) 19: 477-96.
(4)        Pfaller M and Diekema D. Epidemiology of invasive candidiasis: a persistent public health problem.Clinical microbiology reviews. (2007) 20: 133-63.
(5)        Spampinato C and Leonardi D. Candida infections, causes, targets, and resistance mechanisms: traditional and alternative antifungal agents.BioMed research international. (2013) 2013.
(6)        Vandeputte P, Ferrari S, and Coste AT. Antifungal resistance and new strategies to control fungal infections.International journal of microbiology. (2011) 2012.
(7)        Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, and Vartivarian S. The epidemiology of hematogenous candidiasis caused by different Candida species.Clinical Infectious Diseases. (1997) 24: 1122-28.
(8)        Ables AZ, Blumer NA, Valainis GT, Godenick MT, Kajdasz DK, and Palesch YY. Fluconazole prophylaxis of severe Candida infection in trauma and postsurgical patients: a prospective, double-blind, randomized, placebo-controlled trial.Infectious Diseases in Clinical Practice. (2000) 9: 169-75.
(9)        Alexander BD, Schell WA, Miller JL, Long GD, and Perfect JR. Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole.Transplantation. (2005) 80: 868-71.
(10)      Sobel J. Pathogenesis and treatment of recurrent vulvovaginal candidiasis.Clinical Infectious Diseases. (1992) 14: S148-S53.
(11)      Vazquez JA and Sobel JD. Mucosal candidiasis.Infectious disease clinics of North America. (2002) 16: 793-820.
(12)      Kaufman DA. Prevention of invasive Candida infections in preterm infants: the time is now.Expert review of anti-infective therapy. (2008) 6: 393-99.
(13)      Tscherner M, Schwarzmüller T, and Kuchler K. Pathogenesis and antifungal drug resistance of the human fungal pathogen Candida glabrata.Pharmaceuticals. (2011) 4: 169-86.
(14)     Abranches P, Varejão E, da Silva C, de Fátima Â, Magalhães T, da Silva D, de Resende-Stoianoff M, Reis S, Nascimento C, and de Almeida W. Complexes of fluconazole with sodium p-sulfonatocalix [n] arenes: characterization, solubility and antifungal activity.RSC Advances. (2015) 5: 44317-25.
(15)      Charlier C, Hart E, Lefort A, Ribaud P, Dromer F, Denning D, and Lortholary O. Fluconazole for the management of invasive candidiasis: where do we stand after 15 years? Journal of Antimicrobial Chemotherapy. (2006) 57: 384-410.
(16)      Löffler J, Kelly SL, Hebart H, Schumacher U, Lass-Flörl C, and Einsele H. Molecular analysis of cyp51 from fluconazole-resistant Candida albicans strains.FEMS Microbiology Letters. (1997) 151: 263-68.
(17)      Sabatelli F, Patel R, Mann P, Mendrick C, Norris C, Hare R, Loebenberg D, Black T, and McNicholas P. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts.Antimicrobial Agents and Chemotherapy. (2006) 50: 2009-15.
(18)      Déry M and Hasbun R. Fluconazole-resistant Candida: mechanisms and risk factor identification.Current Fungal Infection Reports. (2011) 5: 23-28.
(19)      Arndt CA, Walsh TJ, McCully CL, Balis FM, Pizzo PA, and Poplack DG. Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system.The Journal of infectious diseases. (1988) 157: 178-80.
(20)      Brammer K, Farrow P, and Faulkner J. Pharmacokinetics and tissue penetration of fluconazole in humans.Reviews of infectious diseases. (1990) 12: S318-S26.
(21)      Oude Lashof A, Bock Rd, Herbrecht R, de Pauw B, Krcmery V, Aoun M, Akova M, Cohen J, Siffnerova H, and Egyed M. EORTC Invasive Fungal Infections Group. An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis. (2004).
(22)      Epstein JB, Gorsky M, and Caldwell J. Fluconazole mouthrinses for oral candidiasis in postirradiation, transplant, and other patients.Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. (2002) 93: 671-75.
(23)      Goins RA, Ascher D, Waecker N, Arnold J, and Moorefield E. Comparison of fluconazole and nystatin oral suspensions for treatment of oral candidiasis in infants.The Pediatric infectious disease journal. (2002) 21: 1165-67.
(24)      Lefebvre J-L and Domenge C. A comparative study of the efficacy and safety of fluconazole oral suspension and amphotericin B oral suspension in cancer patients with mucositis.Oral oncology. (2002) 38: 337-42.
(25)      Sholapurkar A, Pai KM, and Rao S. Comparison of efficacy of fluconazole mouthrinse and clotrimazole mouthpaint in the treatment of oral candidiasis.Australian dental journal. (2009) 54: 341-46.
(26)      Taillandier J, Esnault Y, and Alemanni M. A comparison of fluconazole oral suspension and amphotericin B oral suspension in older patients with oropharyngeal candidosis. Multicentre Study Group.Age and ageing. (2000) 29: 117-23.
(27)      Koks C, Crommentuyn K, Mathot R, Mulder J, Meenhorst P, and Beijnen J. Prognostic factors for the clinical effectiveness of fluconazole in the treatment of oral candidiasis in HIV-1-infected individuals.Pharmacological research. (2002) 46: 89-94.
(28)      Lyon JP and de Resende MA. Correlation between adhesion, enzyme production, and susceptibility to fluconazole in Candida albicans obtained from denture wearers.Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. (2006) 102: 632-38.
(29)      Meberg A, Langslet A, Søvde A, and Kolstad A. Candida‐septicemia with chorioretinitis, osteomyelitis and arthritis treated with systemic miconazole and intraarticular amphotericin B.Mycoses. (1977) 20: 257-60.
(30)      Tang C. Successful treatment of Candida albicans osteomyelitis with fluconazole.Journal of Infection. (1993) 26: 89-92.
(31)      Albengres E, Le Louët H, and Tillement J-P. Systemic antifungal agents.Drug safety. (1998) 18: 83-97.
(32)      Denning DW, Venkateswarlu K, Oakley KL, Anderson M, Manning N, Stevens DA, Warnock DW, and Kelly SL. Itraconazole resistance in Aspergillus fumigatus.Antimicrobial agents and chemotherapy. (1997) 41: 1364-68.
(33)      Hoffman HL, Ernst EJ, and Klepser ME. Novel triazole antifungal agents.Expert opinion on investigational drugs. (2000) 9: 593-605.
(34)      Livermore D. The need for new antibiotics.Clinical Microbiology and Infection. (2004) 10: 1-9.
(35)      Meis JF and Verweij PE. Current management of fungal infections.Drugs. (2001) 61: 13-25.
(36)      Franz R, Kelly SL, Lamb DC, Kelly DE, Ruhnke M, and Morschhäuser J. Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains.Antimicrobial Agents and Chemotherapy. (1998) 42: 3065-72.
(37)      Orozco AS, Higginbotham LM, Hitchcock CA, Parkinson T, Falconer D, Ibrahim AS, Ghannoum MA, and Filler SG. Mechanism of Fluconazole Resistance inCandida krusei.Antimicrobial agents and chemotherapy. (1998) 42: 2645-49.
(38)      Parkinson T, Falconer D, and Hitchcock C. Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata.Antimicrobial agents and chemotherapy. (1995) 39: 1696-99.
(39)      Redding SW, Kirkpatrick WR, Saville S, Coco BJ, White W, Fothergill A, Rinaldi M, Eng T, Patterson TF, and Lopez-Ribot J. Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation.Journal of clinical microbiology. (2003) 41: 619-22.
(40)      Ali M, Ahmed M, Ahmed S, Ali SI, Perveen S, Mumtaz M, Haider SM, and Nazim U. Fluconazole and its interaction with metal (II) complexes: SEM, Spectroscopic and antifungal studies.Pakistan Journal of Pharmaceutical Sciences. (2017) 30.
(41)      Zhang CX and Lippard SJ. New metal complexes as potential therapeutics.Current opinion in chemical biology. (2003) 7: 481-89.
(42)      Desai SR and Dharwadkar SR. Study of process induced polymorphic transformations in fluconazole drug.microscopy (SEM). (2009) 7: 9.
(43)      Al-Saif FA and Refat MS. Synthesis, spectroscopic, and thermal investigation of transition and non-transition complexes of metformin as potential insulin-mimetic agents.Journal of thermal analysis and calorimetry. (2013) 111: 2079-96.
(44)      Zhou C-H, Zhang Y-Y, Yan C-Y, Wan K, Gan L-L, and Shi Y. Recent researches in metal supramolecular complexes as anticancer agents.Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). (2010) 10: 371-95.
(45)      Moura EA, Correia LP, Pinto MF, Procópio JVV, de Souza FS, and Macedo RO. Thermal characterization of the solid state and raw material fluconazole by thermal analysis and pyrolysis coupled to GC/MS.Journal of thermal analysis and calorimetry. (2010) 100: 289-93.
(46)      Park HJ, Kim M-S, Lee S, Kim J-S, Woo J-S, Park J-S, and Hwang S-J. Recrystallization of fluconazole using the supercritical antisolvent (SAS) process.International journal of pharmaceutics. (2007) 328: 152-60.
(47)      Caira MR, Alkhamis KA, and Obaidat RM. Preparation and crystal characterization of a polymorph, a monohydrate, and an ethyl acetate solvate of the antifungal fluconazole.Journal of pharmaceutical sciences. (2004) 93: 601-11.
(48)      Herchel R, Šindelář Z, Trávníček Z, Zbořil R, and Vančo J. Novel 1D chain Fe (III)-salen-like complexes involving anionic heterocyclic N-donor ligands. Synthesis, X-ray structure, magnetic, 57Fe Mössbauer, and biological activity studies.Dalton Transactions. (2009): 9870-80.
(49)      Li S-L, Lan Y-Q, Ma J-F, Yang J, Wang X-H, and Su Z-M. Syntheses and Structures of Organic− Inorganic Hybrid Compounds Based on Metal− Fluconazole Coordination Polymers and the β-Mo8O26 Anion.Inorganic chemistry. (2007) 46: 8283-90.
(50)      Pansuriya PB and Patel MN. Synthesis, characterization and biological aspects of novel five-coordinated dimeric-Cu (II) systems.Journal of enzyme inhibition and medicinal chemistry. (2008) 23: 108-19.
(51)      Ren Y, Zhang L, Zhou C-H, and Geng R. Recent development of benzotriazole-based medicinal drugs.Med chem. (2014) 4: 640-62.