Larvicidal Activity of Cinnamic Acid Derivatives: Investigating Alternative Products for Aedes aegypti L. Control.

The mosquito Aedes aegypti transmits the virus that causes dengue, yellow fever, Zika and Chikungunya viruses, and in several regions of the planet represents a vector of great clinical importance. In terms of mortality and morbidity, infections caused by Ae. aegypti are among the most serious arthropod transmitted viral diseases. The present study investigated the larvicidal potential of seventeen cinnamic acid derivatives against fourth stage Ae. aegypti larvae. The larvicide assays were performed using larval mortality rates to determine lethal concentration (LC50). Compounds containing the medium alkyl chains butyl cinnamate (7) and pentyl cinnamate (8) presented excellent larvicidal activity with LC50 values of around 0.21-0.17 mM, respectively. While among the derivatives with aryl substituents, the best LC50 result was 0.55 mM for benzyl cinnamate (13). The tested derivatives were natural compounds and in pharmacology and antiparasitic studies, many have been evaluated using biological models for environmental and toxicological safety. Molecular modeling analyses suggest that the larvicidal activity of these compounds might be due to a multi-target mechanism of action involving inhibition of a carbonic anhydrase (CA), a histone deacetylase (HDAC2), and two sodium-dependent cation-chloride co-transporters (CCC2 e CCC3).

ß-Cyclodextrin/Isopentyl Caffeate Inclusion Complex: Synthesis, Characterization and Antileishmanial Activity.

Isopentyl caffeate (ICaf) is a bioactive ester widely distributed in nature. Our patented work has shown promising results of this molecule against Leishmania. However, ICaf shows poor solubility, which limits its usage in clinical settings. In this work, we have proposed the development of an inclusion complex of ICaf in ß-cyclodextrin (ß-CD), with the aim to improve the drug solubility, and thus, its bioavailability. The inclusion complex (ICaf:ß-CD) was developed applying three distinct methods, i.e., physical mixture (PM), kneading (KN) or co-evaporation (CO) in different molar proportions (0.25:1, 1:1 and 2:1). Characterization of the complexes was carried out by thermal analysis, Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and molecular docking. The ICaf:ß-CD complex in a molar ratio of 1:1 obtained by CO showed the best complexation and, therefore, was selected for further analysis. Solubility assay showed a marked improvement in the ICaf:ß-CD (CO, 1:1) solubility profile when compared to the pure ICaf compound. Cell proliferation assay using ICaf:ß-CD complex showed an IC50 of 3.8 and 2.7 µg/mL against L. amazonesis and L. chagasi promastigotes, respectively. These results demonstrate the great potential of the inclusion complex to improve the treatment options for visceral and cutaneous leishmaniases.

Trypanocidal Mechanism of Action and in silico Studies of p-Coumaric Acid Derivatives.

Trypanosoma species are responsible for chronic and systemic infections in millions of people around the world, compromising life quality, and family and government budgets. This group of diseases is classified as neglected and causes thousands of deaths each year. In the present study, the trypanocidal effect of a set of 12 ester derivatives of the p-coumaric acid was tested. Of the test derivatives, pentyl p-coumarate (7) (5.16 ± 1.28 µM; 61.63 ± 28.59 µM) presented the best respective trypanocidal activities against both epimastigote and trypomastigote forms. Flow cytometry analysis revealed an increase in the percentage of 7-AAD labeled cells, an increase in reactive oxygen species, and a loss of mitochondrial membrane potential; indicating cell death by necrosis. This mechanism was confirmed by scanning electron microscopy, noting the loss of cellular integrity. Molecular docking data indicated that of the chemical compounds tested, compound 7 potentially acts through two mechanisms of action, whether by links with aldo-keto reductases (AKR) or by comprising cruzain (CZ) which is one of the key Trypanosoma cruzi development enzymes. The results indicate that for both enzymes, van der Waals interactions between ligand and receptors favor binding and hydrophobic interactions with the phenolic and aliphatic parts of the ligand. The study demonstrates that p-coumarate derivatives are promising molecules for developing new prototypes with antiprotozoal activity.

Anthelmintic activity of the natural compound (+)-limonene epoxide against Schistosoma mansoni.

Blood fluke of the genus Schistosoma are the etiological agents of human schistosomiasis, an important neglected tropical disease that afflicts over 200 million people worldwide. The treatment for this disease relies heavily on a single drug, praziquantel. Recent reports of praziquantel resistance raise concerns about future control of the disease and show the importance of developing new antischistosomal drugs. Currently, natural products have been a good source for drug development. (+)-Limonene epoxide is a mixture of cis and trans isomers found in many plants. Here, we report the in vitro effect of this natural compound on the survival time of Schistosoma mansoni adult worms. In addition, we examined alterations on the tegumental surface of adult schistosomes by means of confocal laser scanning microscopy. The effects of (+)-limonene epoxide at 25 µg/mL on S. mansoni adult worms were similar to those of the positive control (praziquantel), with reduction in motility and death of all worms after 120 h. Confocal laser scanning microscopy revealed that (+)-limonene epoxide-mediated worm killing was associated with tegumental destruction. Our results, along with the low toxicity of the (+)-limonene epoxide, suggest that this natural compound might be promising for the development of new schistosomicidal agents.

Action mechanism of the monoterpenes (+)-pulegone and 4-terpinyl acetate in isolated guinea pig ileum / Mecanismo de accion de los monoterpenos (+)-pulegona y acetato de 4-terpinil en íleon aislado de cobayo

Recent studies have shown the spasmolytic activity of p-menthane monoterpenes (+)-pulegone and 4-terpinyl acetate (4-T) in guinea pig ileum. Since the action mechanism of these monoterpenes in intestinal smooth muscle is unknown, the present study was conducted to characterize their relaxant mechanism in isolated guinea pig ileum. We tested the involvement of voltage-dependent calcium and potassium channels and muscarinic antagonism. Both the monoterpenes caused a shift in the calcium curve to the right with reduction in the maximum effect. Pretreatment with tetraethylammonium chloride partially inhibited relaxation produced by both 4-T and (+)-pulegone. Both compounds caused a shift in the bethanechol curve to the right with reduction in the maximum effect. The results of this study indicate that the mechanisms of action of the smooth muscle relaxant monoterpenes (+)-pulegone and 4-T possibly involve the partial blockade of calcium channels, the activation of potassium channels, and the non-competitive antagonism of muscarinic receptors.

Estudios recientes han demostrado la actividad espasmolítica de los monoterpenos p-mentano de (+)-pulegona y acetato de 4-terpinilo (4-T) en el íleon de cobayo. Dado que el mecanismo de acción de estos monoterpenos en el músculo liso intestinal es desconocido, el presente estudio se llevó a cabo para caracterizar su mecanismo relajante en íleon aislado de conejillo de indias. Hemos probado la participación de tanto los canales calcio dependiente de voltaje como los canales de potasio y antagonistas muscarínicos. Ambos monoterpenos causaron un desplazamiento en la curva de calcio a la derecha con la reducción en el efecto máximo. El tratamiento previo con cloruro de tetraetilamonio inhibe parcialmente la relajación producida por tanto 4-T y (+)-pulegona. Ambos compuestos causaron un cambio en la curva de betanecol a la derecha con la reducción en el efecto máximo. Los resultados de este estudio indican que los mecanismos de acción de los monoterpenos relajantes del músculo liso (+)-pulegona y 4-T posiblemente implican el bloqueo parcial de los canales de calcio, la activación de los canales de potasio, y el antagonismo no competitivo de los receptores muscarínicos.

Antiulcer effect of epoxy-carvone

Epoxy-carvone is a monoterpene present in essential oils of various plants. It is a derivative of carvone, which has an epoxy group instead of the α- and β-unsaturated ketone group present in carvone. As recent studies have shown that several alcohol terpenes and compounds containing α, β-unsaturated ketone groups present antiulcer effect, the main of the present study was to evaluate the antiulcer effect of epoxy-carvone. The models of ulcers induced by ethanol and indomethacin were used in this study. Epoxy-carvone at the dose of 1 mg/kg did not present antiulcer effect against ulcer induced by ethanol, but at the doses of 10, 30 and 50 mg/kg it presented gastroprotective effect in both ulcer models. Epoxy-carvone also did not affect the gastric secretion in the pylorus ligation test. Moreover, pretreatment with indomethacin or L-nitroarginine methyl ester did not reverse the gastroprotection produced by this monoterpene. This study showed that epoxy-carvone presents antiulcer effect and suggests that this effect does not involve either antisecretory activity or increase of the nitric oxide and prostaglandin synthesis.

Anticonvulsant activity of thymoquinone and its structural analogues

It has been widely reported that the crude oil of Nigella sativa L., Ranunculaceae, seeds and its major chemical component thymoquinone present anticonvulsant activity. These facts led us to verify the pharmacological potential of five structurally related para-benzoquinones on the pentylenotetrazol-induced seizures model, and establish the structural characteristics that influence the anticonvulsant activity of thymoquinone. The unsubstituted para-benzoquinone was the compound that exhibited the highest potency, while 2-methyl-p-benzoquinone was inactive. It was found that the presence of alkyl groups attached to the ring influence the pharmacological activity of the para-benzoquinones. In addition, the number, position, and size of these groups change the anticonvulsant potency of the compounds.

Bioassay-guided evaluation of central nervous system effects of citronellal in rodents

The central nervous system (CNS) depressant and anticonvulsant activities of citronellal (CT) were investigated in animal models. The CT in doses of 100, 200 and 400 mg/kg injected by i.p. route in mice caused a significant decrease in the motor activity of animals when compared with the control group. The highest dose of CT significantly reduced the remaining time of the animals on the Rota-rod apparatus up to 2 h. Additionally, CT at doses 100, 200 and 400 mg/ kg (i.p.) was also capable to promote an increase of latency for development of convulsions induced by pentylenetetrazole (PTZ). It was efficient in prevents the tonic convulsions induced by maximal electroshock (MES) in doses of 200 and 400 mg/kg, resulting in 30 and 40 percent of protection, respectively. This compound was also capable to promote an increase of latency for development of convulsions induced by picrotoxin (PIC) at 400 mg/kg. In the same way, the anticonvulsant effect of CT was affected by pretreatment with flumazenil, a selective antagonist of benzodiazepine site of GABA A receptor. These results suggest a possible CNS depressant and anticonvulsant activities.

Pharmacological effects of the monoterpene alpha, beta-epoxy-carvone in mice

The monoterpene alpha,beta-epoxy-carvone (EC) in doses of 200, 300 or 400 mg/kg injected by i.p. route in mice caused a significant decrease in the motor activity of animals when compared with the control group, up to 120 minutes after the administration. The doses of 300 or 400 mg/kg had induced a significant increase of in the sleeping time of animals not having modified, however, the latency. The EC in the dose of 400 mg/kg reduced the remaining time of the animals on the rotating rod (Rotarod test). These results suggest a possible central effect.

O monoterpeno alfa,beta-epóxi-carvona (EC) nas doses de 200, 300 e 400 mg/kg administrado por via i.p. em camundongos diminuiu significativamente a atividade motora dos animais, quando comparado aos controles, até 120 minutos após a administração. As doses de 300 e 400 mg/kg induziram um aumento significativo do tempo de sono dos animais não alterando, no entanto, a sua latência. O EC na dose de 400 mg/kg induziu uma redução no tempo de permanência dos animais na barra giratória (teste do rotarod). Os resultados sugerem um possível efeito central.