Chemical Composition and Anti-Candida Activity of Mentha suaveolens Ehrh. Essential Oils Obtained by Different Distillation Processes.

A comparative study on essential oils extracted from Mentha suaveolens Ehrh. from Italy is reported. Two extraction procedures were investigated: hydrodistillation and steam distillation, carried out as a continuous and fractionated procedure. Fresh and dried plant material from two harvests was used. The hydrodistillation method yielded a higher amount of essential oil. The dried plant was significantly richer in essential oil per kg of starting plant material. Gas chromatography-mass spectrometry analysis of 112 samples showed that the essential oils belong to the piperitenone oxide-rich chemotype. In addition, piperitenone, p-cymen-8-ol, and limonene were among the most abundant compounds in the different samples. A higher amount of piperitenone oxide was obtained by hydrodistillation, while steam distillation gave a higher percentage of piperitenone and limonene. The essential oils were characterized for their anti-Candida albicans activity; higher potency was observed for the samples rich in piperitenone oxide, with MIC values ranging from 0.39 to 0.78 mg·mL-1 (0.039% and 0.078% p/v). The results of this work provide a deep insight into the methodology of essential oil extraction and the associated chemical variability of M. suaveolens Ehrh. Some of the essential oils are potent against C. albicans and could be considered for potential use in therapy.

Design, Synthesis and Evaluation of New Multifunctional Benzothiazoles as Photoprotective, Antioxidant and Antiproliferative Agents.

A current trend of research in the health field is toward the discovery of multifunctional compounds, capable of interacting with multiple biological targets, thus simplifying multidrug therapies and improving patient compliance. The aim of this work was to synthesize new multifunctional chemical entities bearing a benzothiazole nucleus, a structure that has attracted increasing interest for the great variety of biological actions that it can perform, and already used as a scaffold in several multifunctional drugs. Compounds are reported, divided into two distinct series, synthetized and tested in vitro for the antioxidant, and include UV-filtering and antitumor activities. DPPH and FRAP tests were chosen to outline an antioxidant activity profile against different radical species. The UV-filtering activity was investigated, pre- and post-irradiation, through evaluation of a O/W sunscreen standard formulation containing 3% of the synthetic compounds. The antitumor activity was investigated both on human melanoma cells (Colo-38) and on immortalized human keratinocytes as a control (HaCat). A good antiproliferative profile in terms of IC50 was chosen as a mandatory condition to further investigate apoptosis induction as a possible cytotoxicity mechanism through the Annexin V test. Compound BZTcin4 was endowed with excellent activity and a selectivity profile towards Colo-38, supported by a good antioxidant capacity and an excellent broad-spectrum photoprotective profile.

Machine Learning Data Augmentation as a Tool to Enhance Quantitative Composition-Activity Relationships of Complex Mixtures. A New Application to Dissect the Role of Main Chemical Components in Bioactive Essential Oils.

Scientific investigation on essential oils composition and the related biological profile are continuously growing. Nevertheless, only a few studies have been performed on the relationships between chemical composition and biological data. Herein, the investigation of 61 assayed essential oils is reported focusing on their inhibition activity against Microsporum spp. including development of machine learning models with the aim of highlining the possible chemical components mainly related to the inhibitory potency. The application of machine learning and deep learning techniques for predictive and descriptive purposes have been applied successfully to many fields. Quantitative composition-activity relationships machine learning-based models were developed for the 61 essential oils tested as Microsporum spp. growth modulators. The models were built with in-house python scripts implementing data augmentation with the purpose of having a smoother flow between essential oils' chemical compositions and biological data. High statistical coefficient values (Accuracy, Matthews correlation coefficient and F1 score) were obtained and model inspection permitted to detect possible specific roles related to some components of essential oils' constituents. Robust machine learning models are far more useful tools to reveal data augmentation in comparison with raw data derived models. To the best of the authors knowledge this is the first report using data augmentation to highlight the role of complex mixture components, in particular a first application of these data will be for the development of ingredients in the dermo-cosmetic field investigating microbial species considering the urge for the use of natural preserving and acting antimicrobial agents.

Synthesis and evaluation of antioxidant and antiproliferative activity of 2-arylbenzimidazoles.

Three series of arylbenzimidazole derivatives 3-40, 45 have been simply synthesized and tested for their antioxidant capacity. The 2-arylbenzimidazoles were tested against various radicals by the DPPH, FRAP and ORAC tests and showed different activity profiles. It has been observed that the number and position of the hydroxy groups on the 2-aryl portion and the presence of a diethylamino group or a 2-styryl group are related to a good antioxidant capacity. Furthermore, benzimidazoles showed satisfactory SPF values ​​in vitro compared to the commercial PBSA filter, proving to have a good photoprotective profile. In particular, 2-arylbenzimidazole-5-sulphonic acids 15 and 38, the 2-styryl-benzimidazole 45 showed broad spectrum solar protection against UVA and UVB rays. The antiproliferative effect of the benzimidazoles was tested on human skin melanoma Colo-38 cells. The styrylbenzimidazole 45 exhibited antiproliferative effect at low micromolar concentration against Colo-38 cells and very low antiproliferative activity on normal HaCat keratinocyte cells.

Design, synthesis and evaluation of benzothiazole derivatives as multifunctional agents.

Oxidative stress is the product or aetiology of various multifactorial diseases; on the other hand, the development of multifunctional compounds is a recognized strategy for the control of complex diseases. To this end, a series of benzothiazole derivatives was synthesized and evaluated for their multifunctional effectiveness as antioxidant, sunscreen (filter), antifungal and antiproliferative agents. Compounds were easily synthesized via condensation reaction between 2-aminothiophenols and different benzaldehydes. SAR study, particularly in position 2 and 6 of benzothiazoles, led to the identification of 4g and 4k as very interesting potential compounds for the design of multifunctional drugs. In particular, compound 4g is the best blocker of hERG potassium channels expressed in HEK 293 cells exhibiting 60.32% inhibition with IC50 = 4.79 µM.

Stem Cells as a Target for the Delivery of Active Molecules to Skin by Topical Administration.

Cutaneous stem cells, gained great attention in the field of regenerative medicine as a potential therapeutic target for the treatment of skin and hair disorders and various types of skin cancers. Cutaneous stem cells play a key role in several processes like the renovation of skin structures in the condition of homeostasis and after injuries, the hair follicle growth and the reconstruction and production of melanocytes. Thus, gaining effective access to skin stem cells for therapeutic interventions that often involve active molecules with non-favorable characteristics for skin absorption is a valuable achievement. The topical route with high patient compliance and several other benefits is gaining increasing importance in basic and applied research. However, the major obstacle for topical drug delivery is the effective barrier provided by skin against penetration of the vast majority of exogenous molecules. The research in this field is focusing more and more on new strategies to circumvent and pass this barrier effectively. In this article the existing approaches are discussed considering physical and chemical methods along with utilization of novel drug delivery systems to enhance penetration of drugs to the skin. In particular, attention has been paid to studies finalized to the delivery of molecules to cutaneous stem cells with the aim of transferring signals, modulating their metabolic program, inducing physiological modifications and stem cell gene therapy.

Skin Damages-Structure Activity Relationship of Benzimidazole Derivatives Bearing a 5-Membered Ring System.

In the search for scaffolds for multifunctional compounds we investigated the structure activity relationship of a class of benzimidazole derivatives bearing 5-membered ring. The newly synthesized and the already known compounds were divided into three classes that present different substituent at 5 position of the benzimidazole ring (-H, -COOH or -SO3H) and different heterocycle at position 2 (thiophene, furan or pyrrole). All the derivatives were synthesized and tested to determine their photoprotective profile against UV rays, in vitro antioxidant capacity against different radicals (DPPH and FRAP test), antifungal inhibitory activity (dermatophytes and Candida albicans), antiviral and antiproliferative activity. A Structure-Activity Relationship study indicated compound 10, bearing a pyrrole heterocycle on the benzimidazole ring, as the best multifunctional derivative of the series and as potential candidate for the development of drugs especially in case of melanoma.

Ellagic Acid Containing Nanostructured Lipid Carriers for Topical Application: A Preliminary Study.

Ellagic acid (EA) is a potent antioxidant substance of natural origin characterized by poor biopharmaceutical properties and low solubility in water that limit its use. The aim of the present study was to develop lipid-based nanoparticle formulations able to encapsulate EA for dermal delivery. The EA-loaded nanoparticles were prepared using two different lipid compositions, namely tristearin/tricaprylin (NLC-EA1) and tristearin/labrasol (NLC-EA2). The influence of formulations on size, entrapment efficiency, and stability of EA-loaded nanoparticles was investigated. Cryo-TEM and small-angle X-ray scattering (SAXS) analyses showed that no morphological differences are evident among all the types of loaded and unloaded nanostructured lipid carriers (NLCs). The macroscopic aspect of both NLC-EA1 and NLC-EA2 did not change with time. No difference in size was appreciable between empty and drug-containing NLC, thus the nanoparticle diameter was not affected by the presence of EA and in general no variations of the diameters occurred during this time. The entrapment efficiency of both EA-loaded nanoparticles was almost quantitative. In addition, NLC-EA1 maintained EA stability for almost two months, while NLC-EA2 up to 40 days. FRAP (Ferric reducing ability of plasma) assay showed an antioxidant activity around 60% for both the loaded NLC, as compared to the solution. Although both types of NLC are characterized by some toxicity on HaCaT cells, NLC-EA1 are less cytotoxic than NLC-EA2. Taken together these results demonstrated that the inclusion of EA within NLC could improve the water solubility, allowing for a reduction of the dosage. Moreover, both types of NLC-EA maintained a high antioxidant effect and low toxicity.

Iranian Medicinal Plants: From Ethnomedicine to Actual Studies.

Iran has a rich and diverse cultural heritage, consisting of a complex traditional medicine deeply rooted in the history of the territory that goes back to the Assyrian and Babylonian civilizations. The ethnomedical practices that can be identifiable nowadays derive from the experience of local people who have developed remedies against a wide range of diseases handing down the knowledge from generation to generation over the millennia. Traditional medicine practices represent an important source of inspiration in the process of the development of new drugs and therapeutic strategies. In this context, it is useful to determine the state of the art of ethnomedical studies, concerning the Iranian territory, and of scientific studies on plants used in traditional Iranian medicine. Data regarding 245 plants used in Iranian ethnomedical practices and scientific studies conducted on 89 plants collected in the Iranian territory have been reported. All of the scientific studies here reported draw inspiration from traditional medicine. The World Health Organization (WHO) has repeatedly called for an intensification of the scientific validation processes of traditional medicines intended as an important contribution to public health in various parts of the world. The process of study and validation of Iranian ethnomedical practices appears to be at an early stage.

Indole derivatives as multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity of indole hydrazones.

Two series of indole derivatives 4-17, 20-22 were easily prepared and assayed for their radical-scavenging ability. Arylidene-1H-indole-2-carbohydrazones showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety as well as to the presence of methoxy or 4-(diethylamino) group. On the contrary low antioxidant activity is showed by the isomeric 1H-indol-2-yl(methylene)-benzohydrazides. Furthermore, hydrazones 4-17 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The indole 16 and 17, showing the best antioxidant and photoprotective profile, were included in different formulation and their topical release was evaluated. Varying the formulation composition, it was possible to optimize skin adsorption and solubility of the active indole in the formulation. The antiproliferative effect of the hydrazones 4-17 was tested on human erythroleukemia K562 and melanoma Colo-38 cells. Hydrazones 11, 16 and 17 showed growth inhibition at sub micromolar concentrations on both cell lines. These results indicate indole hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 16 and 17 correlated to their high antiproliferative activity.

Synthesis and Characterization of New Multifunctional Self-Boosted Filters for UV Protection: ZnO Complex with Dihydroxyphenyl Benzimidazole Carboxylic Acid.

The incidence of skin cancer is increasing both because of climate change and the increase in pollution than people's incorrect habits of sun exposure. In these regards, sunscreen and photoprotection are essential tools in consenting the benefits induced by safe solar light exposition and skin cancer prevention. In this work, a new class of sunscreen filter was synthesized by chemical combination of a physical filter (ZnO) and Oxisol (dihydroxyphenyl benzimidazole carboxylic acid), an antioxidant molecule with booster effect. In this work, a new class of filters with new properties was achieved by direct functionalization of particles surface. A full characterization of this multifunctional ingredient (ZnO-Ox) was conducted: Compared with the simple mixture, the new filter acts as a multifunctional molecule showing a higher Sun Protection Factor (SPF), a better cytotoxic profile (MTT and NRU assay), and anti-acne activity. A strong reduction of photocatalytic activity of ZnO was observed, also improving the safety profile.

Moringa oleifera Leaf Extracts as Multifunctional Ingredients for "Natural and Organic" Sunscreens and Photoprotective Preparations.

Moringa oleifera has gained increasing popularity as a food supplement but not in the pharmaceutical and cosmetic area. The aim of this study was the preparation, characterization, and evaluation of extracts from the leaves of Moringa oleifera as a herbal sun care phytocomplex. Three different extracts of Moringa oleifera leaves, from Senegal, have been prepared and chemically characterized in the phenolic fraction by HPLC-DAD and Folin-Ciocalteu test. To explore photoprotective properties, an extensive evaluation of UV filtering, antioxidant (DPPH, FRAP, ORAC, PCL), and anti-hyperproliferative (human melanoma Colo38 cells) capacities have been conducted. Furthermore, a formulation study regarding cosmetic prototypes has been carried out in order to determine the Sun Protection Factor (SPF), which was assessed in vitro. The extracts were demonstrated to confer significant values of protection, with an SPF 2, that corresponds to a 50% protection against UV-B rays, at concentrations as low as 2% to 4%. Finally, the evaluation on potential irritation of the finished formulations was conducted by Patch Test and no significant irritant potential was observed. These evidence enlarged the already significant number of activities and potential uses of this plant, which is well-known for its importance in the medicinal and nutritional fields.

Monoolein aqueous dispersions as a delivery system for quercetin.

This study describes the preparation, characterization and in vitro release of monoolein aqueous dispersions (MAD) encapsulating quercetin (QT). As emulsifier, sodium cholate was employed at two different concentrations, namely 0.15% and 0.25% with respect to the total weight of the formulation. Cryogenic Transmission electron microscopy and X-ray analysis indicated that MAD015 are a mixture of vesicles and cubic structures, whilst MAD025 are mainly characterized by unilamellar vesicular structures. Photon correlation spectroscopy (PCS) and Sedimentation Field Flow Fractionation (SdFFF) showed a MAD size higher than 300 nm that over 100 days from analysis reduces up to 200 nm. In vitro Franz cell experiments showed that the two systems had a similar behaviour in the release of QT. Experiments on antioxidant activity of MAD containing QT demonstrated that their activity parallel with the content of encapsulated QT within the MAD formulations produced. Taken together these results allow us to conclude that MAD can be potentially proposed for the delivery of QT.

Design, synthesis and biological evaluation of novel hydroxy-phenyl-1H-benzimidazoles as radical scavengers and UV-protective agents.

An ever-increasing incidence of skin neoplastic diseases is registered. Therefore, it is important to protect the skin from the UV radiation that reaches the epidermis and dermis but also to block ROS generated by them. Our attention was attracted in developing new compounds provided with both UV filtering and antioxidant capacities. To this end, 2-phenyl-1H-benzimidazole-5-sulfonic acid (PBSA), a known UV filter, was selected as lead compound for its lack of antioxidant activity, high water solubility and good safety profile. PBSA was sequentially modified introducing hydroxyls on the phenyl ring and also substituting the functional group in position 5 of the benzimidazole ring. At the end of the synthetic study, a new, very potent class of antioxidants has been obtained. Surprisingly some of the developed molecules, while devoid of significant UV-filtering activity was endowed with potent UV-filtering booster capability if associated with known commercial UVB and UVA filters.

Essential Oil Extraction, Chemical Analysis and Anti-Candida Activity of Calamintha nepeta (L.) Savi subsp. glandulosa (Req.) Ball-New Approaches.

A comprehensive study on essential oils extracted from different Calamintha nepeta (L.) Savi subsp. glandulosa (Req.) Ball samples from Tarquinia (Italy) is reported. In this study, the 24-h steam distillation procedure for essential oil preparation, in terms of different harvesting and extraction times, was applied. The Gas chromatography-mass spectrometry (GC/MS) analysis showed that C. nepeta (L.) Savi subsp. glandulosa (Req.) Ball essential oils from Tarquinia belong to the pulegone-rich chemotype. The analysis of 44 samples revealed that along with pulegone, some other chemicals may participate in exerting the related antifungal activity. The results indicated that for higher activity, the essential oils should be produced with at least a 6-h steam distillation process. Even though it is not so dependent on the period of harvesting, it could be recommended not to harvest the plant in the fruiting stage, since no significant antifungal effect was shown. The maximum essential oil yield was obtained in August, with the highest pulegone percentage. To obtain the oil with a higher content of menthone, September and October should be considered as the optimal periods. Regarding the extraction duration, vegetative stage material gives the oil in the first 3 h, while material from the reproductive phase should be extracted at least at 6 or even 12 h.

Design, Synthesis and Evaluation of Antiproliferative Activity of New Benzimidazolehydrazones.

The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazone mojety at the 2-position is described. The new N'-(4-arylidene)-1H-benzo[d]imidazole-2-carbohydrazides were evaluated for their cytostatic activity toward the murine leukemia (L1210), human T-cell leukemia (CEM), human cervix carcinoma (HeLa) and human pancreas carcinoma cells (Mia Paca-2). A preliminary structure-activity relationship could be defined. Some of the compounds possess encouraging and consistent antiproliferative activity, having IC50 values in the low micromolar range.

Antidermatophytic Action of Resorcinol Derivatives: Ultrastructural Evidence of the Activity of Phenylethyl Resorcinol against Microsporum gypseum.

In this work, we evaluated the antidermatophytic activities of three resorcinol derivatives that have a history of use in dermo-cosmetic applications to discover molecules with multiple dermatological activities (i.e., multi-target drugs), thereby reducing the cost and time necessary for new drug development. The antidermatophytic activities of the three skin lighteners were evaluated relative to the known antifungal drug fluconazole on nine dermatophytes responsible for the most common dermatomycoses: Microsporum gypseum, Microsporum canis, Trichophyton violaceum, Arthroderma cajetani, Trichophyton mentagrophytes, Epidermophyton floccosum, Nannizzia gypsea, Trichophyton rubrum and Trichophyton tonsurans. Among the three tested resorcinols, only two showed promising properties, with the ability to inhibit the growth of all tested dermatophytes; additionally, the IC50 values of these two resorcinols against the nine dermatophytes confirmed their good antifungal activity, particularly for phenylethyl resorcinol against M. gypseum. Ultrastructural alterations exhibited by the fungus were observed using scanning electron microscopy and transmission electron microscopy and reflected a dose-dependent response to treatment with the activation of defence and self-preservation strategies.

Design, synthesis and biological activity of a novel Rutin analogue with improved lipid soluble properties.

Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis.

A Multi-Target Approach toward the Development of Novel Candidates for Antidermatophytic Activity: Ultrastructural Evidence on α-Bisabolol-Treated Microsporum gypseum.

Multi-target strategies are directed toward targets that are unrelated (or distantly related) and can create opportunities to address different pathologies. The antidermatophytic activities of nine natural skin lighteners: α-bisabolol, kojic acid, ß-arbutin, azelaic acid, hydroquinone, nicotinamide, glycine, glutathione and ascorbyl tetraisopalmitate, were evaluated, in comparison with the known antifungal drug fluconazole, on nine dermatophytes responsible for the most common dermatomycoses: Microsporum gypseum, Microsporum canis, Trichophyton violaceum, Nannizzia cajetani, Trichophyton mentagrophytes, Epidermophyton floccosum, Arthroderma gypseum, Trichophyton rubrum and Trichophyton tonsurans. α-Bisabolol showed the best antifungal activity against all fungi and in particular; against M. gypseum. Further investigations were conducted on this fungus to evaluate the inhibition of spore germination and morphological changes induced by α-bisabolol by TEM.