**1. Introduction**

Imidazole (1,3-diaza-2,4-cyclopentadiene) is a heterocyclic aromatic compound that can be found in many biological molecules such as histidine, histamine, or in natural nucleotides. It is a highly versatile pharmacophore; therefore, there are several reports of a wide range of biological activities in molecules containing an imidazole motif such as antifungal, antituberculosis, antibiotic, cytotoxic, anti-inflammatory, antioxidant, and analgesic, amongs<sup>t</sup> many others [1–4].

Imidazole derivatives, being di-, tri-, and tetra-substituted, have shown antioxidant activity through di fferent antioxidant methodologies [5–7]. This is a useful property to counteract oxidative stress, a condition when reactive oxygen species (ROS) overcome the natural cellular antioxidant defense system. As the aging process, along with several chronic and degenerative human diseases, have been linked to oxidative stress such as cardiovascular, neurodegenerative, and cancerous ones [8,9], compounds with antioxidant properties are of high interest for researchers.

One of the neurodegenerative diseases in which oxidative stress has been regarded as one of the underlying causes is Alzheimer's disease (AD) [10], being that this disease is the most frequent cause of dementia in elderly people [11]. As the cholinergic deficit is heavily related to the disease progression, inhibitors of the enzyme acetylcholinesterase (AChEI) are potential drugs for the treatment of AD patients [12]. Imidazole bearing molecules have been also evaluated as AChEI with interesting results [13].

Xanthine oxidase (XO) is a key enzyme in purine metabolism, and is involved in uric acid production as the final metabolite. High production of uric acid can lead to gout; therefore, inhibition of this enzyme has been targeted as a therapeutic approach, with imidazole having been employed for a long time as a sca ffold for XO inhibitors [14]. As the activity of XO produces both uric acid and reactive oxygen species, a XO inhibitor with antioxidant properties could show a good therapeutic profile, inhibiting the enzyme and controlling the oxidative damage to tissues near it [14,15].

The literature has shown numerous imidazole derivatives with tri-substitutions, of both alkyl and aryl types, with the aryl types frequently heterocyclic in nature. In a broad sense, in recent years, trisubstituted imidazoles have been synthesized many times, providing new synthetic methodologic alternatives, or in the search of particular biological properties [4]. Alternatively, this article proposes a group of trisubstitutions, where only small variations are introduced in one of them, to conduct a more finely-detailed structure–activity relationship (SAR) of the biological assays performed.

Based on the broad literature for the biological activities of imidazole derivatives and the above-mentioned SAR strategy, in this work, we present the synthesis of 2,4,5-triphenylimidazoles with substitutions in their A ring to perform an initial screening of their activities as antiproliferative, antioxidant, AChE, and XO inhibitor compounds, in order to find new leaders with these biological profiles. To complement the in vitro evaluations, molecular docking and in silico analysis of their ADME properties was made to select the best candidates and set the path for studies on new drug families.

### **2. Materials and Methods**
