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 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.
Treatment of pain and fever remains an important challenge for modern medicine. Non-steroidal anti-inflammatory drugs (NSAIDs) are the pharmacological options most often used, but their frequent use ...exposes the patient to serious side effects and dangerous drug interactions. In this context, thiophene derivatives are promising therapeutic alternatives. In this study, we evaluated the in vivo and in silico antinociceptive and antipyretic properties of RMD86, a thiophene derivative. At 100 mg/kg, RMD86 induced no significant changes in the motor coordination of mice in the Rotarod test. At 25, 50, and 100 mg/kg RMD86 significantly reduced the number of abdominal contortions induced by acetic acid (antinociceptive activity) in mice when compared to the control. In the formalin test, for the first phase, there was a reduction in licking times at doses of 50 and 100 mg/kg. In the second phase, reduction occurred at all doses. In the hot plate test, RMD86 (at 100 mg/kg) increased latency time in the first 30 min. For antipyretic activity, RMD86, when compared to the reference drug acetaminophen (250 mg/kg), significantly reduced pyrexia at 30, 60, and 120 min, at dosages of 25, 50 and 100 mg/kg. Molecular docking studies revealed that RMD86 presents a greater number of interactions and lower energy values than both the co-crystallized ligand and the reference drug (meloxicam) against COX-1 and COX-2 isoenzymes. The results give evidence of the analgesic and antipyretic properties like NSAIDs suggesting its potential for pain therapy.
Antipyretic activity; Antinociceptive activity; 2-amino-thiophene derivative; Molecular docking; Biological sciences; Neuroscience; Behavioral neuroscience; Behavioral test; Nervous system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Fifty 2-(arylidene)amino-4,5-cycloalkylbthiophene-3-carbonitrile derivatives were screened for their in vitro antifungal activities against Candida krusei and Cryptococcus neoformans. Based on ...experimentally determined minimum inhibitory concentration (MIC) values, we conducted computer-aided drug design studies molecular modelling, chemometric tools (CPCA, PCA, PLS) and QSAR-3D that enable the prediction of three-dimensional structural characteristics that influence the antifungal activities of these derivatives. These predictions provide direction with regard to the syntheses of new derivatives with improved biological activities, which can be used as therapeutic alternatives for the treatment of fungal infections.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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Previous issue date: 2015-03-26
Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Natural products represent a vast source of molecules with pharmacological potential and serve as a basis for seeking and obtaining of new bioactive substances semi-synthetic and synthetic. Based on this knowledge, the interest for new pharmacologically active substances, resulted in the isolation, extraction and synthesis of various bioactive molecules. The medicinal chemistry uses natural products as template for the synthesis of new molecules that are capable of acting against various diseases that affect the global population. Natural products and bioactive molecules thiophenes are widely cited in the literature. This study evaluated two methods (conventional and ultrasonic) synthesis of new 2-aminotiofenos using as precursors various natural products through Gewald reaction by comparing several variables. 13 reactions were analyzed by varying the solvent, base, temperature, agitation mode, time and number of steps. There was the formation of at least one by-product in all reactions. Among the variables, the seconding most effective were: ultrasonic methodology, the lower temperature and shorter reaction time. The ultrasonic energy reactions conducted more quickly (in less reaction time), forming fewer byproducts of the reaction by magnetic stirring. The temperature variable is also essential to this study, the best results being obtained at lower possible temperature (ambient or ice bath). The isolation of some byproducts of the reactions was carried out, but the 1H NMR analysis allowed to identify neither the desired end product (adduct of Gewald) or intermediate (Knoevenagel adduct). New methodological changes and isolation of other byproducts still need to be carried out to prove the success of the reactions and to obtain new adducts Gewald. This study allowed the start of the optimization of reaction conditions of Gewald reaction using natural products as precursors and assist future work in the area.
Os produtos naturais representam uma vasta fonte de moléculas com um potencial farmacológico e servem como base na busca e obtenção de novas substâncias bioativas semi-sintéticas e sintéticas. Baseados nesse conhecimento, o interesse por novas substâncias farmacologicamente ativas, resultou no isolamento, extração e síntese de diversas moléculas bioativas. A química medicinal utiliza como modelo os produtos naturais para a síntese de novas moléculas, que sejam capazes de atuarem frente a várias enfermidades que acometem a população mundial. Os produtos naturais e os tiofenos são moléculas bioativas largamente citadas na literatura. Esse trabalho avaliou duas metodologias (convencional e ultrassônica) de síntese de novos 2-aminotiofenos utilizando como precursores vários produtos naturais através da reação de Gewald, comparando diversas variáveis. Foram analisadas 13 reações, variando o solvente, base, temperatura, modo agitação, tempo e quantidade de etapas. Houve a formação de pelo menos um subproduto em todas as reações. Dentre as variáveis, as que destacaram mais eficazes foram: a metodologia ultrassônica, a menor temperatura e o menor tempo reacional. A energia ultrassônica conduziu as reações de forma mais rápida (em menor tempo reacional), formando menos subprodutos do que a reação por agitação magnética. A variável temperatura foi também essencial para esse estudo, sendo os melhores resultados obtidos em menor temperatura possível (temperatura ambiente ou banho de gelo). O isolamento de alguns subprodutos das reações foi realizado, porém a análise por RMN 1H não permitiu identificar nem os produtos finais desejados (aduto de Gewald), nem o intermediário (aduto de Knoevenagel). Novas alterações metodológicas e o isolamento de outros subprodutos precisam ainda ser realizados para comprovar o sucesso das reações e a obtenção de novos adutos de Gewald. Este estudo permitiu o início da otimização das condições reacionais da reação de Gewald utilizando produtos naturais como precursores e auxiliará os trabalhos futuros na área.
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