Monoterpenes and their derivatives as agents for cardiovascular disease management: A systematic review and meta-analysis

BackgroundMonoterpenes are one of the most studied plant's secondary metabolites, they are found abundantly in essential oils of aromatic plants. They also have a great range of pharmacological properties, such as antihypertensive, bradycardic, antiarrhythmic and hypotensive. In the face of the burden caused by cardiovascular disease (CVDs) worldwide, studies using monoterpenes to assess their cardiovascular effects have increased over the years.PurposeThis systematic review aimed to summarize the use of monoterpenes in animal models of any CVDs.MethodsPubMed, SCOPUS, LILACS and Web of Science databases were used to search for articles that used monoterpenes, in any type of administration, to treat or prevent CVDs in animal models. The PRISMA guidelines were followed. Two independent researchers extracted main characteristics of studies, methods and outcomes. Data obtained were analyzed qualitatively and quantitatively.ResultsAt the ending of the search process, 33 articles were selected for the systematic review. Of these, 17 articles were included in the meta-analysis. A total of 16 different monoterpenes were found for the treatment of hypertension, myocardial infarction, pulmonary hypertension, cardiac hypertrophy and arrhythmia. The main actions include hypotension, bradycardia, vasodilatation, antiarrhythmic, and antioxidant and antiapoptotic properties. From our data, it can be suggested that monoterpenes may be a significant source for new drug development. However, there is still a need to apply these knowledge into clinical research and a long path to pursue before putting them in the market.ConclusionThe variability of cardiovascular effects demonstrated by the monoterpenes highlighted them as a promising candidates for treatment or prevention of CVDs. Nevertheless, studies that investigate their biological sites of action needs to be further encouraged.     

Novel inhibitors of human glucose-6-phosphate dehydrogenase (HsG6PD) affect the activity and stability of the protein

BackgroundThe pentose phosphate pathway (PPP) has received significant attention because of the role of NADPH and R-5-P in the maintenance of cancer cells, which are necessary for the synthesis of fatty acids and contribute to uncontrollable proliferation. The HsG6PD enzyme is the rate-limiting step in the oxidative branch of the PPP, leading to an increase in the expression levels in tumor cells; therefore, the protein has been proposed as a target for the development of new molecules for use in cancer.MethodsThrough in vitro studies, we assayed the effects of 55 chemical compounds against recombinant HsG6PD. Here, we present the kinetic characterization of four new HsG6PD inhibitors as well as their functional and structural effects on the protein. Furthermore, molecular docking was performed to determine the interaction of the best hits with HsG6PD.ResultsFour compounds, JMM-2, CCM-4, CNZ-3, and CNZ-7, were capable of reducing HsG6PD activity and showed noncompetitive and uncompetitive inhibition. Moreover, experiments using circular dichroism and fluorescence spectroscopy showed that the molecules affect the structure (secondary and tertiary) of the protein as well as its thermal stability. Computational docking analysis revealed that the interaction of the compounds with the protein does not occur at the active site.ConclusionsWe identified two new compounds (CNZ-3 and JMM-2) capable of inhibiting HsG6PD that, compared to other previously known HsG6PD inhibitors, showed different mechanisms of inhibition.General significanceScreening of new inhibitors for HsG6PD with a future pharmacological approach for the study and treatment of cancer.     

Neuropharmacological and molecular docking studies of xanthones from Swertia corymbosa

Anxiety represents a public health problem consistently found to be the most prevalent class of mental disorders among people of all ages. Xanthones possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study, we aimed to investigate anxiolytic-like antidepressant and anticonvulsant properties of isolated xanthones from Swertia corymbosa. We evaluated anxiolytic-like activity of compounds 1–3 in the mouse elevated plus maze (EPM) and open field test (OF). We examined the influence on locomotor activity in mouse to determine if the effect observed in the actophotometer specific. We used step-through rotarod tests to evaluate the motor function and muscle grip. Compounds 1–3 significantly induced an increase in the number of entries into open arms and a decrease in time spent into closed arms at the dose of 50?mg/kg body weight (BW). The compounds also induced increase of rearing and decrease grooming at the doses of 25 and 50?mg/kg BW during the OF test. In addition, compounds induced a significant increase of time taken to enter at the center of the experimental set at the dose of 50?mg/kg BW during the open field test. The compounds 1–3 significantly delayed the onset as well as decreased the pentylenetetrazole and isoniazid-induced seizure tests. Compound 3 pretreatment significantly improved survivals in pentylenetetrazole and isoniazid-induced seizure tests. In silico studies reveal its possible mechanism of action shed on light to develop novel drugs against CNS disorders.     

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D₂ antagonism studies were performed using the climbing mouse assay model and 5-HT_2A antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.     

Acetylcholinesterase inhibitory activity of stigmasterol & hexacosanol is responsible for larvicidal and repellent properties of Chromolaena odorata

BackgroundChromolaena odorata, has been traditionally known for its insect repellent property. Aim of this study was to determine larvicidal tendency of C. odorata on Culex quinquefasciatus and isolate compounds responsible for this activity and to determine the mechanism of action of these compounds.MethodsC. odorata plant extract was screened for mosquito larvicidal activity. The extract was fractionated using chromatography and the bioactive fraction showing larvicidal activity was identified. The chemical nature of the compounds in the bioactive fraction was determined using NMR and Mass spectrometry.ResultsWe identified phytosterols and alkanols to be the compounds regulating larvicidal activity in the bioactive fraction of the plant extract. Stigmasterol and 1-hexacosanol were identified to be the chief orchestrators of larvicidal activity and their mode of action has been observed to be neurotoxicity. At a molecular level both stigmasterol and 1-hexacosanol were found to be inhibiting acetylcholinesterase activity in C. quinquefasciatus & A. aegypti. The acetylcholinesterase inhibitory effect was validated in vitro using recombinant acetylcholinesterase and ex vivo in larval homogenates of Culex and Aedes. Electrophysiological studies using electroantennography have shown enhanced neural response to these compounds.ConclusionsNeurotoxic effect of C. odorata derived stigmasterol and 1-hexacosanol, exerted through acetylcholinesterase inhibition was responsible for the mortality of C. quinquefasciatus, A. aegypti & Chironomus riparius. EAG studies pointed out hyper-excitability of the olfactory system by these compounds.General significanceThese compounds are natural agents for mosquito control that can be used in vector control as larvicidal compounds, pending further investigations.     

Synthesis,and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids

This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED₅₀ = 32.08 mg/kg, MES test) and 9 (ED₅₀ = 40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action.     

Comparative Effects of Alicyclic Compounds and Quinones on Inhibition of Lettuce Fruit Germination

Germination of lettuce (Lactuca sativa L. cv. Great Lakes) fruitswas inhibited by many alicyclic compounds including monoterpenes.Quinones were particularly active. The hydrocarbons showed littleactivity correlated with their insolubility in water while compoundscontaining a keto group conjugated with a double bond showedhighest activity. As in previous studies the lipophilicity ofthe molecule was one of the main contributing factors to inhibition,provided that the value was not extreme, as for the hydrocarbons.In natural compounds noted for high inhibitory activity, severaldifferent substituents were present in the molecule and it seemslikely that each contributes different factors to the overalleffect. Some of these compounds are well known plant constituentsimplicated in allelopathy. Lettuce germination, Lactuca saliva, monoterpenes, quinones, abscisic acid, lipophilicity, inhibitory activity     

Esculentosides: Insights into the potential health benefits,mechanisms of action and molecular targets

BackgroundEsculentosides and related phytolaccosides form a group of oleanene-type saponins isolated from plants of the Phytolaccaceae family, essentially Phytolacca esculenta, P. americana and P. acinosa. This chemical family offers a diversity of glycosylated compounds, including molecules with a mono-, di- or tri-saccharide unit at position C-3, and with or without a glucose residue at position C-28. The esculentosides, which derive essentially from the sapogenin jaligonic acid or its 30-methyl ester phytolaccagenin, exhibit anti-inflammatory, antifungal and anticancer activities.PurposeThe objective of the review was to identify the 26 esculentosides (ES) and phytolaccosides known to date, including 16 monodesmosidic and 10 bidesmosidic saponins, and to review their pharmacological properties and molecular targets.MethodologyThe retrieval of potentially relevant studies was done by systematically searching of scientific databases like Google Scholar and PubMed in January-May 2020. The main keywords used as search terms were related to esculentosides, phytolaccosides and Phytolaccaceae. The systematic search retrieved about 110 papers that were potentially relevant and after an abstract-based selection, 68 studies were analyzed in details and discussed.ResultsThe structural relationship between the compounds and their sapogenin precursors has been studied. In addition, the pharmacological properties of the main ES, such as ES-A, -B and -H, have been analyzed to highlight their mode of action and potential targets. ES-A is a potent inhibitor of the release of cytokines and this anti-inflammatory activity contributes to the anticancer effects observed in vitro and in vivo. Potential molecular targets of ES-A/B include the enzymes cyclooxygenase 2 (COX-2) and casein kinase 2 (CK2). In addition, the targeting of the protein high-mobility group box 1 (HGMB1) by ES-A/B is proposed, based on molecular modeling and the structural analogy with the related saponin glycyrrhizin, a potent HGMB1 alarmin inhibitor.ConclusionMore work is needed to properly characterize the molecular targets but otherwise compounds like ES-A and ES-H emerge as potent anti-inflammatory and anticancer agents and ES-B as an antifungal agent. A preclinical development of these three compounds should be considered.     

Neuroprotective activity and cytotoxic potential of two Parmeliaceae lichens: Identification of active compounds

BackgroundLichens are symbiotic organisms capable of producing unique secondary metabolites, whose pharmacological activities are attracting much interest.PurposeThe present study aimed to investigate the in vitro neuroprotective effects and anticancer potential of methanol extracts of two Parmeliaceae lichens: Cetraria islandica and Vulpicida canadensis. The chemical composition of the two lichens was also determined.MethodsNeuroprotective activity was studied with respect to the antioxidant properties of the extracts; radical scavenging tests (ORAC and DPPH assays) were performed and oxidative stress markers (intracellular ROS production, caspase-3 activity, MDA and glutathione levels) were assessed in a hydrogen peroxide-induced oxidative stress model in astrocytes. Cytotoxic activity was tested against human HepG2 (hepatocellular carcinoma) and MCF-7 (breast adenocarcinoma) cell lines.ResultsCell viability studies identified a single concentration for each extract that was subsequently used to measure oxidative stress markers. Lichen extracts were able to reverse the oxidative damage caused by hydrogen peroxide, thus promoting astrocyte survival. Both lichen extracts also had anticancer activity in the cell lines, with IC₅₀ values of 19.51–181.05 µg/ml. The extracts had a high total phenolic content, and the main constituents identified by HPLC were fumarprotocetraric acid in Cetraria islandica, and usnic, pinastric and vulpinic acids in Vulpicida canadensis. The biological activities of the lichen extracts can be attributed to these secondary metabolites.ConclusionThe lichen species studied are promising sources of natural compounds with neuroprotective activity and cytotoxic potential, and warrant further research.     

In vivo evaluation of diaminodiphenyls: Anticonvulsant agents with minimal acute neurotoxicity

Several diaminodiphenyl analogs were assessed in vivo for their capacity to inhibit seizure induction and propagation in rodents. Both 3,4′- and 4,4′-diaminodiphenyl compounds prevented seizures for as long as 4 h after maximal electric shock induction. 4,4′-Diphenyl compounds bridged by a methylene, sulfide, or carbonyl linker also attenuated focal seizure acquisition in a kindling model. Of these analogs, based upon data generated in two rodent species, 4,4′-thiodianiline (1) was identified as the most active compound, significantly reducing seizure staging scores and after-discharge duration for several hours after systemic administration. All compounds were devoid of acute in vivo neurotoxicity at doses well above those required for anticonvulsant activity.     

Synthesis and pharmacological evaluation of novel isoquinoline N-sulphonylhydrazones designed as ROCK inhibitors

In this study, we synthesized a new congener series of N-sulphonylhydrazones designed as candidate ROCK inhibitors using the molecular hybridization of the clinically approved drug fasudil (1) and the IKK-β inhibitor LASSBio-1524 (2). Among the synthesized compounds, the N-methylated derivative 11 (LASSBio-2065) showed the best inhibitory profile for both ROCK isoforms, with IC₅₀ values of 3.1 and 3.8?µM for ROCK1 and ROCK2, respectively. Moreover, these compounds were also active in the scratch assay performed in human breast cancer MDA-MB 231 cells and did not display toxicity in MTT and LDH assays. Molecular modelling studies provided insights into the possible binding modes of these N-sulphonylhydrazones, which present a new molecular architecture capable of being optimized and developed as therapeutically useful ROCK inhibitors.     

Phytochemical Composition and Biological Activities of Dyssodia tagetiflora Lag.

While plants of the genus Dyssodia are used by man to a certain extent, few phytochemical and pharmacological studies have been performed with species of this genus. D. tagetiflora is an endemic plant of Mexico and has been used as fodder. The aim of this research was to isolate and identify the main bioactive components and evaluate the insecticidal, antioxidant, genotoxic and cytoprotective activities of D. tagetiflora. The isolated substances included an essential oil composed of six monoterpenes, and extracts containing two flavonols, three flavonol‐glycosides and four thiophenes. The compounds were characterized using spectroscopic and spectrometric methods, including GC/MS, MS and NMR. The essential oil showed insecticidal activity against Drosophila melanogaster larvae. The methanolic extract of D. tagetiflora (DTME) had strong antioxidant activity against DPPH and ABTS radicals; DTME showed no evidence of genotoxic or cytotoxic effects. In contrast, DTME showed a cytoprotective effect attenuating the formation of H₂O₂‐induced micronuclei in Vicia faba roots. This report is the first to describe the phytochemical and biological activity of D. tagetiflora.     

Synthesis and in vivo diuretic activity of some new benzothiazole sulfonamides containing quinoxaline ring system

A series of new 6-substituted-N-[3-{2-(substituted phenyl)-ethenyl} quinoxaline-2(1H)-ylidene]-1,3-benzothiazole-2-amine (4a–f) were designed and synthesized by condensing 2-amino-benzothiazole-6-sulfonic acid amide (1) with chalcones of quinoxaline-2-one (3a–f) in a hope to obtain promising and a new class of diuretic agents. Structures of all the newly synthesized compounds were characterized by spectral data and elemental analysis. The pharmacological studies in experimental rats indicates that compound 4c possesses excellent in vivo diuretic activity of 1.13 and appears to be a better diuretic agent than the reference drugs, acetazolamide (1.0) and urea (0.88). Insight of the binding mode of the synthesized compounds (ligand) into the binding sites of carbonic anhydrase enzyme (PDF code: 4KUV) was provided by docking studies, performed with the help of Maestro 9.0 docking software. Further pharmacokinetic and toxicological studies are needed to confirm the safety of compound 4c which emerged as a lead diuretic compound.     

Bioactive compounds of Crocus sativus L. and their semi-synthetic derivatives as promising anti-Helicobacter pylori,anti-malarial and anti-leishmanial agents

Abstract

Crocus sativus L. is known in herbal medicine for the various pharmacological effects of its components, but no data are found in literature about its biological properties toward Helicobacter pylori, Plasmodium spp. and Leishmania spp. In this work, the potential anti-bacterial and anti-parasitic effects of crocin and safranal, two important bioactive components in C. sativus, were explored, and also some semi-synthetic derivatives of safranal were tested in order to establish which modifications in the chemical structure could improve the biological activity. According to our promising results, we virtually screened our compounds by means of molecular modeling studies against the main H. pylori enzymes in order to unravel their putative mechanism of action.     

Aromatic esters of progesterone as 5α-reductase and prostate growth inhibitors

The aim of this study was to determine the biological activity of 4 steroidal derivatives (9a, 9b and 10a, 10b) prepared from the commercially available 17α acetoxyprogesterone, where 9a, 9b, have the Δ⁴-3-oxo structure and 10a and 10b an epoxy group at C-4 and C-5.

These steroids were tested as inhibitors of 5α-reductase enzyme, which is present in androgen-dependent tissues and converts testosterone to its more active reduced metabolite dihydrotestosterone.

The pharmacological effect of these steroids was demonstrated by the significant decrease of the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with steroids 10a and 10b. For the studies in vitro the IC₅₀ values were determined by measuring the steroid concentration that inhibits 50% of the activity of-5α-reductase. In this study we also determined the capacity of these steroids to bind to the androgen receptor present in the rat prostate cytosol.

The results from this work indicated that compounds 9a, 9b, 10a, and 10b inhibited the 5α reductase activity with IC₅₀ values of 360, 370, 13 and 4.9 nM respectively. However these steroids did not bind to the androgen receptors since none competed with labeled mibolerone. Steroid 10b, an epoxy steroidal derivative containing bromine atom in the ester moiety, was the most active inhibitor of 5α-reductase enzyme, present in human prostate homogenates with an IC₅₀ value of 4.9 nM and also showed in vivo pharmacological activity since it decreased the weight of the prostate from hamsters treated with testosterone in a similar way as finasteride.     

N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H3 receptor and cancer resistance proteins

Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment, the ability of novel histamine H₃ receptor ligands to reverse the cancer MDR was evaluated, using the ABCB1 efflux pump inhibition assay in mouse MDR T-lymphoma cells. The most active compounds displayed significant cytotoxic and antiproliferative effects as well as a very potent MDR efflux pump inhibitory action, 3–5-fold stronger than that of reference inhibitor verapamil. Although these compounds possess weak antagonistic properties against histamine H₃ receptors, they are valuable pharmacological tools in the search for novel anticancer molecules. Furthermore, for the most active compounds, an insight into mechanisms of action using either, the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp, was performed.     

Synthesis and application of β-carbolines as novel multi-functional anti-Alzheimer’s disease agents

The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer’s disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.     

Antiproliferative activity of some 1,4-dimethylcarbazoles on cells that express estrogen receptors: part I

Several 9H-carbazole derivatives are used for various pharmacological applications. Many of these compounds demonstrated cytotoxic and anticancer activities. In this work, we have investigated the cytotoxic activity of some substituted carbazoles against cancer cell lines (MCF-7, and ISK). The derivative 2a showed the highest inhibitory activity against both cell lines.     

Potential Inhibitors of Angiogenesis. Part II: 3-(Azolylmethylene)-2,3-dihydrobenzo[b]furan-2-ones

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)-2,3-dihydrobenzo[b]furan-2-ones 8-10 and 3-(3,5-dimethylpyrrol-2-ylmethylene)-2,3-dihydrobenzo[b]furan-2-one 11, analogues of SU-5416, as potential inhibitors of angiogenesis, are reported. Compounds 8 and 11 were prepared by a Knoevenagel reaction starting from 2-hydroxyphenylacetic acid 2 and 4-formylimidazole 5 or 2-formyl-3,5-dimethylpyrrole 7, followed by acid-catalysed cyclodehydration. For compounds 9 and 10, an alternative method was used; it consisted in carrying out the Knoevenagel reaction with the 2,3-dihydrobenzo[b]furan-2-ones 3 and 4. The antiangiogenic activity of these compounds was evaluated in the three-dimensional in vitro rat aortic rings test at 1 μM. At this concentration, compound 11 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density index at 1 μM of 11 and SU-5416 were 30±10 and 22±4% of control, respectively.