Computer-aided drug design supporting sunscreen research: a showcase study using previously synthesized hybrid UV filter-antioxidant compounds.

CONTEXT: Although quantum mechanical calculations have proven effective in accurately predicting UV absorption and assessing the antioxidant potential of compounds, the utilization of computer-aided drug design (CADD) to support sustainable synthesis research of new sunscreen active ingredients remains an area with limited exploration. Furthermore, there are ongoing concerns about the safety and effectiveness of existing sunscreens. Therefore, it remains crucial to investigate photoprotection mechanisms and develop enhanced strategies for mitigating the harmful effects of UVR exposure, improving both the safety and efficacy of sunscreen products. A previous study conducted synthesis research on eight novel hybrid compounds (I-VIII) for use in sunscreen products by molecular hybridization of trans-resveratrol (RESV), avobenzone (AVO), and octinoxate (OMC). Herein, time-dependent density functional theory (TD-DFT) calculations performed in the gas phase on the isolated hybrid compounds (I-VIII) proved to reproduce the experimental UV absorption. Resveratrol-avobenzone structure-based hybrids (I-IV) present absorption maxima in the UVB range with slight differences between them, while resveratrol-OMC structure-based hybrids (V-VIII) showed main absorption in the UVA range. Among RESV-OMC hybrids, compounds V and VI exhibited higher UV absorption intensity, and compound VIII stood out for its broad-spectrum coverage in our simulations. Furthermore, both in silico and in vitro analyses revealed that compounds VII and VIII exhibited the highest antioxidant activity, with compound I emerging as the most reactive antioxidant within RESV-AVO hybrids. The study suggests a preference for the hydrogen atom transfer (HAT) mechanism over single-electron transfer followed by proton transfer (SET-PT) in the gas phase. With a strong focus on sustainability, this approach reduces costs and minimizes effluent production in synthesis research, promoting the eco-friendly development of new sunscreen active ingredients. METHODS: The SPARTAN'20 program was utilized for the geometry optimization and energy calculations of all compounds. Conformer distribution analysis was performed using the Merck molecular force field 94 (MMFF94), and geometry optimization was carried out using the parametric method 6 (PM6) followed by density functional theory (DFT/B3LYP/6-31G(d)). The antioxidant behavior of the hybrid compounds (I-VIII) was determined using the highest occupied molecular orbital (εHOMO) and the lowest unoccupied molecular orbital (εLUMO) energies, as well as the bond dissociation enthalpy (BDE), ionization potential (IP), and proton dissociation enthalpy (PDE) values, all calculated at the same level of structural optimization. TD-DFT study is carried out to calculate the excitation energy using the B3LYP functional with the 6-31G(d) basis set. The calculated transitions were convoluted with a Gaussian profile using the Gabedit program.

Unlocking hot trub's potential: a simple method for extracting bitter acids and xanthohumol.

BACKGROUND: Hot trub is a macronutrient- and micronutrient-rich by-product generated in the brewing industry, which is still underrated as a raw material for reprocessing purposes. In this context, this study aimed to investigate the extraction of bitter acids' and xanthohumol from hot trub as well as identify the significance of parameters for the process. The research assessed various extraction parameters, such as pH, ethanol concentration, temperature, and solid-to-liquid ratio, using a Plackett-Burman design. RESULTS: Ethanol concentration and pH were the most significant parameters affecting extraction yield. ß-acids were found to be the principal components of the bitter acids, with a maximum concentration near 16 mg g-1, followed by iso-α-acids and α-acids achieving 6 and 3.6 mg g-1, respectively. The highest yields of bitter acids were observed in the highest ethanol concentration, while pH was relevant to extraction process in treatments with low ethanol ratios. Concerning the xanthohumol extraction, the approach achieved maximum concentration (239 µg g-1) in treatments with ethanol concentration above 30%. Despite their variances, the phytochemicals exhibited comparable extraction patterns, indicating similar interactions with macromolecules. Moreover, the characterization of the solid residues demonstrated that the extraction process did not bring about any alterations to the chemical and total protein profiles. CONCLUSION: Ethanol concentration was found to have the most significant impact on the extraction of bitter acids and xanthohumol, while temperature had no significant effect. The solid remains resulting from the extraction showed potential for use as a protein source. © 2024 Society of Chemical Industry.

Using ordered mesoporous silica SBA-15 to limit cutaneous penetration and transdermal permeation of organic UV filters.

Avobenzone (AVO), oxybenzone (OXY), and octyl methoxycinnamate (OMC), are widely used UV filters. The aim of this study was to investigate the effect of incorporation in mesoporous silica (SBA-15) on their cutaneous deposition and permeation. Stick formulations containing "free" and "incorporated" UV filters (SF1 and SF2, respectively) were prepared and characterized with respect to their physicochemical, thermal, and functional properties. Cutaneous delivery experiments using porcine skin with quantification by UHPLC-MS/MS, demonstrated that skin deposition of AVO and OXY after application of SF2 for 6 and 12 h was significantly lower than that from SF1 at each time-point (Student t-test, p < 0.05): e.g. OXY permeation across the skin was 30-, 12- and 1.5-fold lower after 6, 12 and 24 h, respectively, following application of SF2. Cutaneous biodistribution profiles of AVO and OXY to 800 µm evidenced a significant decrease in the amounts in the viable epidermis and dermis. In contrast, deposition of the more lipophilic OMC was not significantly different (p ˃ 0.05). In vitro photoprotective efficacy results demonstrated that adsorption/entrapment of UV filters enhanced the sun protection factor by 94%. In conclusion, SBA-15, an innovative mesoporous material, increased photoprotection by UV filters while reducing their cutaneous penetration and transdermal permeation.

SPF enhancement provided by rutin in a multifunctional sunscreen.

Unprotected chronic exposure to solar radiation can contribute to premature skin cancer and sunscreens are a key factor to avoid those detrimental effects. Currently, there is a growing interest in the photoprotector and antioxidant potential of bioactive substances, such as rutin, that could increase the sun protection factor (SPF) value and, also, donate multifunctional characteristics to sunscreens. Recent in vitro findings indicated that rutin, when incorporated into sunscreens, can provide antioxidant activity and SPF improvement. However, clinical studies are fundamental to determine this activity, due to the lack of repeatability of in vitro methodology and low correlation with the in vivo data. We aimed at evaluating the clinical safety and in vivo SPF of rutin by comparing sunscreen formulations containing 0.1% (w/w) rutin, 3.0% (w/w) butyl methoxydibenzoylmethane and 8.0% (w/w) octyl dimethyl PABA (2-ethylhexyl 4-(dimethylamino)benzoato) with a similar bioactive-free preparation. Additionally, skin hydration, in vitro SPF and in vitro antioxidant activity of rutin, in association with the ultraviolet (UV) filters, were investigated. The safety profile of the formulations under sun-exposed skin conditions qualified the formulas for clinical efficacy assays. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) test confirmed the antioxidant properties of rutin, revealing around 40% increase in radical scavenging potential when the bioactive compound was present. Rutin in combination with the UV filters robustly elevated the clinical SPF around 70%, when compared with the bioactive-free formulation. To date, this is the first report in the specialized literature of an in vivo SPF measurement of a rutin-containing photoprotective preparation, supporting the claim that rutin is an effective and safe bioactive compound to be used in multifunctional sunscreens.

Diethylamino hydroxybenzoyl hexyl benzoate (DHHB) as additive to the UV filter avobenzone in cosmetic sunscreen formulations - Evaluation of the photochemical behavior and photostabilizing effect.

The aim of the present study was to investigate the photochemical behavior of DHHB and its photostabilizing effect on avobenzone (AVO) in different sunscreen formulations. The formulations were subjected to photostability studies by HPLC and spectrophotometry. In vitro phototoxicity was assessed using 3T3 fibroblast cultures. The mechanism of interaction between DHHB and AVO was investigated by steady state and time-resolved fluorescence spectroscopy. All formulations provided ultra-protection against UVA radiation. HPLC results demonstrated that DHHB did not present a photostabilizing effect on AVO. Fluorescence spectroscopy showed that AVO and DHHB interact by a static quenching mechanism and DHHB did not affect the AVO excited state lifetime. In addition, the energy transfer by Förster mechanism (FRET), which is the most often mechanism responsible for singlet-singlet quenching, is unlikely in this work. These results suggest why DHHB did not work as a photostabilizer on AVO singlet excited state. Phototoxicity results demonstrated that combinations containing DHHB (C2) did not show a phototoxic potential. Finally, although DHHB was considered to be photostable for all formulations studied (F2 and F3) it did not increase the photostability of AVO (F3). Thus, we suggested that formulations containing DHHB (F2) should be considered more advantageous than formulations containing AVO and AVO/DHHB (F1 and F3 respectively).

Mangiferin and naringenin affect the photostability and phototoxicity of sunscreens containing avobenzone.

Efficient UV-absorbing molecules are designed to protect against UV-light exposure. However, the development of photostable sunscreens is important to preserve the photoprotective efficacy and to prevent the formation of reactive oxygen species (ROS) and photodegradation products, which can promote phototoxic or photoallergic contact dermatitis. The aim of this study was to evaluate the effects of mangiferin and naringenin on the photostability and phototoxicity of sunscreens containing avobenzone. Cosmetic sunscreen formulations containing octocrylene (OCT), octyl methoxycinnamate (OMC) and avobenzone (AVO) were prepared and supplemented or not with mangiferin, naringenin, or with both compounds in combination. For photostability studies, samples of the formulations were spread onto glass plates, exposed to UVA radiation and then analyzed by high performance liquid chromatography (HPLC) to determine UV filters and the antioxidants recovery. The phototoxicity of the UV filters and antioxidants was evaluated using 3T3 fibroblast cultures that were subjected (or not) to irradiation according to OECD TG 432. The photostability studies demonstrated that AVO and naringenin showed the highest photodegradation when present in formulation FN (containing octocrylene, avobenzone, octyl methoxycinnamate and naringenin). The addition of mangiferin to this combination (FMN) resulted in an improved photostability of both substances compared to FN. The in vitro phototoxicity test showed that only avobenzone was considered phototoxic. The combination containing AVO/naringenin exhibited phototoxic potential; however, this was reduced by the addition of mangiferin (combination CMN). The results of this study are promising because it was demonstrated that mangiferin could increase the photostability and reduce the phototoxic potential of the combination of naringenin and AVO.

Synthesis, antioxidant and photoprotection activities of hybrid derivatives useful to prevent skin cancer.

Chronic ultraviolet (UV) radiation exposure is a major cause of skin cancer. A novel series of hybrid derivatives (I-VIII) for use in sunscreen formulations were synthesized by molecular hybridization of t-resveratrol, avobenzone, and octyl methoxycinnamate, and were characterized. The antioxidant activity values for VIII were comparable than to those of t-resveratrol. Compounds I-III and VI demonstrated Sun Protector Factor superior to that of t-resveratrol. Compounds I and IV-VIII were identified as new, broad-spectrum UVA filters while II-III were UVB filters. In conclusion, novel hybrid derivatives with antioxidant effects have emerged as novel photoprotective agents for the prevention of skin cancer.

Drug-excipient compatibility studies in binary mixtures of avobenzone.

During preformulation studies of cosmetic/pharmaceutical products, thermal analysis techniques are very useful to detect physical or chemical incompatibilities between the active and the excipients of interest that might interfere with safety and/or efficacy of the final product. Differential scanning calorimetry (DSC) was used as a screening technique for assessing the compatibility of avobenzone with some currently used cosmetic excipients. In the first phase of the study, DSC was used as a tool to detect any interaction. Based on the DSC results alone, cetearyl alcohol, isopropyl myristate, propylparaben, diethylhexyl syringylidene malonate, caprylic capric triglyceride, butylated hydroxytoluene (BHT), glycerin, cetearyl alcohol/ceteareth 20, cetearyl alcohol/sodium lauryl sulfate/sodium cetearyl sulfate, and paraffinum liquidum exhibit interaction with avobenzone. Stressed binary mixtures (stored at 50°C for 15 days) of avobenzone and excipients were evaluated by high-performance liquid chromatography. Binary mixtures were further investigated by infrared (IR) spectroscopy. Based on DSC, isothermal stress testing, and fourier transform infrared results; avobenzone is incompatible with caprylic capric triglyceride, propylparaben, and BHT.

New bioactive chalcones in propolis from El Salvador.

2',3'-Dihydroxy-4,4'-dimethoxychalcone (1) and 2',3',4-trihydroxy-4'-methoxy-chalcone, two new chalcones, were isolated from propolis from El Salvador. The compounds showed significant antibacterial and antifungal activity and moderate toxicity to Artemia salina nauplii.