Hybrid Compounds as Direct Multitarget Ligands: A Review de Oliveira Pedrosa, Michelle; Duarte da Cruz, Rayssa Marques; de Oliveira Viana, Jessika ...
Current topics in medicinal chemistry,
04/2017, Volume:
17, Issue:
9
Journal Article
Peer reviewed
Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single ...molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years.
Natural products using plants have received considerable attention because of their potential to treat various diseases. Arrabidaea chica (Humb. & Bonpl.) B. Verlot is a native tropical American vine ...with healing properties employed in folk medicine for wound healing, inflammation, and gastrointestinal colic. Applying nanotechnology to plant extracts has revealed an advantageous strategy for herbal drugs considering the numerous features that nanostructured systems offer, including solubility, bioavailability, and pharmacological activity enhancement. The present study reports the preparation and characterization of chitosan-sodium tripolyphosphate nanoparticles (NPs) charged with A. chica standardized extract (AcE). Particle size and zeta potential were measured using a Zetasizer Nano ZS. The NP morphological characteristics were observed using scanning electron microscopy. Our studies indicated that the chitosan/sodium tripolyphosphate mass ratio of 5 and volume ratio of 10 were found to be the best condition to achieve the lowest NP sizes, with an average hydrodynamic diameter of 150±13 nm and a zeta potential of +45±2 mV. Particle size decreased with AcE addition (60±10.2 nm), suggesting an interaction between the extract's composition and polymers. The NP biocompatibility was evaluated using human skin fibroblasts. AcE-NP demonstrated capability of maintaining cell viability at the lowest concentrations tested, stimulating cell proliferation at higher concentrations. Antiulcerogenic activity of AcE-NP was also evaluated with an acute gastric ulcer experimental model induced by ethanol and indomethacin. NPs loaded with A. chica extract reduced the ulcerative lesion index using lower doses compared with the free extract, suggesting that extract encapsulation in chitosan NPs allowed for a dose reduction for a gastroprotective effect. The AcE encapsulation offers an approach for further application of the A. chica extract that could be considered a potential candidate for ulcer-healing pharmaceutical systems.
Natural products are compounds extracted from plants, marine organisms, fungi or bacteria. Many researches for new drugs are based on these natural molecules, mainly by beneficial effects on health, ...health, efficacy, and therapeutic safety. Leishmaniosis, Chagas disease and African sleeping sickness are neglected diseases caused by the Leishmania and Trypanosoma ssp. parasites. These infections mainly affect population of developing countries; they have different symptoms, and may often lead to death. The therapeutic drugs available to treat these diseases are either obsolete, toxic, or have questionable efficacy, possibly through encountering resistance. Discovery of new, safe, effective, and affordable molecules is urgently needed. Natural organisms, as marine metabolites, alkaloids, flavonoids, steroids, terpene and coumarins provide innumerable molecules with the potential to treat these diseases. This study examines studies of natural bioactive compounds as antileishmanial and antitrypanosomal agents.
The search for new drugs with anti-inflammatory properties remains a challenge for modern medicine. Among the various strategies for drug discovery, deriving new chemical entities from known ...bioactive natural and/or synthetic compounds remains a promising approach. Here, we designed and synthesized CVIB, a codrug developed by association of carvacrol (a phenolic monoterpene) with ibuprofen (a non-steroidal anti-inflammatory drug). In silico pharmacokinetic and physicochemical properties evaluation indicated low aqueous solubility (LogP ≥5.0). Nevertheless, the hybrid presented excellent oral bioavailability, gastrointestinal tract absorption, and low toxicity. CVIB did not present cytotoxicity in peripheral blood mononuclear cells (PBMCs), and promoted a significant reduction in IL-2, IL-10, IL-17, and IFN-γ cytokine levels in vitro. The LD50 was estimated to be approximately 5000 mg/kg. CVIB was stable and detectable in human plasma after 24 h. In vivo anti-inflammatory evaluations revealed that CVIB at 10 and 50 mg/kg i.p. caused a significant decrease in total leukocyte count (p < 0.01) and provoked a significant reduction in IL-1β (p < 0.01). CVIB at 10 mg/kg i.p. efficiently decreased inflammatory parameters better than the physical mixture (carvacrol + ibuprofen 10 mg/kg i.p.). The results suggest that the codrug approach is a good option for drug design and development, creating the possibility of combining NSAIDs with natural products in order to obtain new hybrid drugs may be useful for treatment of inflammatory diseases.
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•CVIB - a new codrug of ibuprofen and carvacrol was synthesized.•CVIB show no cytotoxicity, and no toxicity in mice.•In vitro, CVIB reduces levels of IL-2, IL-10, IL-17 and IFN-γ cytokines.•In vivo, CVIB promoted decreases in total leukocyte counts and in IL-1β levels.•CVIB displayed superior anti-inflammatory profiles to those of the physical mixture.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
As energias renováveis surgem como uma maneira de mitigar os prejuízos ambientais causados pelas tradicionais fontes de energia, propondo também, uma diversificação da matriz energética. Dentre os ...diversos vetores energéticos possíveis, as microalgas surgem como uma boa opção para geração de energia por possuírem uma alta capacidade de conversão de energia solar em energia química, tornando amplas as possibilidades para obtenção de biomassa algal em aplicações energéticas. Por meio delas é possível produzir biodiesel, bioetanol, gás metano e gás hidrogênio como combustível. O presente trabalho, avalia o potencial energético da microalga Oedogonium sp. por meio de sua análise físico-química e de poder calorífico, assim como a viabilidade da sua densificação em forma de pellets, a fim de aproveitá-la como matéria sólida para combustão. Para isso, foram realizadas análises calorimétrica, termogravimétrica e imediata, onde nessa última foi possível obter os teores de umidade, cinza, carbono fixo e voláteis presentes na biomassa. Os resultados foram satisfatórios, nos quais o poder calorífico superior foi igual a 16,13 MJ/kg, valor superior ao encontrado para lenha comercial e dentro dos padrões impostos pelas normas europeia, sueca e intencional de padronização de pellets.
The number of mosquito populations resistant to insecticides is increasing along with the reemerging of vector‐borne diseases. New technologies are under evaluation to complement the strategies used ...against these mosquitoes. Transgenic mosquitoes are one approach that some countries are considering and they are being evaluated to control the wild population. Although they have achieved success in population suppression of Aedes aegypti (L.) (Diptera: Culicidae), these studies have not demonstrated what the outcomes are when releases are interrupted (ceased). In this study, after demonstrating suppression of Ae. aegypti using transgenic technology, changes in the spatial distribution of the infestation and the abundance of the vector Ae. aegypti were assessed in the post‐release period, along with fluctuation of transgenic mosquitoes in two areas of Brazil. In both pilot trials, there was an average suppression of ca. 70% of the wild population due to the release of transgenic males compared to the pre‐release period. In Juazeiro (Mandacaru), in the post‐release phase, the number of eggs per trap ranged between 0.06 and 14.41 (mean ± SE = 4.44 ± 0.44), and the ovitrap index (OI = number of ovitraps with eggs/total number of ovitraps recovered) ranged from 0.01 to 0.43 (0.13 ± 0.01). In Jacobina (Pedra Branca), during the post‐release phase, the number of eggs per trap ranged between 1 and 7.2 (1.72 ± 0.72), and the OI ranged from 1 to 0.83 (0.095 ± 0.032). The mosquito population in Juazeiro (Mandacaru) remained suppressed for 17 weeks after the release interruption, whereas in Jacobina (Pedra Branca) suppression lasted 32 weeks. In Juazeiro, transgenic larvae were detected up to 5 months after the interruption of the over‐flooding releases of transgenic males. In Jacobina, they were found up to 2 months after the release interruption. The number of eggs collected increased 4–5 months after the release interruption, which indicated that the Ae. aegypti population had been re‐established after the interruption of releases. The results demonstrate that the technique requires a continuous release in the treated areas, and after suppression, the release rate can be decreased and used as a barrier against external migration.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract The number of mosquito populations resistant to insecticides is increasing along with the reemerging of vector‐borne diseases. New technologies are under evaluation to complement the ...strategies used against these mosquitoes. Transgenic mosquitoes are one approach that some countries are considering and they are being evaluated to control the wild population. Although they have achieved success in population suppression of A edes aegypti (L.) ( D iptera: C ulicidae), these studies have not demonstrated what the outcomes are when releases are interrupted (ceased). In this study, after demonstrating suppression of A e. aegypti using transgenic technology, changes in the spatial distribution of the infestation and the abundance of the vector A e. aegypti were assessed in the post‐release period, along with fluctuation of transgenic mosquitoes in two areas of Brazil. In both pilot trials, there was an average suppression of ca. 70% of the wild population due to the release of transgenic males compared to the pre‐release period. In Juazeiro (Mandacaru), in the post‐release phase, the number of eggs per trap ranged between 0.06 and 14.41 (mean ± SE = 4.44 ± 0.44), and the ovitrap index ( OI = number of ovitraps with eggs/total number of ovitraps recovered) ranged from 0.01 to 0.43 (0.13 ± 0.01). In Jacobina (Pedra Branca), during the post‐release phase, the number of eggs per trap ranged between 1 and 7.2 (1.72 ± 0.72), and the OI ranged from 1 to 0.83 (0.095 ± 0.032). The mosquito population in Juazeiro (Mandacaru) remained suppressed for 17 weeks after the release interruption, whereas in Jacobina (Pedra Branca) suppression lasted 32 weeks. In Juazeiro, transgenic larvae were detected up to 5 months after the interruption of the over‐flooding releases of transgenic males. In Jacobina, they were found up to 2 months after the release interruption. The number of eggs collected increased 4–5 months after the release interruption, which indicated that the A e. aegypti population had been re‐established after the interruption of releases. The results demonstrate that the technique requires a continuous release in the treated areas, and after suppression, the release rate can be decreased and used as a barrier against external migration.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
O aumento de vendas de produtos cosméticos e de higiene pessoal deve ser atentamente acompanhado pelos setores regulatórios competentes, uma vez que mais de oito mil matérias-primas são usadas na ...formulação destes produtos e muitas podem ocasionar efeitos adversos tóxicos ou mesmo alergias. Assim, este trabalho visou investigar quais as finalidades do uso de cosméticos entre mulheres, conhecer os mais utilizados e saber os locais de aquisição destes produtos. Tratouse de um estudo transversal, descritivo e exploratório, tendo como instrumento de coleta de dados um questionário com perguntas objetivas, aplicado entre 102 mulheres. A higiene (65,7%) foi respondida como a principal finalidade de uso. Os produtos com maior frequência de utilização foram os perfumes e desodorantes (90,2%), maquiagens (74,5%), produtos para depilação (74,5%) e tinturas de cabelos (41,2%). A maior parte das mulheres (63,7%) relatou comprar os cosméticos em revistas. Diante dos resultados expostos, pode-se inferir que as mulheres utilizam variados tipos de cosméticos, com diferentes finalidades, o que pode implicar em risco para saúde.
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Previous issue ...date: 2013-09-26
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
The use of biodegradable polysaccharides in development of new drug delivery
systems has gained much acceptance. The granules of hydrogels containing a therapeutic
agent formed from the sodium alginate polymer in the presence of divalent ions are studied as
a multiparticulate system for controlled release site specific, to protect the drug from adverse
conditions and to improve its manufacture. The great majority of the substances used in actual
therapeutic derived from the utilization of molecular modification, and the heterocyclic
compounds that present sulfur atoms in its composition are the target of this strategy, since
they exhibit antibacterial, antifungal, antiviral and antitumor activities. The thiophene
derivatives containing the cycloalkyl group linked to the ring thiophenic present important
pharmacological activities, mainly antifungal activities, being considered important molecules
due the increasing demand for new drugs with this activity, but they have limited
pharmacokinetic properties owing to its highly hydrophobic character. This study aimed to
obtain a multiparticulate system of calcium alginate beads containing 2-(2, 4-dichlorobenzylidene)-amino-5,6-dihydro-4H-cyclopentylbthiophene-3-carbonitrile
(5CN06LSVM),
a derivative thiophenic, by ionotropic gelation method from aqueous solution of
sodium alginate 3% and O / W emulsion drug 0.1%, mixed in 5 different ratios (A, B, C, D
and E) with solution of calcium chloride 10%. The morphology, the scanning electron
microscopy (SEM), the yield of the granules, the loading rate, swelling and erosion and the
thermal analysis were evaluated. The resulting granules, with the exception of sample B,
were oval, not agglomerated and with a surface fissures. The yield ranged between 82% and
107%. The highly hydrophobic compound can be entrapped within the granules. The granules
showed low degree o swelling in the simulation solution of gastric juice, but in phosphate
buffer pH 7.4 swelled quickly with complete erosion of the polymer network in 60 minutes.
The thermo gravimetric analyses showed that thermal stability of the drug was better when
incorporated into the granules. I was concluded from this study, it is possible to obtain
multiparticulate system using a simple, easy, and reproducible method, can be used for oral
administration of hydrophobic drugs.
O uso de polissacarídeos biodegradáveis no desenvolvimento de novos sistemas
transportadores de fármaco tem ganhado bastante aceitação. Os grânulos de hidrogel contendo
um agente terapêutico formado a partir do polímero alginato de sódio em presença de íons
divalentes, são estudados como um sistema multiparticulado para liberação controlada sítio
especifica, para proteção do fármaco das condições adversas do meio e para melhorar a sua
fabricação. A grande maioria das substâncias utilizadas na terapêutica atual derivou da
utilização da estratégia de modificação molecular, e os compostos heterocíclicos que
apresentam átomos de enxofre em sua composição são alvo dessa estratégia, visto que
apresentam atividades antibacteriana, antifúngica, antiviral e antitumoral. Os derivados
tiofênicos contendo o grupo cicloalquil ligado ao anel tiofênico apresentam importantes
atividades farmacológicas, principalmente antifúngicas, sendo consideradas moléculas
importantes devido a crescente demanda por novos fármacos com esta atividade, porém eles
apresentam limitadas propriedades farmacocinéticas devido ao seu caráter altamente
hidrofóbico. Este trabalho objetivou obter um sistema multiparticulado de grânulos de
alginato de cálcio contendo o 2-(2,4-dicloro-benzilideno)-amino-5,6-diidro-4Hciclopentilbtiofeno-3-carbonitrila
(5CN06-LSVM),
um
derivado
tiofênico,
pelo método de
gelificação ionotrópica, a partir de uma solução aquosa de alginato de sódio 3% e emulsão
O/A do fármaco 0,1%, misturadas em 5 diferentes proporções (A, B, C, D e E) com uma
solução de cloreto de cálcio a 10%. A morfologia, a microscopia eletrônica de varredura
(MEV), o rendimento dos grânulos, a taxa de carregamento, o intumescimento e erosão e a
análise térmica foram avaliadas. Os grânulos resultantes, com exceção da amostra B, foram
ovais, não aglomerados e com uma superfície apresentando fissuras. O rendimento variou
entre 82% e 107%. O composto altamente hidrofóbico pode ser aprisionado até 67,17%
dentro dos grânulos. Os grânulos mostraram baixo grau de intumescimento na solução de
simulação de suco gástrico, mas em tampão fosfato pH 7,4 intumesceram rapidamente com
erosão completa da rede polimérica em 60 minutos. A análise termogravimétrica mostrou que
a estabilidade térmica do fármaco era melhor quando incorporado aos grânulos. Concluiu-se
com este estudo, que é possível obter um sistema multiparticulado, utilizando um método
simples, fácil e reprodutível, possível de ser utilizado para administração oral de fármacos
hidrofóbicos.
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