Synthesis, molecular properties prediction and cytotoxic screening of 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones Angélica Faleiros da Silva Maia a , Raoni Pais Siqueira b , Fabrício Marques de Oliveira c , Joana Gasperazzo Ferreira b , Silma Francielle da Silva a , Clarice Alves Dale Caiuby a , Leandro Licursi de Oliveira d , Sérgio Oliveira de Paula d , Rafael Aparecido Carvalho Souza e , Silvana Guilardi e , Gustavo Costa Bressan b,⇑ , Róbson Ricardo Teixeira a,⇑ a Departamento de Química, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil b Departmento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil c Instituto Federal de Minas Gerais (IFMG), Campus Ouro Branco, Rua Afonso Sardinha, 90, Ouro Branco, MG 36420-000, Brazil d Departamento de Biologia Celular, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil e Instituto de Química, Universidade Federal de Uberlândia, Av. João Naves de Ávila, 2160-Bloco 1D, Santa Mônica, Uberlândia, MG 39400-902, Brazil article info Article history: Received 9 March 2016 Revised 21 April 2016 Accepted 22 April 2016 Available online 25 April 2016 Keywords: Isobenzofuran-1(3H)-one Phthalides 3-(2-Aryl-2-oxoethyl)isobenzofuran-1(3H)- ones Cytotoxicity abstract In the present investigation, a collection of nineteen 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones was synthesized and screened for their cytotoxic activity against a panel of three leukemia cancer cell lines. The compounds were prepared via ZrOCl 2 8H 2 O catalyzed condensation reactions between phthalaldehy- dic acid and different acetophenones. The reactions were carried out free of solvent and the isobenzofu- ran-1(3H)-ones were obtained in good yields (80–92%). The identities of the synthesized compounds were confirmed upon IR and NMR ( 1 H and 13 C) spectroscopy as well as high resolution mass spectrometry analyses. Structures of compounds 1, 4 and 16 were also investigated by X-ray analysis. The synthesized compounds were submitted to in vitro bioassays against HL-60, K562 and NALM6 cancer cell lines using MTT cytotoxicity assay. After 48 h of treatment, twelve derivatives were able to reduce cell viability and presented IC 50 values equal to or below 20 lmol L 1 against at least one of the evaluated lineages. The most active compound corresponded to 3-(3-methylphenyl-2-oxoethyl)isobenzofuran-1(3H)-one (18) (IC 50 values obtained for HL-60, K562 and NALM6 were, respectively, 13.5 lmol L 1 , 8.83 lmol L 1 , and 5.24 lmol L 1 ). In addition, compound 18 was capable of triggering apoptosis on NALM6 cells. All isoben- zofuranones herein evaluated did not present cytotoxicity on peripheral blood mononuclear cells (PBMC), suggesting selective cytotoxic effect on leukemic cells. A computational study allowed prediction of pharmacokinetics and drug-likeness properties of the synthesized compounds. DFT calculations were performed to obtain the energy values of HOMO, LUMO, and dipole moments of isobenzofuranones. Ó 2016 Elsevier Ltd. All rights reserved. Cancer is a worldwide disease that affects around fourteen mil- lion people every year. Moreover, at least eight million of deaths caused by this disease are estimated to occur annually. 1 Hemato- logical malignancies (leukemia or lymphoma) are the fourth most diagnosed cancer in adults (around 9% of the cases), but are responsible for around 50% of the cases in children younger than 15. 2,3 Although several chemotherapeutic regimes have been suc- cessfully approached for fighting cancer nowadays, the way on how patients respond to treatments is still a puzzle. Furthermore, most chemotherapies are associated with severe side-effects and cancer resistance, highlighting the necessity of a constant effort toward the development of novel therapies. 4 Heterocycles play an important role in several branches of chemistry. 5 A myriad of natural products possessing important biological activities are heterocyclic in nature. 6 The vast majority of agrochemicals and pharmaceuticals (approximately more than 70%) bears at least one heterocyclic ring. 7,8 In addition, several dyes (such as malveine), polymers, and luminophores have heterocyclic moieties. The isobenzofuran-1(3H)-ones, also known as phthalides, are a class of heterocycles presenting a benzene ring (I) fused to a c-lactone one (II) (Fig. 1). During the last decades several natural products containing this structural motif have been isolated and presenting important biological activities. 9 In particular, http://dx.doi.org/10.1016/j.bmcl.2016.04.065 0960-894X/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. Tel.: +55 31 3899 3209; fax: +55 31 3899 3065. E-mail addresses: gustavo.bressan@ufv.br (G.C. Bressan), robsonr.teixeira@ufv.br (R.R. Teixeira). Bioorganic & Medicinal Chemistry Letters 26 (2016) 2810–2816 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl