RESUMO
Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.
Assuntos
Curcumina , Curcumina/química , Fator de Necrose Tumoral alfa , Interleucina-6 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Relação Estrutura-AtividadeRESUMO
Herein, we describe the synthesis and evaluation of anti-inflammatory activities of new curcumin derivatives. The thirteen curcumin derivatives were synthesized by Steglich esterification on one or both of the phenolic rings of curcumin with the aim of providing improved anti-inflammatory activity. Monofunctionalized compounds showed better bioactivity than the difunctionalized derivatives in terms of inhibiting IL-6 production, and known compound 2 presented the highest activity. Additionally, this compound showed strong activity against PGE2. Structure-activity relationship studies were carried out for both IL-6 and PGE2, and it was found that the activity of this series of compounds increases when a free hydroxyl group or aromatic ligands are present on the curcumin ring and a linker moiety is absent. Compound 2 remained the highest activity in modulating IL-6 production and showed strong activity against PGE2 synthesis.
Assuntos
Anti-Inflamatórios , Curcumina , Polifenóis , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Interleucina-6 , Polifenóis/química , Relação Estrutura-AtividadeRESUMO
In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its causative agent, SARS-CoV-2, many of which focus on its main protease (Mpro). We hereby used two approaches based on molecular docking simulation to explore the interaction of four libraries of semisynthetic nitrogenous heterocyclic compounds with Mpro. Libraries L1 and L2 contain 52 synthetic derivatives of the natural compound 2-propylquinoline, whereas libraries L3 and L4 contain 65 compounds synthesized using the natural compound physostigmine as a precursor. Validation through redocking suggested that the rigid receptor and flexible receptor approaches used for docking were suitable to model the interaction of this type of compounds with the target protein, although the flexible approach seemed to provide a more realistic representation of interactions within the active site. Using empirical energy score thresholds, we selected 58 compounds from the four libraries with the most favorable energy estimates. Globally, favorable estimates were obtained for molecules with two or more substituents, putatively accommodating in three or more subsites within the Mpro active site. Our results pave the way for further experimental evaluation of the selected compounds as potential antiviral agents against SARS-CoV-2.
Assuntos
Antivirais/química , Tratamento Farmacológico da COVID-19 , COVID-19 , Proteases 3C de Coronavírus , Compostos Heterocíclicos/química , Simulação de Dinâmica Molecular , Pandemias , Inibidores de Proteases/química , SARS-CoV-2/enzimologia , Antivirais/uso terapêutico , COVID-19/epidemiologia , Domínio Catalítico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Inibidores de Proteases/uso terapêuticoRESUMO
Leishmania panamensis is a relevant causative agent of tegumentary leishmaniasis in several Latin American countries. Available antileishmanial drugs have several limitations including relatively high toxicity, difficult administration, high production costs and the emergence of resistance in circulating strains. Therefore, the identification of new molecules as potential therapeutics for leishmaniasis is of great relevance. Here, we developed a murine model of L. panamensis infection and evaluated the effect of a new compound in vivo. After treatment of animals with the compound, we observed a significant reduction of inflammation and parasite load at the inoculation site, in a dose-dependent manner. We observed a reduction in IL-10 production by popliteal lymph nodes cells of infected mice. These results pave the way for future evaluation of this compound as a potential antileishmanial drug or as a suitable scaffold for lead optimization strategies.
Assuntos
Antiprotozoários , Leishmania , Leishmaniose , Animais , Antiprotozoários/uso terapêutico , Cloroquina/uso terapêutico , Modelos Animais de Doenças , Feminino , Leishmaniose/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Preparações FarmacêuticasRESUMO
Alzheimer's disease (AD) is the most common form of dementia among the elderly and has become a leading public health concern worldwide. It represents a huge economic and psychological burden to caregivers and families. The presence of extracellular amyloid beta (Aß) plaques is one of the hallmarks of this neurodegenerative disorder. Amyloid plaques are comprised of aggregates of Aß peptides, mainly Aß42, originated by the cleavage of the amyloid precursor protein (APP). Aß is a crucial target for the treatment of AD, but to date, no effective treatment for the clearance of Aß has been found. We have identified four new hexahydropyrroloindoles (HPI) synthetic compounds that are able to inhibit the aggregation of Aß42 and/or disaggregate the fibril. Docking experiments suggest that the nonpolar component of the interaction of compounds with Aß42 contributes favorably to the binding free energy of each complex. Molecular dynamics simulations suggested fibril disaggregating activity of compounds 1 via interaction with hydrophobic moieties of the fibril. Consistently, compounds 1 and 2 were able to mitigate Aß42 fibrils induced death in rat pheochromocytoma cells (PC 12). One of the compounds reduces the formation of Aß aggregates in vivo and the paralysis associated with Aß toxicity in Caenorhabditis elegans. Our study thus augments efforts for the identification and characterization of new agents that may help stop or delay the progression of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Indóis/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Pirróis/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Indóis/farmacologia , Células PC12 , Agregação Patológica de Proteínas/metabolismo , Pirróis/farmacologia , RatosRESUMO
Dengue virus causes dengue fever, a debilitating disease with an increasing incidence in many tropical and subtropical territories. So far, there are no effective antivirals licensed to treat this virus. Here we describe the synthesis and antiviral activity evaluation of two compounds based on the quinoline scaffold, which has shown potential for the development of molecules with various biological activities. Two of the tested compounds showed dose-dependent inhibition of dengue virus serotype 2 in the low and sub micromolar range. The compounds 1 and 2 were also able to impair the accumulation of the viral envelope glycoprotein in infected cells, while showing no sign of direct virucidal activity and acting possibly through a mechanism involving the early stages of the infection. The results are congruent with previously reported data showing the potential of quinoline derivatives as a promising scaffold for the development of new antivirals against this important virus.
Assuntos
Antivirais/síntese química , Vírus da Dengue/metabolismo , Quinolinas/síntese química , Proteínas do Envelope Viral/metabolismo , Animais , Antivirais/química , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Estrutura Molecular , Quinolinas/química , Quinolinas/farmacologia , Sorogrupo , Células VeroRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity.