In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents Cristina Fonseca-Berzal a,b,⇑ , Fernando A. Rojas Ruiz c , José A. Escario a,b , Vladimir V. Kouznetsov c , Alicia Gómez-Barrio a,b a CEI Campus Moncloa, UCM-UPM & CSIC, Madrid, Spain b Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain c Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, A.A. 678 Bucaramanga, Colombia article info Article history: Received 18 November 2013 Revised 17 December 2013 Accepted 18 December 2013 Available online 9 January 2014 Keywords: Trypanosoma cruzi Chloroquinoline derivatives Cytotoxicity Lipinski’s rule OSIRIS software abstract In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI 7 , SI 3 , SI 12 and SI BZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI = 12.73). These results, supported by the in silico prediction of a good oral bio- availability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential tem- plate for designing trypanocidal prototypes. Ó 2014 Elsevier Ltd. All rights reserved. Although more than a century has elapsed since the discovery of Chagas disease (American trypanosomiasis), the etiological treatment of a neglected tropical disease that is currently endemic in poor rural areas of 21 countries along Central and South America is still unsatisfactory. 1 The parasitic illness caused by the hemofla- gellate Trypanosoma cruzi and endemically transmitted by triato- mine vectors, has in the last years emerged in non-endemic countries outside Latin America since the increase of international migrations and the existence of non-vectorial mechanisms of transmission (e.g., congenital route), 2,3 infecting this way about 10 million people worldwide. 1 Focusing on the chemotherapy, nif- urtimox (a 5-nitrofuran) and benznidazole (a 2-nitroimidazole), the only two drugs up to now commercialized for the specific treatment of Chagas disease, were introduced more than forty years ago and their accessibility to patients has been discontinued through this time. 4 Although they are effective in the early stages of the trypanosomiasis, both display a limited activity during the chronic infection. 5 Moreover, the toxicity associated to these drugs 6 and the existence of T. cruzi strains naturally resistant to them, 7 also hinder the effectiveness of these treatments. The epi- demiological data, together with the lack of either a suitable che- motherapy or a vaccine, supports the priority in the development of new prototypes of anti-T. cruzi agents. In the present work, a first series of 16 different 7-chloroquino- line molecules substituted at the C-4 position by either benzyl- amino fragment or N-(aminoalkyl)-1,3-thiazolidin-4-one moiety, previously synthesized and tested against Plasmodium falciparum, 8 has been evaluated as potential antichagasic compounds according to the trypanocidal activity exhibited by some thiazolidine deriva- tives 9,10 and diverse aminoquinolines. 11,12 Concretely, the biologi- cal properties associated to the substituted 1,3-thiazolidin-4-ones have led to the introduction of this structure whether in several antimicrobial agents 13 as well as in trypanocidal prototypes with promising in vitro activity. 14,15 Nevertheless, data of neither 7- chloroquinoline-thiazolidinone derivatives (called chloroquine hy- brids) nor other 4-arylaminomethylquinolines tested on T. cruzi models have been found in literature. Likewise, a second series of 4-aryloxy-7-chloroquinoline molecules 16 also assessed as antima- larial drug prototypes (data not published), has been in vitro eval- uated as potential trypanocidal agents. Both series of compounds were synthesized by employing straightforward and efficient procedures. 8,16 Benzylamino or aryloxy fragments were connected to the 4,7-chloroquinoline ring (DCQ) by nucleophilic substitution S N Ar using commercial benzyl- amines or substituted phenols to give compounds 1–4 and com- pounds 17–22, respectively. Chloroquinoline–thiazolidinone hybrids 5–16 were assembled via a synthetic two-step protocol that includes the preparation of diamines based on DCQ ring through nucleophilic substitution of DCQ and a,x-diaminoalkanes 0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.12.071 ⇑ Corresponding author. Tel.: +34 913941818; fax: +34 3941815. E-mail address: crfonseca@pdi.ucm.es (C. Fonseca-Berzal). Bioorganic & Medicinal Chemistry Letters 24 (2014) 1209–1213 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl