Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity.
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ABSTRACT:
SUBMITTER: McFarland MM
PROVIDER: S-EPMC5118980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundConventional treatment for toxoplasmosis have severe side effects and the inability to completely eradicate the disease. Therefore, the acquisition of new anti-Toxoplasma drugs has always been of interest among researchers. In the present study, we prepare a new indole-triazole derivatives and evaluated their potential anti-parasitic activity against tachyzoites of Toxoplasma RH strain.Materials and methodsIn this study, after synthesis of the two new compounds of indole-triazole, the effect of their different concentrations (2-1024 μg/ml) were determined on Toxoplasma tachyzoites using flow cytometry. Furthermore, tachyzoites were exposed to different concentrations of compounds (4, 16, 64, 265, 1024 μg/ml) for 1.5 h and their infectivity were evaluated in BALB/c mice.ResultsThe flow cytometry results indicated the benzyl derivative of indole-triazole in various concentrations had a lethal effect on tachyzoites between 11.93% and 89.66%, while the naphthalene derivative had a lethality of 26.63%-66.82%. The infectivity analysis showed that the survival time of mice at concentrations of 1024 μg/ml and 512 μg/ml of benzyl derivatives was significantly increased (P = 0.008 and P = 0.016, respectively), compared to that in the negative control group. Furthermore, survival time of mice was statistically significant at the concentration of 1024 μg/ml for naphthyl derivative (P = 0.012).ConclusionFindings of the current study suggested indole triazole compounds, based on their structure and enzymes targeting, have a considerable effect on tachyzoites of T. gondii RH strain and can be considered as a new anti-Toxoplasma agent.
| S-EPMC8777237 | biostudies-literature
Project description:The currently available anti-Toxoplasma agents have serious limitations. This systematic review was performed to evaluate drugs and new compounds used for the treatment of toxoplasmosis. Data was systematically collected from published papers on the efficacy of drugs/compounds used against Toxoplasma gondii (T. gondii) globally during 2006-2016. The searched databases were PubMed, Google Scholar, Science Direct, ISI Web of Science, EBSCO, and Scopus. One hundred and eighteen papers were eligible for inclusion in this systematic review, which were both in vitro and in vivo studies. Within this review, 80 clinically available drugs and a large number of new compounds with more than 39 mechanisms of action were evaluated. Interestingly, many of the drugs/compounds evaluated against T. gondii act on the apicoplast. Therefore, the apicoplast represents as a potential drug target for new chemotherapy. Based on the current findings, 49 drugs/compounds demonstrated in vitro half-maximal inhibitory concentration (IC50) values of below 1 ?M, but most of them were not evaluated further for in vivo effectiveness. However, the derivatives of the ciprofloxacin, endochin-like quinolones and 1-[4-(4-nitrophenoxy) phenyl] propane-1-one (NPPP) were significantly active against T. gondii tachyzoites both in vitro and in vivo. Thus, these compounds are promising candidates for future studies. Also, compound 32 (T. gondii calcium-dependent protein kinase 1 inhibitor), endochin-like quinolones, miltefosine, rolipram abolish, and guanabenz can be repurposed into an effective anti-parasitic with a unique ability to reduce brain tissue cysts (88.7, 88, 78, 74, and 69%, respectively). Additionally, no promising drugs are available for congenital toxoplasmosis. In conclusion, as current chemotherapy against toxoplasmosis is still not satisfactory, development of well-tolerated and safe specific immunoprophylaxis in relaxing the need of dependence on chemotherapeutics is a highly valuable goal for global disease control. However, with the increasing number of high-risk individuals, and absence of a proper vaccine, continued efforts are necessary for the development of novel treatment options against T. gondii. Some of the novel compounds reviewed here may represent good starting points for the discovery of effective new drugs. In further, bioinformatic and in silico studies are needed in order to identify new potential toxoplasmicidal drugs.
| S-EPMC5247447 | biostudies-literature
Project description:The use of biologically active compounds has become a realistic option for the treatment of malignant tumors due to their cost-effectiveness and safety. In this review, we aimed to highlight the main natural biocompounds that target leukemic cells, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their therapeutic potential in the treatment of leukemia: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). It provides a basis for researchers and hematologists in improving basic and clinical research on the development of new alternative therapies in the fight against leukemia, a harmful hematological cancer and the leading cause of death among patients.
| S-EPMC8124534 | biostudies-literature
Project description:Toxoplasma gondii and Cryptosporidium parvum, members of the phylum Apicomplexa, are significant pathogens of both humans and animals worldwide for which new and effective therapeutics are needed. Here, we describe the activity of the antibiotic boromycin against Toxoplasma and Cryptosporidium Boromycin potently inhibited intracellular proliferation of both T. gondii and C. parvum at half-maximal effective concentrations (EC50) of 2.27 nM and 4.99 nM, respectively. Treatment of extracellular T. gondii tachyzoites with 25 nM boromycin for 30 min suppressed 84% of parasite growth, but T. gondii tachyzoite invasion into host cells was not affected by boromycin. Immunofluorescence of boromycin-treated T. gondii showed loss of morphologically intact parasites with randomly distributed surface antigens inside the parasitophorous vacuoles. Boromycin exhibited a high selectivity for the parasites over their host cells. These results suggest that boromycin is a promising new drug candidate for treating toxoplasmosis and cryptosporidiosis.
| S-EPMC8097477 | biostudies-literature
Project description:Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
| S-EPMC3306180 | biostudies-literature
Project description:During the last decade, noroviruses have gained media attention as the cause of large scale outbreaks of gastroenteritis on cruise ships, dormitories, nursing homes, etc. Although noroviruses do not multiply in food or water, they can cause large outbreaks because approximately 10-100 virions are sufficient to cause illness in a healthy adult. Recently, it was shown that the activity of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) enzyme may be important in norovirus infection. In search of anti-noroviral agents based on the inhibition of ACAT1, we synthesized and evaluated the inhibitory activities of a class of pyranobenzopyrone molecules containing amino, pyridine, substituted quinolines, or 7,8-benzoquinoline nucleus. Three of the sixteen evaluated compounds possess ED(50) values in the low micrometer range. 2-Quinolylmethyl derivative 3A and 4-quinolylmethyl derivative 4A showed ED(50) values of 3.4 and 2.4 ?M and TD(50) values of >200 and 96.4 ?M, respectively. The identified active compounds are suitable for further modification for the development of anti-norovirus agents.
| S-EPMC3348348 | biostudies-literature
Project description:Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes.
| S-EPMC8308569 | biostudies-literature
Project description:Demethylisoencecalin (1) and caleins A (4) and C (5) (3.16-31.6 mg/kg, p.o.), the major components from an infusion of Calea ternifolia controlled postprandial glucose levels during an oral sucrose tolerance test (OSTT, 3 g/kg) in normal and nicotinamide/streptozotocin (NA/STZ, 40/100 mg/kg) hyperglicemic mice. The effects were comparable to those of acarbose (5 mg/kg). During the isolation of 1, 4, and 5, four additional metabolites not previously reported for the plant, were obtained, namely 6-acetyl-5-hydroxy-2-methyl-2-hydroxymethyl-2H-chromene (3), herniarin (6), scoparone (7), and 4',7-dimethylapigenin (8). In addition, the structure of calein C (5) was confirmed by X-ray analysis. Pharmacological evaluation of the essential oil of the species (31.6-316.2 mg/kg, p.o.) provoked also an important decrement of blood glucose levels during an OSTT. Gas chromatography coupled with mass spectrometry (GC-MS) analysis of the headspace solid phase microextraction (HS-SPME)-adsorbed compounds and active essential oil obtained by hydrodistillation revealed that chromene 1 was the major component (19.92%); sesquiterpenes represented the highest percentage of the essential oil content (55.67%) and included curcumene (7.10%), spathulenol (12.95%) and caryophyllene oxide (13.0%). A suitable High Performance Liquid Chromatography (HPLC) method for quantifying chromenes 1 and 6-hydroxyacetyl-5-hydroxy-2,2-dimethyl-2H-chromene (2) was developed and validated according to standard protocols.
| S-EPMC6155573 | biostudies-literature
Project description:We identified four anti-inflammatory sulfur-containing compounds from garlic, and their chemical structures were identified as Z- and E-ajoene and oxidized sulfonyl derivatives of ajoene. The sulfur compounds inhibited the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) and the expression of the pro-inflammatory cytokines tumor necrosis factor-?, interleukin-1?, and interleukin-6 in lipopolysaccharide (LPS)-activated macrophages. Western blotting and reverse transcription-polymerase chain reaction analysis demonstrated that these sulfur compounds attenuated the LPS-induced expression of the inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA. Moreover, these sulfur-containing compounds suppressed the nuclear factor-?B (NF-?B) transcriptional activity and the degradation of inhibitory-?B? in LPS-activated macrophages. Furthermore, we observed that they markedly inhibited the LPS-induced phosphorylations of p38 mitogen-activated protein kinases and extracellular signal-regulated kinases (ERK) at 20??M. These data demonstrate that the sulfur compounds from garlic, (Z, E)-ajoene and their sulfonyl analogs, can suppress the LPS-induced production of NO/PGE(2) and the expression of iNOS/COX-2 genes by inhibiting the NF-?B activation and the phosphorylations of p38 and ERK. Taken together, these data show that Z- and E-ajoene and their sulfonyl analogs from garlic might have anti-inflammatory therapeutic potential.
| S-EPMC3491620 | biostudies-literature
Project description:Chronic infection with Toxoplasma gondii is attested by the detection of specific anti-Toxoplasma IgG. A wide panel of serologic methods is currently marketed, and the most suitable method should be chosen according to the laboratory resources and the screened population. This systematic review of evaluation studies aimed at establishing an overview of the performances, i.e. sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of marketed anti-Toxoplasma IgG assays, and discussing their technical characteristics to guide further choice for routine diagnostic use. According to PRISMA guidelines, the search performed in PubMed and Web of Science databases recovered 826 studies, of which 17 were ultimately included. Twenty commercial anti-Toxoplasma IgG assays were evaluated, in comparison with an accepted reference method. Most of them were enzyme-immunoassays (EIAs, n = 12), followed by agglutination tests (n = 4), immunochromatographic tests (n = 3), and a Western-Blot assay (WB, n = 1). The mean sensitivity of IgG assays ranged from 89.7% to 100% for standard titers and from 13.4% to 99.2% for low IgG titers. A few studies pointed out the ability of some methods, especially WB to detect IgG early after primary infection. The specificity of IgG assays was generally high, ranging from 91.3% to 100%; and higher than 99% for most EIA assays. The PPV was not a discriminant indicator among methods, whereas significant disparities (87.5%-100%) were reported among NPVs, a key-parameter assessing the ability to definitively rule out a Toxoplasma infection in patients at-risk for opportunistic infections.
| S-EPMC8078101 | biostudies-literature