The Antitumor Activity of Piplartine: A Review.

Cancer is a worldwide health problem with high mortality in children and adults, making searching for novel bioactive compounds with potential use in cancer treatment essential. Piplartine, also known as piperlongumine, is an alkamide isolated from Piper longum Linn, with relevant therapeutic potential. Therefore, this review covered research on the antitumor activity of piplartine, and the studies reported herein confirm the antitumor properties of piplartine and highlight its possible application as an anticancer agent against various types of tumors. The evidence found serves as a reference for advancing mechanistic research on this metabolite and preparing synthetic derivatives or analogs with better antitumor activity in order to develop new drug candidates.

Nanoemulsions and Solid Microparticles Containing Pentyl Cinnamate to Control Aedes aegypti.

The Aedes aegypti mosquito is a vector of severe diseases with high morbidity and mortality rates. The most commonly used industrial larvicides have considerable toxicity for non-target organisms. This study aimed to develop and evaluate liquid and solid carrier systems to use pentyl cinnamate (PC), derived from natural sources, to control Ae. aegypti larvae. The liquid systems consisting of nanoemulsions with different lecithins systems were obtained and evaluated for stability over 30 days. Microparticles (MPs) were obtained by the spray drying of the nanoemulsions using maltodextrin as an adjuvant. Thermal, NMR and FTIR analysis indicated the presence of PC in microparticles. Indeed, the best nanoemulsion system was also the most stable and generated the highest MP yield. The PC larvicidal activity was increased in the PC nanoemulsion system. Therefore, it was possible to develop, characterize and obtain PC carrier systems active against Ae. aegypti larvae.

Essential Oils: Chemistry and Pharmacological Activities.

In this review, we provide an overview of the current understanding of the main mechanisms of pharmacological action of essential oils and their components in various biological systems. A brief introduction on essential oil chemistry is presented to better understand the relationship of chemical aspects with the bioactivity of these products. Next, the antioxidant, anti-inflammatory, antitumor, and antimicrobial activities are discussed. The mechanisms of action against various types of viruses are also addressed. The data show that the multiplicity of pharmacological properties of essential oils occurs due to the chemical diversity in their composition and their ability to interfere with biological processes at cellular and multicellular levels via interaction with various biological targets. Therefore, these natural products can be a promising source for the development of new drugs.

Piplartine-Inspired 3,4,5-Trimethoxycinnamates: Trypanocidal, Mechanism of Action, and In Silico Evaluation.

Chagas disease (CD) is one of the main neglected tropical diseases that promote relevant socioeconomic impacts in several countries. The therapeutic options for the treatment of CD are limited, and parasite resistance has been reported. Piplartine is a phenylpropanoid imide that has diverse biological activities, including trypanocidal action. Thus, the objective of the present work was to prepare a collection of thirteen esters analogous to piplartine (1-13) and evaluate their trypanocidal activity against Trypanosoma cruzi. Of the tested analogues, compound 11 ((E)-furan-2-ylmethyl 3-(3,4,5-trimethoxyphenyl)acrylate) showed good activity with IC50 values = 28.21 ± 5.34 µM and 47.02 ± 8.70 µM, against the epimastigote and trypomastigote forms, respectively. In addition, it showed a high rate of selectivity to the parasite. The trypanocidal mechanism of action occurs through the induction of oxidative stress and mitochondrial damage. In addition, scanning electron microscopy showed the formation of pores and leakage of cytoplasmic content. Molecular docking indicated that 11 probably produces a trypanocidal effect through a multi-target mechanism, including affinity with proteins CRK1, MPK13, GSK3B, AKR, UCE-1, and UCE-2, which are important for the survival of the parasite. Therefore, the results suggest chemical characteristics that can serve for the development of new trypanocidal prototypes for researching drugs against Chagas disease.

Enhancing the antischistosomal activity of carvacryl acetate using nanoemulsion.

Aim: To formulate a carvacryl acetate nanoemulsion (CANE) and test its antischistosomal activity. Materials & methods: CANE was prepared and tested in vitro on Schistosoma mansoni adult worms and both human and animal cell lines. Next, CANE was administered orally to mice infected with either a prepatent infection or a patent infection of S. mansoni. Results: CANE was stable during 90 days of analysis. CANE showed in vitro anthelmintic activity, and no cytotoxic effects were observed. In vivo, CANE was more effective than the free compounds in reducing worm burden and egg production. Treatment with CANE was more effective for prepatent infections than praziquantel. Conclusion: CANE improves antiparasitic properties and may be a promising delivery system for schistosomiasis treatment.

Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma.

Cancer is a principal cause of death in the world, and providing a better quality of life and reducing mortality through effective pharmacological treatment remains a challenge. Among malignant tumor types, squamous cell carcinoma-esophageal cancer (EC) is usually located in the mouth, with approximately 90% located mainly on the tongue and floor of the mouth. Piplartine is an alkamide found in certain species of the genus Piper and presents many pharmacological properties including antitumor activity. In the present study, the cytotoxic potential of a collection of piplartine analogs against human oral SCC9 carcinoma cells was evaluated. The analogs were prepared via Fischer esterification reactions, alkyl and aryl halide esterification, and a coupling reaction with PyBOP using the natural compound 3,4,5-trimethoxybenzoic acid as a starting material. The products were structurally characterized using 1H and 13C nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry for the unpublished compounds. The compound 4-methoxy-benzyl 3,4,5-trimethoxybenzoate (9) presented an IC50 of 46.21 µM, high selectively (SI > 16), and caused apoptosis in SCC9 cancer cells. The molecular modeling study suggested a multi-target mechanism of action for the antitumor activity of compound 9 with CRM1 as the main target receptor.

Synthesis of Coumarin and Homoisoflavonoid Derivatives and Analogs: The Search for New Antifungal Agents.

A set of twenty-four synthetic derivatives, with coumarin and homoisoflavonoid cores and structural analogs, were submitted for evaluation of antifungal activity against various species of Candida. The broth microdilution test was used to determine the Minimum Inhibitory Concentration (MIC) of the compounds and to verify the possible antifungal action mechanisms. The synthetic derivatives were obtained using various reaction methods, and six new compounds were obtained. The structures of the synthesized products were characterized by FTIR spectroscopy: 1H-NMR, 13C-NMR, and HRMS. The coumarin derivative 8 presented the best antifungal profile, suggesting that the pentyloxy substituent at the C-7 position of coumarin ring could potentiate the bioactivity. Compound 8 was then evaluated against the biofilm of C. tropicalis ATCC 13803, which showed a statistically significant reduction in biofilm at concentrations of 0.268 µmol/mL and 0.067 µmol/mL, when compared to the growth control group. For a better understanding of their antifungal activity, compounds 8 and 21 were submitted to a study of the mode of action on the fungal cell wall and plasma membrane. It was observed that neither compound interacted directly with ergosterol present in the fungal plasma membrane or with the fungal cell wall. This suggests that their bioactivity was due to interaction involving other pharmacological targets. Compound 8 was also subjected to a molecular modeling study, which showed that its antifungal action mechanism occurred mainly through interference in the redox balance of the fungal cell, and by compromising the plasma membrane; not by direct interaction, but by interference in ergosterol synthesis. Another important finding was the antifungal capacity of homoisoflavonoids 23 and 24. Derivative 23 presented slightly higher antifungal activity, possibly due to the presence of the methoxyl substituent in the meta position in ring B.

A Narrative Review of the Antitumor Activity of Monoterpenes from Essential Oils: An Update.

Monoterpenes are a group of natural products that have been widely studied due to their therapeutic potential against various pathologies. These compounds are abundant in the chemical composition of essential oils. Cancer is a term that covers more than 100 different types of malignant diseases and is among the leading causes of death in the world. Therefore, the search for new pharmacotherapeutic options applicable to cancer is urgent. In this review, studies on the antitumor activity of monoterpenes found in essential oils were selected, and botanical, chemical, and pharmacological aspects were discussed. The most investigated monoterpenes were carvacrol and linalool with highly significant in vitro and in vivo tumor inhibition in several types of cancers. The action mechanisms of these natural products are also presented and are wildly varied being apoptosis the most prevalent followed by cell cycle impairment, ROS production, autophagy, necroptosis, and others. The studies reported here confirm the antitumor properties of monoterpenes and their anticancer potential against various types of tumors, as demonstrated in in vitro and in vivo studies using various types of cancer cells and tumors in animal models. The data described serve as a reference for the advancement in the mechanistic studies of these compounds and in the preparation of synthetic derivatives or analogues with a better antitumor profile.

Acute autonomic effects of rose oxide on cardiovascular parameters of Wistar and spontaneously hypertensive rats.

AIMS: Anti-inflammatory molecules, such as rose oxide (RO), are likely to exert therapeutic effects in systemic arterial hypertension (SAH), a disease associated with abnormal immune responses. We aimed to investigate acute autonomic effects of RO on hemodynamic parameters of Wistar and spontaneously hypertensive rats (SHR). METHODS: Rats were anesthetized and femoral artery and veins were cannulated. Next day, blood pressure (BP) and heart rate (HR) were recorded. Acute effects of RO (1.25, 2.5, or 5.0 mg/kg; iv) on BP, HR, and variability of systolic arterial pressure (SAP) and pulse interval (PI) were assessed. The effects of RO were also investigated in SHR, which received atropine (2 mg/kg), propranolol (4 mg/kg), or hexamethonium (20 mg/kg) 15 min before receiving RO. Vasorelaxant effects of RO (10-10 to 10-4 M) on aortic rings of rats were also assessed. KEY FINDINGS: In Wistar rats, none of the RO doses evoked significant changes in BP, HR, and variability of SAP and PI. On the other hand, in SHR, RO elicited reduction in mean arterial pressure (MAP), and prevented the increase in the low frequency power (LF) of the SAP spectra. Pretreatment with atropine or propranolol did not alter hypotension, but attenuated RO-induced bradycardia. Hexamethonium prevented RO-induced hypotension and bradycardia. RO exerted vasorelaxant effects on aortic rings with (Wistar and SHR) or without functional endothelium (SHR only). SIGNIFICANCE: Rose oxide, a monoterpene with anti-inflammatory properties, acts as an antihypertensive molecule due to its ability to acutely promote hypotension and bradycardia in spontaneously hypertensive rats.

Efficacy of carvacryl acetate in vitro and following oral administration to mice harboring either prepatent or patent Schistosoma mansoni infections.

Schistosomiasis is a major public health problem that afflicts more than 240 million individuals globally, particularly in poor communities. Treatment of schistosomiasis relies heavily on a single oral drug, praziquantel, and there is interest in the search for new antischistosomal drugs. This study reports the anthelmintic evaluation of carvacryl acetate, a derivative of the terpene carvacrol, against Schistosoma mansoni ex vivo and in a schistosomiasis animal model harboring either adult (patent infection) or juvenile (prepatent infection) parasites. For comparison, data obtained with gold standard antischistosomal drug praziquantel are also presented. Initially in vitro effective concentrations of 50% (EC50) and 90% (EC90) were determined against larval and adult stages of S. mansoni. In an animal with patent infection, a single oral dose of carvacryl acetate (100, 200, or 400 mg/kg) caused a significant reduction in worm burden (30-40%). S. mansoni egg production, a process responsible for both life cycle and pathogenesis, was also markedly reduced (70-80%). Similar to praziquantel, carvacryl acetate 400 mg/kg had low efficacy in pre-patent infection. In tandem, although carvacryl acetate had interesting in vitro schistosomicidal activity, the compound exhibited low efficacy in terms of reduction of worm load in S. mansoni-infected mice.

Analysis of the mechanisms of action of isopentenyl caffeate against Leishmania.

Leishmaniasis is a neglected parasitic disease for which the conventional treatment can be considered inefficient and extremely aggressive, generating several and severe side effects. Therefore, the discovery of new drug candidates is important for the improvement in the quality of life of patients. Previously, we reported the promising results of isopentyl caffeate (ICaf) against Leishmania chagasi (agent of visceral leishmaniasis) and Leishmania amazonensis (agent of cutaneous leishmaniasis) promastigotes, displaying IC50 of 1.56 and 1.71 µM, respectively. Herein, we aimed to decipher the mechanisms of anti-Leishmania action of ICaf. Light and scanning electron microscopy assays showed relevant morphological changes in promastigotes when treated with ICaf, including rounding of the parasite body, shortening of the flagellum, blebs on the plasma membrane and cellular aggregation. The parasite mitochondrion was targeted by ICaf, resulting in a significant reduction in its metabolic activity and electric membrane potential followed by an increase in the production of reactive oxygen species, which culminated in the loss of plasma membrane integrity and parasite death. Relevantly, ICaf also had a potent anti-amastigote action. The IC50 values calculated for intracellular amastigotes of L. amazonensis were 3.27, 1.60 and 1.52 µM, while for L. chagasi the values were 2.48, 1.84 and 1.60 µM, respectively, after treating the infected macrophages with ICaf for 24, 48 and 72 h. ICaf was well tolerated by THP-1 macrophages, which gave rise to excellent selectivity indexes considering both Leishmania species. The current results suggest that ICaf may emerge as a chemotherapeutic alternative for the treatment of leishmaniasis.

Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum.

In low-income populations, neglected diseases are the principal cause of mortality. Of these, leishmaniasis and malaria, being parasitic, protozoan infections, affect millions of people worldwide and are creating a public health problem. The present work evaluates the leishmanicidal and antiplasmodial action of a series of twelve p-coumaric acid derivatives. Of the tested derivatives, eight presented antiparasitic activities 1-3, 8-12. The hexyl p-coumarate derivative (9) (4.14 ± 0.55 µg/mL; selectivity index (SI) = 2.72) showed the highest leishmanicidal potency against the Leishmania braziliensis amastigote form. The results of the molecular docking study suggest that this compound inhibits aldehyde dehydrogenase (ALDH), mitogen-activated kinase protein (MPK4), and DNA topoisomerase 2 (TOP2), all of which are key enzymes in the development of Leishmania braziliensis. The data indicate that these enzymes interact via Van der Waals bonds, hydrophobic interactions, and hydrogen bonds with phenolic and aliphatic parts of this same compound. Of the other compounds analyzed, methyl p-coumarate (64.59 ± 2.89 µg/mL; IS = 0.1) demonstrated bioactivity against Plasmodium falciparum. The study reveals that esters presenting a p-coumarate substructure are promising for use in synthesis of derivatives with good antiparasitic profiles.

Bioactivity and Molecular Docking Studies of Derivatives from Cinnamic and Benzoic Acids.

Over the last decade, there has been a dramatic increase in the prevalence and gravity of systemic fungal diseases. This study aimed therefore at evaluating the antifungal potential of ester derivatives of benzoic and cinnamic acids from three Candida species. The compounds were prepared via Fischer esterification, and the antifungal assay was performed by the microdilution method in 96-well microplates for determining the minimal inhibitory concentrations (MICs). The findings of the antifungal tests revealed that the analogue compound methyl ferulate, methyl o-coumarate, and methyl biphenyl-3-carboxylate displayed an interesting antifungal activity against all Candida strains tested, with MIC values of 31.25-62.5, 62.5-125, and 62.5 µg/ml, respectively. A preliminary Structure-Activity Relationship study of benzoic and cinnamic acid derivatives has led to the recognition of some important structural requirements for antifungal activity. The results of molecular docking indicate that the presence of the enoate moiety along with hydroxyl and one methoxy substitution in the phenyl ring has a positive effect on the bioactivity of compound 7 against Candida albicans. These observations further support the hypothesis that the antifungal activity of compound 7 could be due to its binding to multiple targets, specifically to QR, TS, and ST-PK. Additional experiments are required in the future to test this hypothesis and to propose novel compounds with improved antifungal activity.

Antimicrobial Activity of 4-Chlorocinnamic Acid Derivatives.

The microbial resistance of fungi and bacteria is currently considered a major public health problem. Esters derived from cinnamic acid have a broad spectrum of pharmacological properties that include antimicrobial activity. In this study, a collection of structurally related 4-chlorocinnamic acid esters was prepared using Fischer esterification reactions, alkyl or aryl halide esterification, and Mitsunobu and Steglich reactions. All of the esters were submitted to antimicrobial tests against strains of the species Candida albicans, Candida glabrata, Candida krusei, Candida guilliermondii, Pseudomonas aeruginosa, and Staphylococcus aureus. The compounds also were subjected to molecular docking study with the enzyme 14α-demethylase. Twelve esters derived from 4-chlorocinnamic acid were obtained, with yields varying from 26.3% to 97.6%, three of which were unpublished. The ester methyl 4-chlorocinnamate (1) presented activity against S. aureus at the highest concentration tested. In the antifungal evaluation, all of the esters were bioactive, but methoxyethyl 4-chlorocinnamate (4) and perillyl 4-chlorocinnamate (11) were the most potent (MIC = 0.13 and 0.024 µmol/mL, respectively). The data of molecular docking suggested that all the compounds present good affinity towards the active site related to antifungal activity. Therefore, the esters tested may be inhibitors of the enzyme 14α-demethylase. In addition, the results demonstrate that substituents of short alkyl chains with presence of heteroatom, such as oxygen, or those with a perillyl type terpenic substructure promote better antifungal profiles.

Therapeutic Potential of Vanillin and its Main Metabolites to Regulate the Inflammatory Response and Oxidative Stress.

Many phenolic compounds found in foods and medicinal plants have shown interesting therapeutic potential and have attracted the attention of the pharmaceutical industry as promising pharmacologically active compounds in health promotion and disease prevention. Vanillin is a phenolic aldehyde, widely used as a flavoring agent in the food, pharmaceutical, and cosmetics industries. A variety of pharmacological activities has been attributed to this compound and its main metabolites, vanillic acid and vanillyl alcohol, including their anti-inflammatory ability. The relationship of the anti- inflammatory effects of vanillin, vanillic acid, and vanillyl alcohol and their actions on oxidative stress is well established. Considering that the inflammatory process is related to several pathologies, including new diseases with few therapeutic options, and limited efficiency, the search for effective treatment strategies and discovery of new anti-inflammatory agents capable of modulating inflammation becomes necessary. Therefore, in this review, we discuss the therapeutic potential of vanillin and its main metabolites for the treatment of inflammatory diseases and their actions on redox status. In addition, the molecular docking evaluation of vanillin, its metabolites and isoeugenol were carried out into the phospholipase A2 binding site.

Antifungal activity of cinnamic acid and benzoic acid esters against Candida albicans strains.

Candida albicans is an important opportunistic fungal pathogen capable of provoking infection in humans. In the present study, we evaluated the antifungal effect of 23 ester derivatives of the cinnamic and benzoic acids against 3 C. albicans strains (ATCC-76645, LM-106 and LM-23), as well as discuss their Structure-Activity Relationship (SAR). The antifungal assay results revealed that the screened compounds exhibited different levels of activity depending on structural variation. Among the ester analogues, methyl caffeate (5) and methyl 2-nitrocinnamate (10) were the analogues that presented the best antifungal effect against all C. albicans strains, presenting the same MIC values (MIC = 128 µg/mL), followed by methyl biphenyl-2-carboxylate (21) (MIC = 128, 128 and 256 µg/mL for C. albicans LM-106, LM-23, and ATCC-76645, respectively). Our results suggest that certain molecular characteristics are important for the antifungal action.

Negative inotropism of terpenes on guinea pig left atrium: structure-activity relationships.

The aim of this work was to evaluate the pharmacological effect of seven structurally related terpenes on the contractility of cardiac muscle. The effect of terpenes was studied on isolated electrically driven guinea pig left atrium. From concentration-response curves for inotropic effect were determined the EC50 and relative potency of such terpenes. Our results revealed that all terpenes, except phytol, showed ability to reduce the contractile response of guinea pig left atrium. Further, relative potency was directly related to the number of isoprene units and to the lipophilicity of the compounds. For example, sesquiterpenes farnesol and nerolidol showed higher relative potency when compared with the monoterpenes citronellol, geraniol and nerol. We can conclude that most of the evaluated terpenes showed a promising negative inotropism on the atrial muscle. Future studies are necessary to investigate their action mechanism.

Essential Oils and Their Constituents: An Alternative Source for Novel Antidepressants.

Depression is a disease that has affected a high proportion of the world's population and people of different ages, incapacitating them from good performance at work and in social relationships, and causing emotional disorders to millions of families. Therefore, the search for new therapeutic agents is considered a priority for the discovery of more effective forms of treatment. In this review, studies of essential oils and their constituents in experimental models related to depression are discussed. The mechanisms of action of the oils and the presence of psychoactive constituents in their chemical compositions are discussed. The data in the review show the therapeutic potential of essential oils and their chemical constituents for use in depressive disorders. Advanced studies using humans are needed to confirm the antidepressant properties described in animals.

Antiparasitic activity of nerolidol in a mouse model of schistosomiasis.

Schistosomiasis is a major public health problem worldwide, especially in poor communities. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new antischistosomal drugs. Nerolidol is a sesquiterpene present as an essential oil in several plants that has been approved by the FDA. This study evaluated the in vivo antischistosomal activity of nerolidol in a mouse model of schistosomiasis infected with either adult or juvenile stages of Schistosoma mansoni. A single dose of nerolidol (100, 200 or 400 mg/kg) administered orally to mice infected with adult schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest nerolidol dose (400 mg/kg) caused significant reduction in a total worm burden of 70.06% (P < 0.001). Additionally, the technique of quantitative and qualitative oograms showed that a single 400 mg/kg nerolidol dose achieved an immature egg reduction of 84.6% (P < 0.001). In faecal samples, the Kato-Katz method also revealed a reduction of 75.2% in eggs/g at a dose of 400 mg/kg (P < 0.001). Furthermore, scanning electron microscopy revealed that nerolidol-mediated worm killing was associated with tegumental damage. In contrast to activity against adult S. mansoni infection, oral treatment with nerolidol 400 mg/kg had low efficacy in mice harbouring juvenile schistosomes. Since nerolidol is already in use globally as a food additive and has a proven safety record, evaluation of this natural compound's potential for treatment of schistosomiasis could be entirely cost effective in the near future.

Structural parameters, molecular properties, and biological evaluation of some terpenes targeting Schistosoma mansoni parasite.

The use of natural products has a long tradition in medicine, and they have proven to be an important source of lead compounds in the development of new drugs. Among the natural compounds, terpenoids present broad-spectrum activity against infective agents such as viruses, bacteria, fungi, protozoan and helminth parasites. In this study, we report a biological screening of 38 chemically characterized terpenes from different classes, which have a hydroxyl group connected by hydrophobic chain or an acceptor site, against the blood fluke Schistosoma mansoni, the parasite responsible for schistosomiasis mansoni. In vitro bioassays revealed that 3,7-dimethyl-1-octanol (dihydrocitronellol) (10) was the most active terpene (IC50 values of 13-52 µM) and, thus, we investigated its antischistosomal activity in greater detail. Confocal laser scanning microscopy revealed that compound 10 induced severe tegumental damage in adult schistosomes and a correlation between viability and tegumental changes was observed. Furthermore, we compared all the inactive compounds with dihydrocitronellol structurally by using shape and charge modeling. Lipophilicity (miLogP) and other molecular properties (e.g. molecular polar surface area, molecular electrostatic potential) were also calculated. From the 38 terpenes studied, compound 10 is the one with the greatest flexibility, with a sufficient apolar region by which it may interact in a hydrophobic active site. In conclusion, the integration of biological and chemical analysis indicates the potential of the terpene dihydrocitronellol as an antiparasitic agent.