**4. Conclusions**

A series of 13 derivatives of 2,4,5-trisubstituted imidazole were synthesized and their structures were characterized and confirmed through a series of spectroscopic and spectrometric techniques. Their antioxidant activities were analyzed with DPPH radical-scavenging and ABTS radical cation scavenging assays. In DPPH, the most active compounds were **3** and **10** (EC50 of 0.141 and 0.174 mg/mL, respectively), bearing a *p*-OH and *p*-dimethylamino substitution in their A ring; in ABTS, the most active compounds were again **10** and **3** with an EC50 of 0.162 and 0.168 mg/mL, respectively. This suggests the important role of heteroatoms with a free pair of electrons and acid phenolic hydrogens, so future derivatives should maintain these characteristics for improved antioxidant activity.

In the enzymatic assays, though not as active as the controls, **1** showed the best activity in AChE inhibition with 25.8% of inhibition, followed by the nitro containing compounds **12** (22.4%) and **11** (21.2%). The most active XO inhibitor was **3**, with an IC50 of 85.8 μg/mL and a *p*-OH substitution. Present results point out that aromatic and positively charged groups are important for AChE inhibition activity, as the literature suggests. For XO inhibition, an oxygen in the *para* position appears to improve triphenyl imidazole derivatives activities, though an unexpected result for compound **12** suggests that future derivatives with nitrogen in the *ortho* position should be further explored.

The antiproliferative activity was evaluated against six cell lines from different anatomic origins, and the synthesized compounds showed from moderate to very good activities. Amongst the most active compounds were **2** (*o*-OH), **10** (*p*-N(CH3)2), and **11** (*p*-NO2), where the last was outstanding as it was the first or second most active against all of the evaluated cell lines. Further expansion of this family of derivatives could maintain a nitrogen in the *para* position of the A ring, as it appears this favors their antiproliferative activity, with additional structure modulations.

In the in silico analysis, the docking against the EGFR and HER2 receptors had the agreemen<sup>t</sup> of **11** being amongs<sup>t</sup> the two better binding affinities results. The ADME predictions of the 13 synthesized compounds showed that they are overall suitable for oral administration, with **11** and **12** having better pharmacokinetics and drug-likeness properties, which combined with their in vitro results point them as good candidates for being lead compounds in further derivations in the search of new drugs, especially as AChE inhibitors or as antiproliferative agents.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2076-3417/10/8/2889/s1, Figure S1: 1H-NMR Compound 2, Figure S2: 1H-NMR extension Compound 2, Figure S3: 13C-NMR Compound 2, Figure S4: 1H-NMR Compound 4, Figure S5: 13C-NMR Compound 4, Figure S6: 1H-NMR Compound 7, Figure S7: 13C-NMR Compound 7, Figure S8: 1H-NMR Compound 8, Figure S9: 13C-NMR Compound 8, Figure S10: 1H-NMR Compound 9, Figure S11: 13C-NMR Compound 9, Figure S12: 1H-NMR Compound 11, Figure S13: 13C-NMR Compound 11.

**Author Contributions:** Conceptualization, I.C.-G.; Methodology, E.N.-I., J.M.P., R.S.-A., D.C., L.D.-R., and V.W.B.-C.; Software, A.E.-C. and V.G.-G.; Formal analysis, E.N.-I. and R.A.C.-S.; Investigation, I.C.-G. and R.D.-M.; Writing—original draft preparation, E.N.-I. and I.C.-G.; Writing—review and editing, A.E.-C., R.A.C.-S., R.D.-M., and L.D.-R.; Supervision, I.C.-G. and L.D.-R.; Funding acquisition, V.G.-G. and R.D.-M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** We gratefully acknowledge the Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California for the financing given for the realization of this project. E.N.-I. acknowledges CONACYT for the doctoral fellowship. J.M.P. thanks the Spanish Government for financial support through project PGC2018-094503-B-C22 (MCIU/AEI/FEDER, UE).

**Conflicts of Interest:** The authors declare no conflict of interest.
