In Vitro Activities of 7-Substituted 9-Chloro and 9-Amino-2-Methoxyacridines and Their Bis- and Tetra-Acridine Complexes against
            <i>Leishmania infantum</i>

Giorgio, Carole Di; Delmas, F.; Filloux, Nathalie; Robin, Maxime; Seferian, Laetitia; Azas, Nadine; Gasquet, M.; Costa, Muriel; Timon‐David, P.; Galy, Jean‐Pierre

doi:10.1128/aac.47.1.174-180.2003

Cited by 48 publications

(29 citation statements)

References 31 publications

(36 reference statements)

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“…Comparison of the activity of EC with that of other compounds indicates the antileishmanial potential of the natural product tested. This activity seems superior to that observed for the antiulcer agent omeprazole against different leishmanial species (27), similar to that demonstrated for some naphthoquinones and ␥-pyrones (27,28), and inferior to that determined for aphidicolin derivatives, aromatic dications, some tetra-acridine complexes, and an essential oil from the leaves of Croton cajucara (4,15,29,43). The mechanism of killing is still a matter of debate; promastigote damage by EC was irreversible, suggesting fatal metabolic injury.…”

Section: Discussionmentioning

confidence: 86%

Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

Savoia

Avanzini

Allice

et al. 2004

Antimicrob Agents Chemother

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Strains of the marine ciliate protist Euplotes crassus produce exclusive terpenoids called euplotins that play an ecological role. Among these derivatives, euplotin C is the main of four secondary metabolites isolated from cultures of this protozoon and represents the sesquiterpene taxonomic marker from E. crassus. Because different terpenoid metabolites of plant origin showed a certain antimicrobial activity, we assessed the compound euplotin C, purified by high-pressure liquid chromatography and solubilized in two solubility enhancers, against the protozoa Leishmania major and Leishmani infantum, the fungus Candida albicans, and nine strains of gram-positive and gram-negative microorganisms. An activity of euplotin C against Leishmania promastigotes was demonstrated (50% lethal doses were 4.6 or 8.1 g/ml depending on the agent used to solubilize the compound), while the effect was less evident on Candida and nearly absent on bacteria. A nonsignificant cytotoxicity (50% lethal dose, >200 g/ml) against the J774 cell line was observed. A leishmanicidal activity was also shown by the living, euplotin-producing cells of E. crassus cultured together with promastigotes; this activity increased with time from 10 min to 6 h of incubation. This study provides an initial rationale for the evaluation of euplotin C and other similar natural products as alternative or possibly synergistic compounds for current antiprotozoon chemotherapeutics.In recent years, several reports have been published on the scientifically confirmed antimicrobial activity of some natural products derived from plants (1,8,13,14,30,34,38,39) or of bioactive metabolites of microbial origin (26,32,33,35,40). Natural products showing effective action of pharmaceutical and medical relevance have also been recovered from marine organisms. Some bioactive antiviral, antitumor, antimicrobial, or generally cytotoxic compounds have been extracted from species of starfish and sponges. For example, extracts from the starfish Asterina pectifera are active against Aspergillus spp. and Cryptococcus neoformans (7), while various sponges exhibit antibacterial properties which are due to the presence of a metabolic product or to host microorganisms (12,25).Recently, four sesquiterpenes-euplotin A, euplotin B, euplotin C (EC), and their biogenetic precursor preuplotinhave been isolated from Euplotes crassus, a eukaryotic unicellular marine ciliate (16,19). All strains of this ciliate morphospecies (taxonomically described by microscopic, outwardly identifying features) produce the same compounds. Notably, euplotins, and in particular EC, are biosynthesized in relative large amounts, suggesting an important ecological role of this substance in the adaptive strategy of the organism. A similar terpenoid (udoteatrial hydrate) was isolated from Udotea flabellum (36), a tropical seaweed belonging to the phylum Chlorophyta that contributes to the structure of coral reefs. Indeed, it has been suggested that strong similarities in anthozoan metabolite biosynthesis reveal the ev...

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Section: Discussionmentioning

confidence: 86%

Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

Savoia

Avanzini

Allice

et al. 2004

Antimicrob Agents Chemother

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“…[63][64][65][66][67][68][69] Antituberculosis activity were predicted for our compound set 5-20 within the range of 0.364<Pa<0.684. Although no direct correlation were observed between Pa values and MIC values, it was notable that most active three compounds had good Pa scores (Pa>0.5).…”

Section: )mentioning

confidence: 99%

Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole–Thiourea Scaffold as Antituberculosis Agents

Tatar

Karakuş

Küçükgüzel

et al. 2016

Biological & Pharmaceutical Bulletin

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“…Additional evidence that the quinoline and 9-aminoacridine hits identified in the ELEC system are particularly good leads for further development is based on previous studies of these compounds as potential antimalarial compounds. Here it was shown that these relatively basic compounds with high LogP (lipophilicity) values favor their intracellular transport, which is responsible for the observed activity and selectivity (54)(55)(56)(57). Furthermore, it has been demonstrated that certain acridines (54,(58)(59)(60)(61) can inhibit DNA synthesis in Leishmania and/or Plasmodium, interfering with DNA transcription (topoisomerase II).…”

Section: Discussionmentioning

confidence: 99%

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

Peniche

Osorio

Renslo

et al. 2014

Antimicrob Agents Chemother

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e Leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (ELEC) derived from the draining lymph nodes of Leishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infected in vitro with L. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active against L. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC 50 ). We found 24 compounds (7%) that had an in vitro therapeutic index (IVTI; 50% cytotoxic/effective concentration [CC 50 ]/EC 50 ) > 100; 19 of the compounds had an EC 50 below 1 M. According to PubChem searchs, 17 of those compounds had not previously been reported to be active against Leishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis.

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In Vitro Activities of 7-Substituted 9-Chloro and 9-Amino-2-Methoxyacridines and Their Bis- and Tetra-Acridine Complexes against Leishmania infantum

Cited by 48 publications

References 31 publications

Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole–Thiourea Scaffold as Antituberculosis Agents

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

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