Antiprotozoal Compounds from Psorothamnus polydenius

A previous screen of ϳ200,000 compounds from the PubChem database identified 70 compounds possessing 50% effective concentrations (EC 50 s) below 1 M against Leishmania major promastigotes that were not toxic to mammalian epithelial cancer cells at this concentration (E. Combinations of existing antileishmanial drugs have also been studied. Different combinations of treatment with single-dose liposomal amphotericin B followed by short courses of miltefosine were extremely effective, with a single dose of liposomal amphotericin B at 5 mg/kg of body weight followed by a 10-day course of miltefosine resulting in a cure rate of 98% (32). This combination was evaluated together with other combinations consisting of (i) a single dose of 5 mg/kg liposomal amphotericin with a 10-day course of paromomycin and (ii) a 10-day course of both paromomycin and miltefosine, with all of these combinations providing a cure rate of 97% or greater (33). When given in a single 10 mg/kg dose, liposomal amphotericin B was shown to be highly effective against VL, producing a cure rate of 95.7% (30). Single-dose liposomal amphotericin B is proposed to play a central role in a VL elimination program in India, Nepal, and Bangladesh (12).SharlowDespite these improvements in VL treatment on the Indian subcontinent, unmet needs in leishmaniasis chemotherapy still exist. In Africa, only the antimonial drug sodium stibogluconate and liposomal amphotericin B are registered for treating VL. Antimonial compounds, which have been replaced by the drugs listed above for treating VL on the Indian subcontinent due to widespread antimonial resistance (31), have been used for many years against leishmaniasis, and their use is plagued by the long duration of therapy and by the associated side effects (15,18,23,31). Liposomal amphotericin B appears to be less effective against VL in Brazil (1) and in Africa (1, 14, 26) compared to India, and the expense of liposomal amphotericin B also limits its widespread use (9). Paromomycin is inexpensive and is thus a good candidate for VL treatment in African countries, but a 15 mg/kg/day regimen of paramomycin for 21 days was inferior to standard treatment with sodium stibogluconate (20 mg/kg

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“…Selected compounds were evaluated for toxicity against Vero cells (African green monkey kidney cells) as described previously (25).…”

Section: Chemicalsmentioning

confidence: 99%

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Zhu

Pandharkar

Werbovetz

2012

Antimicrob Agents Chemother

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“…The fraction containing the substance 6 was purified by another column chromatography on silica gel (toluene/ethyl acetate/ethanol gradient system). The structures of the flavonoids 1-6 were unambiguously determined by means of spectroscopic methods ( 1 H, 13 C and 2D NMR experiments COSY, HSQC, HMBC and NOESY) and compared to those previously reported [9][10][11][12][13][14] . Compounds 5 and 6 were also tested against M. tuberculosis.…”

Section: Extraction and Fractionation Proceduresmentioning

confidence: 99%

“…20 Salem and Werbovetz described leishmanicidal and trypanocidal activities of this same chalcone isolated from Psorothamnus polydenius. 14 Lin et al 21 synthesized and evaluated a series of flavonols, flavanones and chalcones for inhibitory activity against M. tuberculosis H 37 Rv. The authors also relate that the presence of a halogen substituent on ring A of 2´-hydroxychalcone led to an increase in anti-tubercular activity.…”

Section: Structures Of the Compounds Identified In Fractions Of Ethmentioning

confidence: 99%

Evaluation of anti-Mycobacterium tuberculosis activity of Campomanesia adamantium (Myrtaceae)

Pavan¹,

Leite²,

Coelho³

et al. 2009

Quím. Nova

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Recebido em 1/7/08; aceito em 19/12/08; publicado na web em 11/5/09The anti-Mycobacterium tuberculosis activity of Campomanesia adamantium fruits extracts were evaluated. Six compounds, identified as flavanones and chalcones were quantified by HPLC-DAD-UV. Promising antitubercular activity was observed with ethyl acetate extract (MIC 62.5 μg/mL) and their fractions (MIC values ranging from 39 to above 250 μg/mL). The better MIC result of 39 μg/mL was associated with two fractions that contain bigger amounts of 5,7-dihydroxy-6, 8-di-C-methylflavanone and 2',4'-dihydroxy-3',5'-dimethyl-6'-methoxychalcone. These compounds exhibited MICs >250 and 62.5 μg/mL, respectively, while their mixtures showed values ranging from 62.5 to 7.8 μg/mL, demonstrating a synergism between them.

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“…donovani topoisomerase I (Das et al 2006b ). Besides the abovementioned fl avones, three isofl avanoids, 8-prenylmucronulatol, lyasperin H and smiranicin display antileishmanial activity correlated with topoisomerase II inhibition and kinetoplast DNA (kDNA) linearization (Salem and Werbovetz 2005 ). Acridine compounds, such as 9-anilinoacridine derivatives, display antiparasitic activity against Leishmania and Trypanosoma and their mode of action is via the inhibition of topoisomerase II (Figgitt et al 1992 ).…”

Section: Topoisomerasesmentioning

confidence: 99%

Selection of Molecular Targets for Drug Development Against Trypanosomatids

Smirlis

Soares

2013

Subcellular Biochemistry

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Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.

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Antiprotozoal Compounds from Psorothamnus polydenius

Cited by 65 publications

References 17 publications

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Evaluation of anti-Mycobacterium tuberculosis activity of Campomanesia adamantium (Myrtaceae)

Selection of Molecular Targets for Drug Development Against Trypanosomatids

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