Med Chem Res DOI 10.1007/s00044-016-1688-6 MEDICINAL CHEMISTR Y RESEARCH ORIGINAL RESEARCH Synthesis and cytotoxic evaluation of 7-chloro-4-phenoxyquinolines with formyl, oxime and thiosemicarbazone scaffolds Vladimir V. Kouznetsov 1 ● Felipe Sojo 2,3 ● Fernando A. Rojas-Ruiz 1,4 ● Diego R. Merchan-Arenas 4 ● Francisco Arvelo 2,3 Received: 19 February 2016 / Accepted: 8 July 2016 © Springer Science+Business Media New York 2016 Abstract New 7-chloro-4-phenoxyquinoline derivatives bearing formyl, oxime and thiosemicarbazone functional groups were easily prepared using 4,7-dichloroquinoline and functionalized phenols as inexpensive and commer- cially available starting materials. Their chemical structures were confirmed by use of infrared and 1 H, 13 C nuclear magnetic resonance experiments. All the synthesized com- pounds were evaluated for their cytotoxicity against the cell lines MCF-7, SKBR-3, PC3, HeLa and human dermis fibroblast as non-tumor cells, in vitro using the 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) for assay. The quinoline derivatives 3a and 3d resulted as promising models for antitumor drugs, display- ing good cytotoxic activity against four human cancer cell lines (9.18 μM < IC 50 < 50.75 μM). The phenoxyquinoline 3d stands out by its low unspecific cytotoxicity and high selectivity on tumor lines SKBR-3, HeLa and PC3 cells. Keywords 7-Chloro-4-phenoxyquinoline ● Lipinski’s rule ● OSIRIS software ● In vitro antitumor and cytotoxic analysis Introduction New leads with anticancer potential are needed urgently since anticancer drugs used in clinics are commonly highly toxic and non-selective molecules. In addition, the resistance inci- dence for some chemotherapeutic agents has become remarkable in recent decades. In this sense, the design of more selective and safer anticancer agents stands out as an actual and vital task. Quinolines and their derivatives have shown to display a wide spectrum of biological activities. Quinoline nucleus is generally present in a large number of synthetic and natural molecules with relevant parasites growth inhibition properties. Moreover, different examples have revealed their potent anticancer activity (Afzal et al., 2015; Arafa et al., 2013; Zhao et al., 2005). Currently, quinoline derivatives are available as antimalarial (chloroquine, mefloquine, amodia- quinine, primaquine, etc.), antibacterial (ciprofloxacin, spar- foxacin, gatifloxacin, etc.) or anticancer drugs (camptothecin, irinotecan, topotecan, etc.). Hydroxyquinoline scaffolds also play an important role in anticancer drug development, as their derivatives have shown excellent results through differ- ent mechanism of action such as growth inhibitors by cell cycle arrest, apoptosis and inhibition of angiogenesis or cell migration disruption. Lenvatinib (A) and cabozantinib (B) are anticancer drugs based on the C-4 substituted aryl oxyquinoline skeleton while experimental anticancer drug * Vladimir V. Kouznetsov kouznet@uis.edu.co vkuznechnik@gmail.com Francisco Arvelo franarvelo@yahoo.com 1 Laboratorio de Química Orgánica y Biomolecular, Universidad Industrial de Santander, Parque Tecnologico Guatiguara, Km 2 vía refugio, Piedecuesta, A.A 681011, Colombia 2 Centro de Biociencias Fundación Instituto de Estudios Avanzados- IDEA, Caracas, , Venezuela 3 Laboratorio de Cultivo de Tejidos y Biología de Tumores, Instituto de Biología Experimental, Universidad Central de Venezuela, código postal 1041, Caracas, Venezuela 4 Grupo de Investigación e Innovación en Básicas, Universidad Manuela Beltrán, Calle de los Estudiantes 10-20 Ciudadela Real de Minas, Código Postal, Bucaramanga 680005, Colombia Electronic supplementary material The online version of this article (doi:10.1007/s00044-016-1688-6) contains supplementary material, which is available to authorized users.