Benzophenones display several biological activities, including antioxidant, anticancer, and photoprotective. Furthermore, antioxidants can minimize both ultraviolet absorption and tumor development. In the present investigation, a series of twenty-six 1,2,3-triazole-benzophenone derivatives were synthesized and had their antioxidant, anticancer, and photoprotective effects evaluated. For the compounds synthesis, 4,4’-dihydroxybenzophenone (1a) and 2,4-dihydroxybenzophenone (1b) were propargylated, affording the alkynes bis(4-(prop-2-yn1-yloxy))benzophenone (2a) and (2-hydroxy-4-(prop-2-yn-1-yloxy))benzophenone (2b), respectively. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between the compounds 2a/2b and several benzyl azides gave the 1,2,3-triazole-benzophenone derivatives with yields ranging from 35 to 95%. The 1,2,3-triazole-benzophenone derivatives at the concentration of 0.2 μg mL−1 (a no-cytotoxic concentration) exhibited a solar protection factor (SPF) comparable to positive control benzophonen-3 (BP-3). Concerning their antioxidant and cytotoxic effects, the derivatives from 1b showed high in vitro antioxidant effects as well as cytotoxicity against A549 (lung carcinoma), MCF-7 (breast carcinoma), and HT-144 (metastatic melanoma) cell lines, without significant cytotoxicity to a non-cancerous cell line. Derivatives 19, 20, and 24 induced cell death and cell cycle arrest at G1/S in HT-144 melanoma cells.

The present investigation describes the synthesis of a series of novel triazole derivatives from 4,4'-dihydroxybenzophenone along with their elastase inhibitory activity. The 1,2,3-triazoles were obtained via the copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC), also known as click reaction, between bis(4-(prop-2-yn-1-yloxy))benzophenone and several benzyl azides. It was found that five derivatives exhibited significant inhibitory effects, presenting half maximal inhibitory concentration (IC 50 ) values in the range of 16.6 to 72.1 µM. The most active compound, namely bis(4-(1-(4-iodobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzophenone (IC 50 = 16.6 ± 1.9 µM), was found to bind to elastase with the inhibition constant (K i ) of 11.12 µM, thereby illustrating competitive inhibitory behavior. Further, docking investigations provided insights on the possible binding mode of the most active compound with the elastase.Keywords: elastase, serine protease, CuAAC reaction, benzophenone, 1,2,3-triazole IntroductionBenzophenones are of chemical, medicinal, and industrial interest.1 Several of their derivatives exhibit important biological activities like anticancer, 2,3 antiviral on HIV, 4 antibacterial, 5 activity against Alzheimer's disease, 6 and anti-inflammatory. 7The anti-inflammatory action of benzophenones is well documented in the literature. 8 For instance, ketoprofen is an example of synthetic benzophenone that has been commercialized as an anti-inflammatory drug. Recently, studies have demonstrated that structural modifications carried out on this drug afforded substances with improved anti-inflammatory activity. 9 Miyano et al. 10 synthesized a series of 4-(acyloxy)benzophenones and 4,4'-bis(acyloxy) benzophenones and evaluated their anti-inflammatory activity using human neutrophil elastase (HNE) as a template. The derivatives 4-(pivaloyloxy)benzophenone and 4-(isobutyryloxy)benzophenone showed elastase inhibitory activity with half maximal inhibitory concentration (IC 50 ) of 0.62 and 0.25 µM, respectively. It was found that 4,4'-bis(acyloxy)benzophenones were more potent than the corresponding 4-(acyloxy)benzophenones, highlighting 4,4'-bis(2,2-dimethylpropanoate)benzophenone with IC 50 = 0.12 µM and inhibition constant (K i ) = 7.1 × 10 -8 M.10 Serine proteases are involved in different branches of the immune system and play an important role in inflammation. In a recent investigation from our research group, Martins et al. 11 reported in vitro inhibition of serine proteases by synthetic and natural benzophenones, which showed moderate to high inhibitory effects against all the enzymes. Guttiferone A displayed IC 50 of 2.7 ± 0.1 µM, a value similar to the IC 50 of chymostatin (2.1 ± 0.1 µM), a classical inhibitor of serine protease cathepsin G. Braz. Chem. Soc. 98 Molecular hybridization has been shown to be a promising strategy for obtaining new compounds. It is mainly based on the combination of two or more known bioactive pharmacophoric fragments, by appropriate fusion, into a sing...