Evaluation of the biological effects of 5-Cl-8-oxyquinolinepropoxycalix [4]arene and 8-oxyquinolinepropoxycalix[4]arene in vitro and in vivo Marcos N. Soares Jr. a , Thais M. Gáscon b , Fernando L.A. Fonseca a,b , Karen S. Ferreira a , Izilda A. Bagatin a, ⁎ a Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua Prof. Arthur Riedel, 275, CEP 09972-270, Diadema, SP, Brazil b Fundação do ABC, Faculdade de Medicina, Av. Príncipe de Gales, 821, CEP 09060-650, Santo André, SP, Brazil abstract article info Article history: Received 2 September 2013 Received in revised form 15 February 2014 Accepted 3 April 2014 Available online 13 April 2014 Keywords: Calix[4]arene 8-Hydroxiquinoline Fungicidal activity Cytotoxicity effect Iron depletion The development of antibacterial and antifungal drugs has been the target of several pharmaceutical and chemical industries mainly due to the lack of effective drugs with low or no side effect. In this work, studies were conducted both in vitro and in vivo with 8-oxyquinolinepropoxycalix[4]arene (A) and 5-Cl-8- oxyquinolinepropoxycalix[4]arene (B) ligands, showing fairly good results. Cytotoxicity and fungicidal actions of compounds A and B were determined in Wistar male rats and peritoneal macrophages of mice. A slight change in the total of leukocytes and erythrocytes was observed on the hematologic assays, showing almost no inflammation after using both compounds in Wistar male rats. We have also noted some, but not signif- icant, alteration in liver enzymes representing modest hepatotoxicity. Cytotoxicity of peritoneal macro- phages, in the presence of compound A or B, showed 50% of survival of macrophages. On the other hand, macrophages previously infected with Candida albicans and treated with substance A or B exhibited an in- creased cytokine IL-10 at 24 h incubation. By checking the effect of substance A or B on growing C. albicans, the results pointed that these substances revealed antifungal activity against C. albicans, in 24 h culture with a reduction of yeast cells. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Since the discovery that specific metals are dynamic constituents of many enzymes and pharmacological agents, several chelating agents have been studied towards metallic ions such as Fe, Mg, Co, and V with special interest in biological systems [1]. For instance, increasing studies with chelators have been performed considering the demand for iron in cell proliferation and the problems of excess iron that can cause an increase in DNA synthesis, resulting in the development of cells in tumors and other pathologies [2]. The use of 8-hydroxiquinoline (8HQ) as a chelator for iron is well known and has awakened great interest from the time when 8HQ and its derivatives showed antimicrobial activity. Moreover, studies have shown that 8HQ and derivatives suppress the advancement of melano- ma tumors and leukemia [1]. Results of Mannich bases of 8HQ, such as 7-pyrrolidinomethyl-8-hydroxiquinoline, suggest that cytotoxic effects on myeloma cells could be related to blockage of voltage-activated K + channels [3]. Furthermore, this knowledge that 8-hydroxyquinoline is a strong iron chelator with antioxidant properties has led some scholars to propose its use as drug candidates for the treatment and/or prevention of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. [4]. Recently, intense research has been developed involving calixarenes in a biological content; for example, calixarenes with anti-thrombotic activity [5], bactericidal activity against M. tuberculosis [6], trypanocidal activity [7], antitumor agent [8], anti-mycobacterial activities [9], and through antioxidant and antimicrobial activities [10]. Despite the increased number of studies of drugs with anticancer or bacterial potential, the market is highly deficient with potential antifun- gal drugs requiring investments in this segment. Our group has been studying the physico-chemical properties of modified 8-hydroxyquinoline. Studies on the incorporation of 8- hydroxyquinoline or 5-Cl-8-hydroxyquinoline to calixarene identi- fy this ligand as a good binder for transition metals and hazardous metal ions [11], besides presenting high chemical and thermal stability [12]. Based on the abovementioned, the aim of this study was to develop new compounds with potential antimicrobial or antifungal activities, which could be used as drug candidates for the treatment of fungi dis- eases. For this purpose, in this work, studies of the biological applica- tions of these ligands (A and B—Scheme 1) have shown good results in the outline of (i) cytotoxic activity, (ii) hematologic and biochemical analyses in blood of rats, (iii) cell viability in macrophages and (iv) its fungicidal ability. Materials Science and Engineering C 40 (2014) 260–266 ⁎ Corresponding author at: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua Prof. Arthur Riedel, 275, CEP 09972-270, Diadema, SP, Brazil. Tel.: +55 11 3319 3472; fax: +55 11 4043 6428. E-mail addresses: ibagatin@unifesp.br, ibagatin@gmail.com (I.A. Bagatin). http://dx.doi.org/10.1016/j.msec.2014.04.002 0928-4931/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec