6 research outputs found
SĂntese de hĂbridos 4-metil cumarinas-oxazolinas e 4-metil cumarinas, potenciais hits antifĂşngicos e antichagásicos.
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Combining the pharmacophore features of coumarins and 1,4-substituted 1,2,3-triazoles to design new acetylcholinesterase inhibitors : fast and easy generation of 4-methylcoumarins/1,2,3-triazoles conjugates via Click Chemistry
Coumarins are a large class of compounds that display a range of interesting biological properties, being considered privileged structures because of the ability of their 2H-chromen-2-one nuclei to bind to multiple pharmacological targets. We hypothesized that the linkage of a second pharmacophore nucleus to the 2H-chromen-2-one core, the 1,2,3-triazole moiety, would entail more selective and pharmacologically active coumarins. Therefore, we describe the synthesis of fourteen 4-methylcoumarins/1,4-substituted 1,2,3-triazole conjugates, which were predicted by in silico methods to inhibit acetylcholinesterase (AChE) and proved to be moderate in vitro inhibitors of this enzyme. Molecular docking simulations suggest that the most active of these compounds has a putative binding mode similar to donepezil, both occupying the peripheral anionic site of AChE, which is associated with the secondary noncholinergic functions of the enzyme. This highlights the potential of this series for further optimization in the search of new coumarins for the treatment of Alzheimer’s disease
SĂntese de hĂbridos 4-metil cumarinas-oxazolinas e 4-metil cumarinas, potenciais hits antifĂşngicos e antichagásicos.
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Synthesis and preliminary in vitro evaluation of the antileishmanial potential of 4-methylselenocyanatecoumarins
Introdução: A doença tropical negligenciada leishmaniose ainda Ă© um importante problema de saĂşde pĂşblica que afeta milhões de pessoas em todo o mundo. Relacionada a más condições de vida, esta doença transmitida por vetores apresenta diversas manifestações clĂnicas - desde condições assintomáticas a sistĂŞmicas. As intervenções farmacolĂłgicas estĂŁo desatualizadas e apresentam várias desvantagens, portanto, a busca por novos compostos antileishmaniais Ă© imprescindĂvel. Várias classes de heterocĂclos já foram descritas com potencial antileishmania, e as cumarinas nĂŁo sĂŁo exceção. Esses compostos versáteis tĂŞm um amplo espectro de atividades biolĂłgicas, incluindo propriedades antileishmania. Paralelamente, na Ăşltima dĂ©cada, substâncias contendo selĂŞnio surgiram como uma estratĂ©gia promissora no desenvolvimento de derivados antileishmania mais potentes. Considerando a relevância farmacolĂłgica da classe das cumarinas na quĂmica medicinal e o potencial antileishmania dos compostos de selĂŞnio, a uniĂŁo dessas entidades parece ser uma estratĂ©gia coerente para a obtenção de novas substâncias bioativas. Objetivos: Sintetizar uma sĂ©rie de 4-metilselenocianatocumarinas e avaliar seu potencial antileishmania contra parasitas da espĂ©cie Leishmania amazonensis. MĂ©todos: Oito derivados de 4-metilselenocianatocoumarinas foram sintetizados e caracterizados por tĂ©cnicas espectroscĂłpicas de RMN e IV. As avaliações antileishmania foram realizadas nas formas promastigotas de L. amazonensis. Resultados: A rota sintĂ©tica proposta permitiu a obtenção de compostos inĂ©ditos com rendimentos moderados a satisfatĂłrios (43-80%). A avaliação antileishmania preliminar demonstrou que todos os compostos sintetizados exibiram ação leishmanicida contra as formas promastigotas de L. amazonensis a 100 ÎĽM. A sĂ©rie foi capaz de reduzir a viabilidade das promastigotas em atĂ© 85%. Conclusões: Uma nova sĂ©rie de 4-metilselenocianatocoumarinas foi facilmente obtida em duas etapas. Todos os compostos demonstraram atividade antileishmania em condições in vitro contra parasitas da espĂ©cie L. amazonensis.Introduction: The neglected tropical disease leishmaniasis is still a major public health problem that affects millions of people worldwide. Related to poor living conditions, this vector-borne disease presents multiple clinical manifestations - from asymptomatic to systemic conditions. Current pharmacological interventions are outdated and present several drawbacks, thus the search for new antileishmanial compounds is imperative. Various classes of heterocycles have been described as potential antileishmanial scaffolds, and coumarins are no exception. These versatile compounds have a wide spectrum of biological activities, including antileishmanial properties. In parallel, in the last decade, selenium-containing compounds have emerged as a promising strategy to access more potent antileishmanial derivatives. Given the pharmacological relevance of coumarin class in medicinal chemistry and the antileishmanial potential of selenium compounds, the union of these entities seems to be a coherent strategy for obtaining new bioactive substances. Objectives: To synthesize a series of 4-methylselenocyanatecoumarins and evaluate its antileishmanial potential against Leishmania amazonensis. Methods: Eight 4-methylselenocyanatecoumarins derivatives were synthesized and characterized using NMR and IR spectroscopy techniques. Antileishmanial assessments were performed against L. amazonensis promastigotes. Results: The proposed synthetic route allowed the generation of novel compounds with moderate to satisfactory yields (43-80%). Preliminary antileishmanial evaluation showed that all synthesized compounds exhibited leishmanicidal action against L. amazonensis promastigotes at 100 ÎĽM. The series was able to reduce promastigotes viability up to 85%. Conclusions: A new series of 4-methylselenocyanatecoumarins was easily obtained in a two-step route. All compounds showed antileishmanial activity on in vitro conditions against L. amazonensis parasites
SĂntese e estudo in silico de derivados 6-amino-sulfonilcumarinas
Uma sĂ©rie de 6-amino-sulfonilcumarinas foi planejada e sintetizada atravĂ©s de reações a temperatura ambiente com rendimentos moderados (50-70%) utilizando aminas aromáticas e alifáticas. Estudos in silico demonstraram que a piruvato quinase de Leishmania braziliensis Ă© um possĂvel alvo para os compostos sintetizados. Ensaios de docagem molecular foram realizados e constatou-se que todos os derivados possuem capacidade de ligar-se ao receptor da enzima. O composto 4f demonstrou ser o mais promissor para inibição da piruvato quinase de Leishmania mexicana, apresentando um escore de ΔG = -7,1 Kcal/mol. Análises toxicolĂłgicas in silico demonstraram que, com exceção do intermediário 3, nenhum dos derivados tĂŞm potencial irritante, mutagĂŞnico ou tumorogĂŞnico. Os compostos sintetizados apresentam caracterĂsticas favoráveis para tornarem-se candidatos a fármacos, segundo os resultados obtidos pela predição farmacocinĂ©tica in silico
Synthesis and Antimycobacterial Evaluation of N-(4-(Benzyloxy)benzyl)-4-aminoquinolines
Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment