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Symmetrical and unsymmetrical substituted 2,5-diarylidene cyclohexanones as anti-parasitic compounds

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Din, Z. U., Almeida-Trapp, M., de Medeiros, L. S., Lazarin-Bidoia, D., Garcia, F. P., Peron, F., et al. (2018). Symmetrical and unsymmetrical substituted 2,5-diarylidene cyclohexanones as anti-parasitic compounds. European Journal of Medicinal Chemistry, 155, 596-608. doi:10.1016/j.ejmech.2018.06.031.

Symmetrical and unsymmetrical bis-aryl-a,b-unsaturated ketones were synthesized in moderate to excellent yield by treating cyclohexanone with various aldehydes. Dimethylammonium dimethylcarbamate (DIMCARB) was used as both catalyst and reaction medium for the synthesis of monoarylidenes cycloadduct intermediates, which was further used to produce diarylidene cyclohexanones. All the 34 compounds synthesized were evaluated for their anti-proliferative activity, particularly against promastigote of Leishmania amazonensis, epimastigoteand trypomastigoteof Trypanosoma cruzi. Eighteen compounds displayed anti-leishmanial activity against promastigotes of L. amazonensis with IC50 values ranging from 2.8 to 10 mM. In addition, two compounds exhibited significant antitrypanosomal activity against epimastigotes of T. cruzi with IC50 values of 5.2 ± 0.8 and 3.0 ± 0.0 mM, while five compounds exhibited activity from 15.0 ± 1.4 to 30.2 ± 1.8 mM against trypomastigote of T. cruzi. Moreover, all compounds were more selective against the parasites than the epithelial cells. The unsymmetrical compounds 16, 28, 30 and 33 can be considered as favorable anti-parasitic lead molecule having IC50 and EC50 values in the low-micromolar range, better than the reference drug benznidazole, and low cytotoxicity against Vero cells. The potent compounds were screened in silico against 17 enzymes of T. cruzi and best scoring were found against Dihydroorotate Dehydrogenase.