RESUMO
A series of thirteen xanthones 3-15 was prepared based on substitutional (appendage) diversity reactions. The series was structurally characterized based on their spectral data and HRMS, and the structures of xanthone derivatives 1, 7, and 8 were determined by single-crystal X-ray diffraction. This series, along with an in-house series of aminated xanthones 16-33, was tested for in-vitro antimicrobial activity against seven bacterial (including two multidrug-resistant) strains and five fungal strains. 1-(Dibromomethyl)-3,4-dimethoxy-9H-xanthen-9-one (7) and 1-(dibromomethyl)-3,4,6-trimethoxy-9H-xanthen-9-one (8) exhibited antibacterial activity against all tested strains. In addition, 3,4-dihydroxy-1-methyl-9H-xanthen-9-one (3) revealed a potent inhibitory effect on the growth of dermatophyte clinical strains (T. rubrum FF5, M. canis FF1 and E. floccosum FF9), with a MIC of 16 µg/mL for all the tested strains. Compounds 3 and 26 showed a potent inhibitory effect on two C. albicans virulence factors: germ tube and biofilm formation.
Assuntos
Antibacterianos/química , Biofilmes/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Xantonas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Biofilmes/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Cristalografia por Raios X , Humanos , Testes de Sensibilidade Microbiana , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Difração de Raios X , Xantonas/síntese química , Xantonas/farmacologiaRESUMO
Antioxidants have long been used in the cosmetic industry to prevent skin photoaging, which is mediated by oxidative stress, making the search for new antioxidant compounds highly desirable in this field. Naturally occurring xanthones are polyphenolic compounds that can be found in microorganisms, fungi, lichens, and some higher plants. This class of polyphenols has a privileged scaffold that grants them several biological activities. We have previously identified simple oxygenated xanthones as promising antioxidants and disclosed as hit, 1,2-dihydroxyxanthone (1). Herein, we synthesized and studied the potential of xanthones with different polyoxygenated patterns as skin antiphotoaging ingredients. In the DPPH antioxidant assay, two newly synthesized derivatives showed IC50 values in the same range as ascorbic acid. The synthesized xanthones were discovered to be excellent tyrosinase inhibitors and weak to moderate collagenase and elastase inhibitors but no activity was revealed against hyaluronidase. Their metal-chelating effect (FeCl3 and CuCl2) as well as their stability at different pH values were characterized to understand their potential to be used as future cosmetic active agents. Among the synthesized polyoxygenated xanthones, 1,2-dihydroxyxanthone (1) was reinforced as the most promising, exhibiting a dual ability to protect the skin against UV damage by combining antioxidant/metal-chelating properties with UV-filter capacity and revealed to be more stable in the pH range that is close to the pH of the skin. Lastly, the phototoxicity of 1,2-dihydroxyxanthone (1) was evaluated in a human keratinocyte cell line and no phototoxicity was observed in the concentration range tested.
Assuntos
Antioxidantes , Queratinócitos/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Pele/metabolismo , Protetores Solares , Xantonas , Antioxidantes/efeitos adversos , Antioxidantes/química , Antioxidantes/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Queratinócitos/patologia , Pele/patologia , Envelhecimento da Pele/efeitos da radiação , Protetores Solares/efeitos adversos , Protetores Solares/química , Protetores Solares/farmacologia , Raios Ultravioleta/efeitos adversos , Xantonas/efeitos adversos , Xantonas/química , Xantonas/farmacologiaRESUMO
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].
Assuntos
Química Farmacêutica , Descoberta de Drogas , HumanosRESUMO
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].
Assuntos
Descoberta de Drogas/métodos , Terapia de Alvo Molecular/métodos , Química Farmacêutica/métodos , HumanosRESUMO
Xanthone derivatives have been described as compounds with a privileged scaffold exhibiting diverse biological/pharmacological activities, what directed the interest to pursue the development of these derivatives into drug candidates. Nevertheless, to achieve this purpose it is crucial to study their pharmacokinetics and toxicity (PK/tox) properties as decision endpoints to continue or interrupt the development investment. This review aims to expose the most relevant analytical methods used in the physicochemical and PK/tox studies in order to detect, quantify, and identify different bioactive xanthones. Analyzing the main results from in vitro and in vivo systems towards ADME properties such as solubility, lipophilicity, pKa, chemical and metabolic stability, permeability, transporters modulation, and plasma protein binding, it is possible to uncover some threats governing the PK properties and to understand the bioavailability and drugability of xanthone derivatives. The last section of this review focuses on a case-study of the development of the drug candidate DMXAA, which has reached clinical trials, to provide the paths and the importance of PK/tox parameters of this scaffold. The data assembled in this review intends to guide for tackling issues in the design of potential lead compounds and drug candidates with a xanthone scaffold.