Thermoresponsive Hydrogel-Loading Aluminum Chloride Phthalocyanine as a Drug Release Platform for Topical Administration in Photodynamic Therapy.

Phthalocyanine aluminum chloride (Pc) is a clinically viable photosensitizer (PS) to treat skin lesions worsened by microbial infections. However, this molecule presents a high self-aggregation tendency in the biological fluid, which is an in vivo direct administration obstacle. This study proposed the use of bioadhesive and thermoresponsive hydrogels comprising triblock-type Pluronic F127 and Carbopol 934P (FCarb) as drug delivery platforms of Pc (FCarbPc)-targeting topical administration. Carbopol 934P was used to increase the F127 hydrogel adhesion on the skin. Rheological analyses showed that the Pc presented a low effect on the hydrogel matrix, changing the gelation temperature from 27.2 ± 0.1 to 28.5 ± 0.9 °C once the Pc concentration increases from zero to 1 mmol L-1. The dermatological platform showed matrix erosion effects with the release of loaded Pc micelles. The permeation studies showed the excellent potential of the FCarb platform, which allowed the partition of the PS into deeper layers of the skin. The applicability of this dermatological platform in photodynamic therapy was evaluated by the generation of reactive species which was demonstrated by chemical photodynamic efficiency assays. The low effect on cell viability and proliferation in the dark was demonstrated by in vitro assays using L929 fibroblasts. The FCarbPc fostered the inhibition of Staphylococcus aureus strain, therefore demonstrating the platform's potential in the treatment of dermatological infections of microbial nature.

Hetero-Diels-Alder Reactions of Quinone Methides: The Origin of the α-Regioselectivity of 3-Methylene-1,2,4-naphthotriones.

The regioselective formation of α- and ß-lapachone via hetero-Diels-Alder reactions was investigated by experimental and computational approaches. The experimentally observed α-selectivity was explored in detail, revealing that the lower energy barrier for the formation of α-lapachone is a result of lower Pauli repulsion throughout the reaction path, when compared to the ß-isomer. By comparing equivalent points on both α- and ß-lapachone potential energy surfaces (PES), according to the activation strain model (ASM) and energy decomposition analysis (EDA), we were able to demonstrate that the Pauli repulsion term increases more significantly when going from reactants to TSß than to TSα, resulting in lower interaction energy in the early stages of the reaction path and in a later transition state for ß-lapachone. Moreover, we confirmed that regio- and diastereoselectivity trends previously reported for other quinone methide intermediates are also observed for 3-methylene-1,2,4-naphthotriones, such as small endo/exo diastereoselectivity, as well as pronounced ortho/meta regioselectivity for reactions performed with dienophile containing electron-releasing groups. The results presented here provide a deeper understanding of the reactivity of quinone methide derivatives, aiding the future rational design of the reaction condition, structural modification of possible quinone methide intermediates, and the development of more selective synthetic routes for quinone derivatives.

Functional Polymeric Systems as Delivery Vehicles for Methylene Blue in Photodynamic Therapy.

Antibiotic-resistant microorganisms have become a global concern, and the search for alternative therapies is very important. Photodynamic therapy (PDT) consists of the use of a nontoxic photosensitizer (PS), light, and oxygen. This combination produces reactive oxygen species and singlet oxygen, which can alter cellular structures. Methylene blue (MB) is a substance from the phenothiazine class often used as a PS. In this work, to facilitate the PS contact within the wounds, we have used Design of Experiments 2(3) plus central point to develop functional polymeric systems. The formulations were composed by poloxamer 407 [15.0, 17.5, or 20.0% (w/w)], Carbopol 934P [0.15, 0.20, or 0.25% (w/w)], and MB [0.25, 0.50, or 0.75% (w/w)]. The sol-gel transition temperature, flow rheometry, in vitro MB release, and ex vivo study of MB cutaneous permeation and retention were investigated. Moreover, the evaluation of photodynamic activity was also analyzed by in vitro degradation of tryptophan by singlet oxygen and using Artemia salina. The determination of the gelation temperature displayed values within the range of 25-37 °C, and the systems with better characteristics were subjected to rheological analysis and in vitro release profiling. The 20/0.15/0.25 formulation showed the best release profile (42.57% at 24 h). This system displayed no significant skin permeation (0.38% at 24 h), and the photooxidation of tryptophan test showed the production of reactive species of oxygen. The toxicity test using A. salina revealed that the MB associated with the light increased the mortality rate by 61.29%. Therefore, investigating the PDT efficacy of the functional polymeric system containing MB will be necessary in the future.

Biological evaluation of hydroxynaphthoquinones as anti-malarials.

BACKGROUND: The hydroxynaphthoquinones have been extensively investigated over the past 50 years for their anti-malarial activity. One member of this class, atovaquone, is combined with proguanil in Malarone®, an important drug for the treatment and prevention of malaria. METHODS: Anti-malarial activity was assessed in vitro for a series of 3-alkyl-2-hydroxy-1,4-naphthoquinones (N1-N5) evaluating the parasitaemia after 48 hours of incubation. Potential cytotoxicity in HEK293T cells was assessed using the MTT assay. Changes in mitochondrial membrane potential of Plasmodium were measured using the fluorescent dye Mitrotracker Red CMXROS. RESULTS: Four compounds demonstrated IC50s in the mid-micromolar range, and the most active compound, N3, had an IC50 of 443 nM. N3 disrupted mitochondrial membrane potential, and after 1 hour presented an IC50ΔΨmit of 16 µM. In an in vitro cytotoxicity assay using HEK 293T cells N3 demonstrated no cytotoxicity at concentrations up to 16 µM. CONCLUSIONS: N3 was a potent inhibitor of mitochondrial electron transport, had nanomolar activity against cultured Plasmodium falciparum and showed minimal cytotoxicity. N3 may serve as a starting point for the design of new hydroxynaphthoquinone anti-malarials.

Singlet oxygen production by pyrano and furano 1,4-naphthoquinones in non-aqueous medium.

The influence of ring size on the photobehaviour of condensed 1,4-naphthoquinone systems, such as pyrano- and furano-derivatives (1 and 2, respectively) has been investigated. The absorption spectra for both families of naphthoquinones reveal clear differences; in the case of 2 they extend to longer wavelengths. A solvatochromic red shift in polar solvents is consistent with the π,π* character of the S(0)→ S(1) electronic transition in all cases. Theoretical (B3LYP) analysis of the HOMO and LUMO Kohn-Sham molecular orbitals of the S(0) state indicates that they are π and π* in nature, consistent with the experimental observation. A systematic study on the efficiency of singlet oxygen generation by these 1,4-naphthoquinones is presented, and values larger than 0.7 were found in every case. In accordance with these results, laser flash photolysis of deoxygenated acetonitrile solutions led to the formation of detectable triplet transient species with absorptions at 390 and 450 nm (1) and at 370 nm (2), with φ(ISC) close to 1. Additionally, the calculated energies for the T(1) states relative to the S(0) states at UB3LYP/6-311++G** are ca. 47 kcal mol(-1) for 1 and 43 kcal mol(-1) for 2. A comparison of the geometrical parameters for the S(0) and T(1) states reveals a marked difference with respect to the arrangement of the exocyclic phenyl ring whilst a comparison of electronic parameters revealed the change from a quinone structure to a di-dehydroquinone diradical structure.

Synthesis of alpha- and beta-pyran naphthoquinones as a new class of antitubercular agents.

A series of alpha- and beta-pyran naphthoquinones (lapachones) have been synthesized and evaluated for their in-vitro antibacterial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar-Blue susceptibility test; the activity was expressed as the minimum inhibitory concentration (MIC) in microg/mL. The synthetic methodology consisted of the formation of methylene and aryl o-quinone methides (o-QMs) generated by Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone with formaldehyde and arylaldehydes. These o-QMs then undergo facile hetero Diels-Alder reactions with dienophiles in aqueous ethanol media. Some naphthoquinones exhibited inhibition with MIC values of 1.25 microg/mL, similar to that of pharmaceutical concentrations currently used in tuberculosis treatment. These results justify further research into the value of these quinones as part of an original treatment for tuberculosis.

N-(4-Chloro-phen-yl)ethanimidamide.

A twisted conformation is found in the title compound, C(8)H(9)ClN(2), with the ethanimidamide residue being twisted substantially to the benzene ring [dihedral angle = 66.54 (14)°]. The conformation about the C=N double bond [1.299 (3) Å] is Z. A two-dimensional array with a zigzag topology is formed in the crystal structure via N-H⋯N and N-H⋯Cl hydrogen-bonding inter-actions.

A photochemical and theoretical study of the triplet reactivity of furano- and pyrano-1,4-naphthoquionones towards tyrosine and tryptophan derivatives.

The photochemical reactivity of the triplet state of pyrano- and furano-1,4-naphthoquinone derivatives (1 and 2) has been examined employing nanosecond laser flash photolysis. The quinone triplets were efficiently quenched by l-tryptophan methyl ester hydrochloride, l-tyrosine methyl ester hydrochloride, N-acetyl-l-tryptophan methyl ester and N-acetyl-l-tyrosine methyl ester, substituted phenols and indole (k q ∼109 L mol-1 s-1). For all these quenchers new transients were formed in the quenching process. These were assigned to the corresponding radical pairs that resulted from a coupled electron/proton transfer from the phenols, indole, amino acids, or their esters, to the excited state of the quinone. The proton coupled electron transfer (PCET) mechanism is supported by experimental rate constants, isotopic effects and theoretical calculations. The calculations revealed differences between the hydrogen abstraction reactions of phenol and indole substrates. For the latter, the calculations indicate that electron transfer and proton transfer occur as discrete steps.

Synthesis and evaluation of new difluoromethyl azoles as antileishmanial agents.

Several compounds of great pharmacological interest contain the triazole and imidazole rings. In order to find new drugs with antileishmanial activity we have synthesized and evaluated new imidazole and triazole compounds carrying either the carbaldehyde or the difluoromethylene functionalities against promastigote forms of Leishmania amazonensis. Among the compounds tested difluoromethylene azoles 4b and 8f have inhibited the parasite growth significantly. Our results show that the introduction of the difluoromethylene moieties has turned the inactive carbaldehydes into active antileishmanial compounds.

Environmentally Responsive Systems for Drug Delivery.

BACKGROUND: In recent decades, the development of the environmentally responsive systems for drug delivery has been well regarded, with enormous potential in different applications. <P><P> Methods: These environmentally sensitive, smart, intelligent formulations have the ability to alter their physical properties in response to small changes in physical or chemical conditions, such as temperature, glucose, pH, ultrasound, light, electric field and redox potential with a huge potential in drug delivery systems. The use of formulations containing smart materials enables to carry the drug to the target tissue, cells and release in a triggered way. Consequently, they have demonstrated several advantages like decreased dose frequency, ease of preparation and administration, prolonged release with reduced side effects, as well as, reduced costs when compared to conventional processes for industrial applications. In this sense, many patents have deposited, displaying different pharmaceutical devices using responsive systems. <P><P> Results: There are more than twenty-five patents deposited about thermoresponsive systems. Furthermore, a few number of patents within glucose responsive, ultrasound responsive and light responsive deposited. There also are about eight patents that are pH-responsive, four as electric-field responsive. Most of them cover more than one type of stimuli. <P><P> Conclusion: Therefore, in this review, since 1975 to 2016, we have categorized, reviewed and discussed the patents, applications, pharmaceutical dosage forms, the importance and perspectives of this environmentally responsive approach as potentially useful therapeutic modality.

Synthesis, Anticlotting and Antiplatelet Effects of 1,2,3-Triazoles Derivatives.

Cardiovascular diseases, such as thrombosis and stroke, represent the major cause of disability and death worldwide; and dysfunctions in platelet aggregation and blood coagulation processes are involved. The regular antithrombotic drugs have unsatisfactory results and may produce side effects. Therefore, alternative therapies have been extensively investigated. OBJECTIVE: The anticoagulant and antiplatelet aggregation potential of a series of six synthetic 1,2,3-triazole derivatives were investigated through in vitro models. METHODS: Coagulation tests included the prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) assays, and were performed on a multichannel coagulometer, using human plasma. The platelet aggregation assays were carried out using human platelet-rich-plasma (PRP). Aggregation was initiated by adding ADP or collagen and monitored turbidimetrically on a Whole Blood Aggregometer. Toxicity of derivatives was evaluated on platelets and red blood cells, by measuring the release of lactate dehydrogenase and hemoglobin, respectively. Moreover, theoretical toxicity of derivatives was calculated using the software Osiris® Property Explorer. RESULTS: All the six derivatives tested inhibited, but with different potencies, the plasma coagulation assessed by the PT and TT assays, and also inhibited platelet aggregation of PRP induced by collagen or ADP. The derivatives did not interfere in the aPTT assay and did not affect the viability of platelets or red blood cells. Theoretical studies also revealed that all derivatives will likely to have low toxicity, great pharmacological and oral bioavailability profiles, and a Druglikeness and Drug score similar to some commercial anticoagulant and antiplatelet drugs. CONCLUSION: 1,2,3-triazoles are potential candidates for molecular modeling of new antithrombotic drugs.

Synthesis of 1H-1,2,3-triazoles and study of their antifungal and cytotoxicity activities.

We report herein the results of antifungal activity of fifteen 1,2,3-triazoles against Candida albicans, Candida krusei, Candida parapsilosis, Candida kefyr, Candida tropicalis, Candida dubliniensis, Tricophyton rubrum, Microporum canis and Aspergillus niger. All of the 1,2,3-triazoles were prepared from 1,3-dipolar cyclizations between aryl azides and alkynes catalyzed by Cu(I), and several of the compounds exhibited antifungal activity with low cytotoxicity. The results demonstrated the potential and importance of developing new 1,2,3-triazoles compounds with antifungal activity.

Synthetic 1,4-pyran naphthoquinones are potent inhibitors of dengue virus replication.

Dengue virus infection is a serious public health problem in endemic areas of the world where 2.5 billion people live. Clinical manifestations of the Dengue infection range from a mild fever to fatal cases of hemorrhagic fever. Although being the most rapidly spreading mosquito-borne viral infection in the world, until now no strategies are available for effective prevention or control of Dengue infection. In this scenario, the development of compounds that specifically inhibit viral replication with minimal effects to the human hosts will have a substantial effect in minimizing the symptoms of the disease and help to prevent viral transmission in the affected population. The aim of this study was to screen compounds with potential activity against dengue virus from a library of synthetic naphthoquinones. Several 1,2- and 1,4-pyran naphthoquinones were synthesized by a three-component reaction of lawsone, aldehyde (formaldehyde or arylaldehydes) and different dienophiles adequately substituted. These compounds were tested for the ability to inhibit the ATPase activity of the viral NS3 enzyme in in vitro assays and the replication of dengue virus in cultured cells. We have identified two 1,4-pyran naphthoquinones, which inhibited dengue virus replication in mammal cells by 99.0% and three others that reduced the dengue virus ATPase activity of NS3 by two-fold in in vitro assays.

Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain.

The purpose of this study was to prepare various 4-substituted N-phenyl-1,2,3-triazole derivatives using click chemistry. The derivatives were screened in vitro for antimicrobial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar Blue susceptibility test. The activity was expressed as the minimum inhibitory concentration (MIC) in µg/mL (µM). Derivatives of isoniazid (INH), (E)-N'-[(1-aryl)-1H-1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, exhibited significant activity with MIC values ranging from 2.5 to 0.62 µg/mL. In addition, they displayed low cytotoxicity against liver cells (hepatoma HepG2) and kidney cells (BGM), thereby providing a high therapeutic index. The results demonstrated the potential and importance of developing new INH derivatives to treat mycobacterial infections.

Synthesis, biological activity, and molecular modeling studies of 1H-1,2,3-triazole derivatives of carbohydrates as alpha-glucosidases inhibitors.

A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the alpha-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including D-xylose, D-galactose, D-allose, and D-ribose. Compounds were screened for alpha-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-O-isopropylidene-beta-D-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D.

2-Amino-5-trifluoromethyl-1,3,4-thiadiazole and a redetermination of 2-amino-1,3,4-thiadiazole, both at 120 K: chains of edge-fused R(2)(2)(8) and R(4)(4)(10) rings, and sheets of R(2)(2)(8) and R(6)(6)(20) rings.

Molecules of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole, C3H2F3N3S, are linked by two independent N-H...N hydrogen bonds into sheets of alternating R(2)(2)(8) and R(6)(6)(20) rings, while the molecules of the unsubstituted 2-amino-1,3,4-thiadiazole, C2H3N3S, are linked, again by two independent N-H...N hydrogen bonds, but into chains of edge-fused R(2)(2)(8) and R(4)(4)(10) rings.