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Continuing with a program to develop new quinone derivatives as biologically active compounds, we designed and synthesized a new series of aryloxy‐quinones, which were evaluated in vitro against Trypanosoma cruzi in epimastigote form. Chemical modifications in three specific moieties on the aryloxy‐quinone core were considered for developing new anti‐T. cruzi agents. The majority of our new quinones showed higher potency (IC50 values of <0.70 µM) than nifurtimox, a known pharmaceutical used as a baseline drug (IC50 values of 7.00 µM); however, only two of them elicited higher selectivity than nifurtimox against Vero cells. A structure–activity relationship analysis provided information about the stereoelectronic features of these compounds, which are responsible for an increase in trypanosomicidal activity. Using a pharmacophore model, we mapped the substitution patterns of the five pharmacophoric features of trypanosomicidal activity. We chose the Epc1 compounds and found no relationship with the trypanosomicidal effects. These results provided useful information about the structural characteristics for developing new aryloxy‐quinones with higher potency against the protozoan parasite T. cruzi.

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A set of new aryloxy-quinones were synthesized and evaluated in vitro against the epimastigote form of Trypanosoma cruzi and their unspecific cytotoxicity was tested on murine macrophages J-774 cells.Most of these novel compounds were found to be extremely more potent and selective than the standard drug nifurtimox. Interestingly, 2-phenoxy-naphthoquinone 3b displayed a remarkable nanomolar inhibitory activity, IC 50 = 20 nM, and a high selectivity index, SI = 625. The E pc1 was determined for the most interesting compounds and no correlation with the trypanosomicidal effect was found. Therefore, an in silico study was carried out to obtain a pharmacophoric model and quantitative structure-trypanosomicidal activity relationship. The designed pharmacophore recognized the more potent and selective molecules, exhibiting five pharmacophoric features. A correlation coefficient R 2 of 0.99 of pIC 50 plotted against the predicted values indicated that the 3D-QSAR equation could be applied to further predictions of newly designed trypanosomicidal compounds. 5 5a,b with nitric acid. 23 The reaction of 6a and 6b with the phenols 2a-c or naphthols 2d,e furnished regiospecifically the corresponding 7-aryloxy-quinoline-5,8-dione derivatives 7a-i (24-92% yield).Scheme 2. Synthesis of compounds of series II (7a-i). Reagents and conditions: (i) Br 2 , MeOH, rt, 5 min; (ii) HNO 3 , H 2 SO 4 , 0 °C, 30 min; 23 (iii) K 2 CO 3 , 2a-e, DMF, rt, 3-5 h.Scheme 3. Synthesis of compounds of series III (11a-i). Reagents and conditions: (i) Br 2 , CHCl 3 , rt, 1.5 h; (ii) CrO 3 , H 2 O/AcOH, rt, 2 h; (iii) K 2 CO 3 , DMF, 2a-e, rt, 2 h.

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